Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([NH:40][C:41]3[N:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[CH:43][N:42]=3)[CH:37]=[CH:38][CH:39]=2)O1.Br[C:53]1[S:57][C:56]([NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[N:55][CH:54]=1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1COCC1>[C:61]([O:60][C:59](=[O:65])[NH:58][C:56]1[S:57][C:53]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:41]3[N:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=[CH:43][N:42]=3)[CH:35]=2)=[CH:54][N:55]=1)([CH3:64])([CH3:62])[CH3:63]
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Reactant: CC1(C)OB(c2cccc(Nc3nccc(C(F)(F)F)n3)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2cccc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.2 %

Procedure:
A sealable reaction tube was charged with, palladium (II) acetate (6.15 mg, 0.027 mmol), butyldi-1-adamantylphosphine (19.64 mg, 0.055 mmol) and THF (4 mL) and was stirred for 10 minutes under nitrogen. N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (200 mg, 0.548 mmol) (Intermediate VII), tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate (199 mg, 0.712 mmol), potassium fluoride (95 mg, 1.643 mmol) and Water (1.333 mL) were then successively added. The tube was capped and the mixture was stirred at 75° C. for 17 hours, cooled to room temperature and quenched by the addition of 25% aqueous NH4OAc. The aqueous layer was extracted twice with ethyl acetate. The combined organic fractions were washed with water and brine, dried over Na2SO4 and concentrated. The product was purified by column chromatography on silica gel (ethyl acetate/hexane) to afford tert-butyl[5-(3-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]carbamate (65.1 mg, 27.2%) as a beige solid. APCI [M+H]+ m/z 382 Step 2:
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=[O:9]>CN(C)C=O>[CH:8]([C:7]1[CH:6]=[CH:5][C:12]([O:13][CH3:14])=[C:11]([CH:10]=1)[C:2]#[N:3])=[O:9]
Reactant: COc1ccc(C=O)cc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1C#N
Temperature: 120 °C
Yield: 66.7 %

Procedure:
Add copper (I) cyanide (4.58 g, 51.2 mmol) to a solution of 3-bromo-4-methoxy-benzaldehyde (10.0 g, 46.5 mmol) in N,N-dimethylformamide (0.2 M). Heat the solution to 120° C. and stir the solution for 1d. Quench with potassium carbonate (sat) and extract with diethyl ether (5×). Wash organic layers with water, dry with sodium sulfate, and concentrate to afford the title compound (5.00 g, 31.0 mmol, 67%): 1H NMR (400 MHz, DMSO-d6) δ 4.04 (s, 3H), 7.47 (d, J=8.6 Hz, 1H), 8.20 (m, 1H), 8.33 (m, 1H), 9.91 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([CH3:29])[CH:23]=[CH:22]2>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH3:29])[CH:23]=[CH:22]4)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: Cc1ccc2cc(Br)ccc2n1
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3nc(C)ccc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg, 0.6 mmol; Example 2B) and 6-bromo-2-methylquinoline (200 mg, 0.9 mmol; Oakwood) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.19 (m, 4H) 2.41 (s, 3H) 2.77 (s, 3H) 2.91-2.98 (m, 1H) 3.08-3.29 (m, 4H) 4.32 (s, 2H) 6.89-6.94 (m, 1H) 6.96-7.01 (m, 1H) 7.21 (s, 1H) 7.52 (d, J=8 Hz, 1H) 7.66 (dd, J=9, 2 Hz, 1H) 7.87 (d, J=2 Hz, 1H) 8.12 (d, J=9 Hz, 1H) 8.32 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 368 (M+H)+.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C@@H:6]1[CH2:23][C@@:21]2([CH3:22])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:24]([O:26][CH3:27])=[O:25])[C@H:16]2[C@H:7]1[C@:8]1([CH3:30])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@H:11]([OH:28])[C@@H:10]([OH:29])[CH2:9]1.[CH3:31][C:32]([CH3:37])([CH3:36])[CH2:33][CH:34]=O>C(O)C.C(=O)([O-])O.[Na+]>[CH3:31][C:32]([CH3:37])([CH3:36])[CH2:33][CH2:34][NH:5][C@@H:6]1[CH2:23][C@@:21]2([CH3:22])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:24]([O:26][CH3:27])=[O:25])[C@H:16]2[C@H:7]1[C@:8]1([CH3:30])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][C@H:11]([OH:28])[C@@H:10]([OH:29])[CH2:9]1
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](N)C[C@]12C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NCCC(C)(C)C)C[C@]12C
Reaction time: 18 h
Yield: 126.2 %

Procedure:
Sodium cyanoborohydride (1.5 g) was added to a mixture of methyl 11α-amino-2β,3α-dihydroxy-5α-androstane-17β-carboxylate (760 mg) and 3,3-dimethyl-butyraldehyde (700 mg) in ethanol (30 ml). The mixture was stirred for 18 h, diluted with 5% sodium hydrogen carbonate solution and extracted with ethyl acetate (3×). The extract was washed with water, dried and evaporated to give a foam (1.18 g) which was purified by preparation t.l.c. in ethyl acetate/0.88 ammonia (50:1) to give the title compound (565 mg) as a foam, [α]D +22.1°, νmax 1725 cm-1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([Cl:17])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(C(=O)O)cc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(C(=O)Cl)cc2ccccc21
Reaction time: 18 h

Procedure:
A suspension of 1-methylindole-2-carboxylic acid (0.805 g, 4.6 mmol) in dichloromethane (3 mL) was treated with oxalyl chloride (0.700 g, 5.52 mmol) and one drop of dimethylformamide. The reaction mixture was shaken for 18 h. The solvent was removed under reduced pressure and dried under high vacuum to afford a quantitative amount of 1-methyl-1H-2-indolecarbonyl chloride. The oil was directly used in the following reaction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH:5]=[CH:6][C:7]1[CH:11]=[CH:10][O:9][C:8]=1[C:12](=[O:38])[CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:16][CH2:15]1)[CH3:2]>[Rh].CO>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][C:7]1[CH:11]=[CH:10][O:9][C:8]=1[C:12](=[O:38])[CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)(=[O:29])=[O:30])([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[CH2:16][CH2:15]1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccoc1C(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: [Rh]
Solvent: CO
Product: CCOC(=O)CCc1ccoc1C(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1

Procedure:
Rhodium on carbon catalyst (15 mg) was added to a solution of the product from Example 145 (100 mg, 0.17 mmol) in methanol (30 mL) and the reaction hydrogenated at 30 psi for 4 hours. The mixture was then filtered through Celite® and evaporated to give an oil. (100 mg). MS (ES+) 579 ([MH]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(C(C)=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:11][C:10]=1[O:16][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(O)ccc1OCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(OCc2ccccc2)c(OC)c1

Procedure:
Using the procedure of Step C of Example 16, 2.76 g of the product of Step A, 1.82 g of potassium carbonate, 15 ml of methyl ethyl ketone and 1.6 ml of ethyl bromoacetate were reacted. Extraction was carried out with methyl ethyl ketone and the organic phase was concentrated to dryness to obtain 3.9 g of crude product which was chromatographed on silica (eluant: hexane-ethyl acetate 8-2) to obtain 3.6 g of the expected product melting at 58° C.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[Cl:7][C:8]([Cl:12])([Cl:11])[CH2:9][OH:10].C(N(CC)CC)C>O>[F:1][C:2](=[CH2:6])[C:3]([O:10][CH2:9][C:8]([Cl:12])([Cl:11])[Cl:7])=[O:4]
Reactant: C=C(F)C(=O)Cl
Reactant: OCC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(F)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 3 h

Procedure:
12 g of 2-fluoroacryloyl chloride and 26 g of 2,2,2-trichloroethanol were introduced into a round-bottomed flask placed in an ice bath. 17 g of triethylamine were added portionwise to the reaction mixture. After reacting for an additional 3 h, approximately 50 ml of water were added. The aqueous and organic phases were subsequently separated and the organic phase was analysed by GC. The conversion of the 2,2,2-trichloroethanol was 52%. The yield of ester, based on the amount of 2-fluoroacrylic acid employed in the first stage, was 67%.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:9]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:10][C:11]([CH3:27])=[C:12]([CH3:26])[C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[CH2:35]([O:37][CH2:38][C:39](Cl)=O)[CH3:36].[OH-].[Na+]>O.ClCCl>[CH2:35]([O:37][CH2:38][C:39]1[N:14]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:13]2[C:12]([CH3:26])=[C:11]([CH3:27])[N:10]=[C:9]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:8]=2[N:7]=1)[CH3:36]
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCNC(=O)OC(C)(C)C)c1C
Reactant: CCOCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
Using the general method of Example 12 Part D, a pyridine solution of tert-butyl 3-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]propylcarbamate (see Example 12 Part C) was treated with ethoxyacetyl chloride (21.81 g, 178 mmol). The crude product was combined with dichloromethane (2 L) and water (2 L). The pH was adjusted to 12 with 50% sodium hydroxide and the mixture was stirred for 30 minutes. The organic phase was separated, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with heptane and then concentrated to remove residual pyridine. This procedure was repeated several times to provide 64.8 g of tert-butyl 3-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]propylcarbamate as a brown tar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[NH2:5].[As](=O)(O)(O)O.O[CH2:18][CH:19]([CH2:21]O)O>>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:4]2[C:3]=1[CH:18]=[CH:19][CH:21]=[N:5]2
Reactant: OCC(O)CO
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=[As](O)(O)O
Product: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Temperature: 140 °C

Procedure:
A mixture of 25.2 g of 3-chloro-6-nitro-aniline, 21 g of arsenic acid and 35.1 ml of glycerine was heated to reflux and after cooling the mixture to 20°~30° C., 25.5 ml of 66° Be sulfuric acid were added thereto. The mixture was heated at 140° C. for 8 hours and was poured over ice. The mixture was filtered and the solid product was dissolved in methylene chloride. The solution was neutralized and extracted with methylene chloride. The combined organic phases were dried, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The 10 g of residue were chromatographed over silica gel and eluted with methylene chloride to obtain 8.61 g of 5-chloro-8-nitro-quinoline melting at 136°-138° C. which was reacted with N-hydroxyphthalimide to obtain 0-(8-nitro-5-quinolyl)-phthalimide melting at 226°-228° C. The latter was reacted to obtain 0-(8-nitro-5-quinolyl)-hydroxylamine melting at 186°-188° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[C@@H:34]([CH3:35])[CH2:33]OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>>[CH2:21]([O:20][C:18]([C:13]1[N:14]([CH2:35][C@@H:34]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH3:33])[C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH:17][CH:16]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C[C@H](C)NC(=O)OC(C)(C)C
Yield: 100 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate b), from ethyl 5-benzyloxyindole-2-carboxylate (commercially available), (S)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO02/010169) and potassium tert-butoxide, to give the desired compound as a light yellow solid (>100%). The so-obtained product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN([CH:29]=[O:30])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[CH2:15]([O:14][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:29]=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCOc1ccccc1OCCCCCC
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCOc1ccc(C=O)cc1OCCCCCC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
1,2-Dihexyloxybenzene (11.14 g; 40 mmol) and N-methylformanilide (5.41 g; 40 mmol) are cooled to 0° C., and phosphorus oxychloride (6.13 g; 40 mmol) is added. Heating is then carried out for 1 hour at 25° C., followed by stirring for 4 hours at 60° C. The reaction mixture is poured onto ice and then adjusted to pH 6. Extraction is carried out with tert-butyl methyl ether (2×200 ml), and washing is carried out with NaHCO3 (2×100 ml). The organic phase is dried over Na2SO4, filtered and concentrated to dryness by evaporation.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[CH3:15][O:14][C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH3:17])[N:5]=[CH:4][CH:3]=[C:2]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2)=[O:13]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OC
Temperature: 130 °C
Reaction time: 5 h
Yield: 29.8 %

Procedure:
After mixing methyl 4-chloro-7-methoxyquinoline-6-carboxylate (described in WO0050405, p. 34, 8.5 g, 33.77 mmol), 5-hydroxyindole (7 g), diisopropylethylamine (8.9 ml) and N-methylpyrrolidone (8.9 ml), the mixture was heated and stirred at 130° C. for 5 hours and then at 150° C. for 8 hours. After standing to cool, the solution was adsorbed onto silica gel and purified with a silica gel column (hexane-ethyl acetate system). Ethanol, diethyl ether and hexane were added to the obtained yellow oil, and crystals precipitated after a period of standing. The crystals were filtered out, washed with diethyl ether and hexane and then dried by aspiration to obtain light yellow crystals (3.506 g, 10.06 mmol, 29.80%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:13][CH2:14][CH3:15])=[N:8]2.[C:16]1([C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:23]2[C:27]([C:28]3[C:33]([C:34]4[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=4)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:25]=[N:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[N:8]2[CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[N:23]([C:22]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:24]=[N:25][N:26]=2)=[CH:39][CH:38]=1
Reactant: CCCc1nc2ncnc(Cl)c2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of NaH (0.016 g of a 60% dispersion in oil, 0.4 mmol) in dry dimethylformamide (1.5 ml) was added 6-Chloro-8-propylpurine (0.044 g, 0.25 mmol) at room temperature. After 20 minutes, the mixture was cooled to 0° C. and N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (0.139 g, 0.25 mmol) was added. The resulting mixture was warmed to room temperature and then stirred at 40° C. for 3 hours. The reaction was cooled, and the content of the flask was poured into ice-water (50 ml) and extracted with ethyl acetate (3×15 ml). The combined organic phase was washed with brine and then dried over anhydrous Na2SO4. Removal of the solvent gave the crude product as a foam which was purified by flash-chromatography on silica-gel using ethyl acetate/hexane (1:3). Yield 0.07 g (foam). NMR (CDCl3): δ 0.96 (t, J=8 Hz, 3H), 1.806 (m, 2H), 2.75 (m, 2H), 5.35 (s, 2H), 6.85-7.54 (m, 22H), 7.85 (m, 1H), 8.72 (s, 1H). FAB-MS: m/e 674 and 676 (M+H).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[Cl-].[Mg+2].[K+].[F:8][C:9]([F:22])([F:21])[S:10]([CH2:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])(=[O:12])=[O:11].[Cl-].[Cl-]>C1COCC1>[F:19][C:17]([F:20])([F:18])[S:14]([CH:13]([S:10]([C:9]([F:8])([F:21])[F:22])(=[O:11])=[O:12])[CH2:3][CH:2]=[CH2:1])(=[O:15])=[O:16]
Reactant: O=S(=O)(CS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=CCBr
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: C=CCC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F
Temperature: 70 °C

Procedure:
Next, 4,4-bis[(trifluoromethyl)sulfonyl]-1-butene was prepared by adding 3 ml of allyl bromide to 31.3 millimoles of the bis[(trifluoromethyl)sulfonyl] methane potassium magnesium chloride in 35 ml of THF. The mixture was stirred at 70° C. under reflux for 8 hours. After removal of solvent by distillation under reduced pressure, 50 ml of 3N hydrochloric acid was added to the residue and the aqueous solution was extracted with ethyl ether. The ethyl ether solution was dried with anhydrous MgSO4. The ethyl ether was removed from the solution and the product was distilled at 0.02 torr.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][CH2:11]2)[C:5]([C:24]#[N:25])=[C:4]([SH:26])[N:3]=1.Cl[CH2:28][C:29]1[N:30]=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[S:32][CH:33]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C@H:10]2[CH2:11][CH2:12][C@H:13]([O:16][Si:17]([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:18])[CH3:19])[CH2:14][CH2:15]2)[C:5]([C:24]#[N:25])=[C:4]([S:26][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[S:32][CH:33]=2)[N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2c(C#N)c(N)nc(S)c2C#N)CC1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
23 mg (0.06 mmol) of the compound from Example 12A (trans isomer), 17 mg (0.07 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 20 mg (0.24 mmol) of sodium bicarbonate are initially charged in 2 ml of dry DMF and stirred at RT for 20 h. The mixture is then directly purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([CH3:4])[CH3:3].[Mg].II.Br[CH2:10][CH2:11][CH:12]=[CH2:13]>O1CCCC1>[CH3:1][C:2]([CH3:5])([CH3:4])[CH2:3][CH2:13][CH2:12][CH:11]=[CH2:10]
Reactant: C=CCCBr
Reactant: CC(C)(C)C
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2,2-Dimethylpropane (15.1 g, 0.10 mol) in dry tetrahydrofuran (80 ml) was added dropwise to a mixture of magnesium turnings (2.43 g, 0.10 mol) in dry tetrahydrofuran (20 ml) containing a single crystal of iodine, at such a rate so as to maintain the solvent at reflux. The resulting solution was allowed to cool to room temperature and decanted from the residual magnesium under nitrogen into a fresh flask. The solution was diluted with dry tetrahydrofuran (150 ml), cooled to -20° C. under an atmosphere of nitrogen treated with cuprous bromide dimethyl sulphide complex and stirred for 20 minutes. The resulting solution was then treated with 4-bromo-1-butene (13.5 g, 0.10 mol) and stirred at -20° C. for 16 hours and then at 20° C. for 4 hours. The reaction mixture as quenched with saturated aqueous ammonium chloride solution (10 ml), diluted with ether (200 ml) and washed with an aqueous solution of ammonia (2×200 ml of 10%). The solution was dried over sodium sulfate and distilled at atmospheric pressure to yield 6,6-dimethyl- 1-heptene as a colourless oil, having a boiling point of 120°-125° C., and the following structural characteristics:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1)=O.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C1COCC1.[BH4-].[Na+]>CO>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[NH:5][CH:4]=2)[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccnc2[nH]cc(C=O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccnc2[nH]cc(CNC3CCN(C(=O)OC(C)(C)C)CC3)c12
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
Methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (160 mg, 0.784 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (188 mg, 0.940 mmol) were combined in MeOH (3 mL) and THF (3 mL) at 50° C. for 3 H. Then sodium borohydride (59 mg, 1.567 mmol) was added at room temperature and allowed to stir for 10 min. The mixture was quenched with water and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated in vacuo to give methyl 3-((1-(tert-butoxycarbonyl)piperidin-4-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (60 mg) which was carried on to the next step. 1H NMR (400 MHz, CD3OD) δ 8.32 (d, 1H, J=5.1 Hz), 7.61-7.62 (m, 2H), 4.07-4.13 (m, 4H), 4.01 (s, 3H), 2.81-2.84 (m, 3H), 1.96-1.98 (m, 2H), 1.45-1.47 (m, 2H), 1.45 (s, 9H). [M+H] found 389.