Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[C:21](Cl)=[N:20][C:19]([N:23]([CH3:28])[CH:24]([CH3:27])[CH2:25][CH3:26])=[CH:18][N:17]=1)[CH2:9][C@@H:10]([OH:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:15][C:16]2[N:17]=[CH:18][C:19]([N:23]([CH3:28])[CH:24]([CH3:27])[CH2:25][CH3:26])=[N:20][C:21]=2[O:14][C@@H:10]([CH2:11][O:12][CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)N(C)c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)N(C)c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
To a solution of (2R)-1-[benzyl({3-chloro-5-[methyl(1-methylpropyl)amino]pyrazin-2-yl}methyl)amino]-3-methoxypropan-2-ol (385 mg) in DMF (10 mL) was added potassium tert-butoxide (126 mg), and the mixture was stirred at room temperature for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 20→50% ethyl acetate/hexane) to give the title compound (300 mg, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=[C:4]2[N+:1]([O-:3])=[O:2])=[N:8]1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc2c([N+](=O)[O-])cccc2n1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
4-Nitroindazole (1.00 g, 6.13 mmol) was dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (2.50 g, 18.1 mmol) was added. The mixture was stirred for 30 minutes and then (2-chloro-ethyl)-dimethyl-amine hydrochloride (1.33 g 9.23 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature. The mixture was filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated in vacuo to remove N,N-dimethylformamide and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) ppm 2.19 (s, 6H), 2.84 (t, 2H, J=6.44) 4.65 (t, 2H, J=6.44), 7.49 (dd, 1H, J1=8.48, J2=7.8), 8.18(m, 1H), 8.20 (m, 1H), 8.91 (s, 1H); MS (DCI/NH3) m/z 235 [M+H]+.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[S:20][C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:22]([CH3:25])[C:23]=2Br)[O:7][C@@H:6]1[CH2:35][O:36]C(=O)C)(=O)C.[CH3:40][O-:41].[Na+]>>[CH2:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:21]2[S:20][C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:35][OH:36])[O:7]3)=[C:23]([O:41][CH3:40])[C:22]=2[CH3:25])=[CH:32][CH:31]=1)[CH3:34]
Reactant: CCc1ccc(Cc2sc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(Br)c2C)cc1
Reactant: C[O-]
Agent: [Na+]
Product: CCc1ccc(Cc2sc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OC)c2C)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(3-bromo-5-(4-ethylbenzyl)-4-methylthiophen-2-yl)-tetrahydro-2H-pyran-3,4,5-triyl triacetate (56) (200 mg, 0.320 mmole) in NaOMe (25 wt % in MeOH, 10 mL, 43.2 mmole) were added cupric oxide (25.5 mg, 0.320 mmole) and KI (53.1 mg, 0.320 mmole). The resulting solution was stirred at 120° C. overnight. The reaction mixture was filtered through Celite® bed and concentrated in vacuo. The crude residue was purified on reverse phase preparative HPLC to yield the title compound 59 (24.3 mg, 0.0595 mmole, 19%) as a yellow solid.
Reaction SMILES: CN(C)C=[N:4][C:5]1[S:6][C:7]([CH3:13])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11].Cl.C([O-])(=O)C.[Na+]>C(O)C>[NH2:4][C:5]1[S:6][C:7]([CH3:13])=[C:8]([Cl:12])[C:9]=1[C:10]#[N:11]
Reactant: Cc1sc(N=CN(C)C)c(C#N)c1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1sc(N)c(C#N)c1Cl
Yield: 86 %

Procedure:
A mixture of 6.1 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-5-methylthien-2-yl)-formamidine, 50 parts of ethanol and 2 parts of concentrated hydrochloric acid is heated at the boil for 1 hour. Thereafter, the mixture is added to a dilute aqueous sodium acetate solution, and the precipitate is filtered off under suction and dried. 4 parts (86% of theory) of 2-amino-4-chloro-3-cyano-5-methylthiophene are obtained.
Reaction SMILES: C[C:2]1[C:7]([C:8]#[N:9])=[C:6]([S:10][CH2:11][CH:12]=O)[N:5]=[C:4]([CH3:14])[CH:3]=1.[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:19]=2[O:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>ClCCCl.CN(C=O)C>[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([N:25]3[CH2:30][CH2:29][N:28]([CH2:12][CH2:11][S:10][C:6]4[N:5]=[C:4]([CH3:14])[CH:3]=[CH:2][C:7]=4[C:8]#[N:9])[CH2:27][CH2:26]3)[C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: Cc1cc(C)c(C#N)c(SCC=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C#N)c(SCCN2CCN(c3cccc4c3OCCO4)CC2)n1
Reaction time: 2 h

Procedure:
4,6-Dimethyl-2-(2-oxo-ethylsulfanyl)nicotinonitrile (2.9 g) was dissolved in 1,2-dichloroethane (150 mL), a solution of 4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazine (2.6 g) in DMF (150 mL) was added, followed by addition of sodium triacetoxyborohydride (14.9 g) and stirring for 2 h. The mixture was poured on water and Na2CO3 added until pH reached 7-8. The mixture was extracted with ethyl acetate, the combined organic phases dried and evaporated to give an oil which was subjected to purification by column chromatography (silica gel; ethyl acetate and heptane) giving an oil which precipitated as the oxalate salt (0.36 g) from acetone. LC/MS (m/z) 397 (MH+), RT=1.91, purity: 97%.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH:14]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)(=O)=O)=CC=1.[C-]#[N:29].[Na+].[Na+].[Cl-]>CS(C)=O>[C:12]([CH2:13][CH:14]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)#[N:29]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCC(NC(=O)OC(C)(C)C)c2ccsc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC(CC#N)c1ccsc1
Temperature: 90 °C

Procedure:
To 3-(tert-butoxycarbonylamino)-3-(thiophen-3-yl)propyl 4-methylbenzenesulfonate (E73B) in DMSO is added NaCN, and the solution is heated to 90° C. for 2 hours. The reaction is cooled, poured into NaCl (sat), and extracted with EtOAc. The organics are dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 25% EtOAc/Hexanes) gives pure tert-butyl 2-cyano-1-(thiophen-3-yl)ethylcarbamate (E73C).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[CH2:11]([C:15]1[CH:20]=[CH:19][C:18]([C@@H:21]([CH3:25])[C:22](Cl)=[O:23])=[CH:17][CH:16]=1)[CH:12]([CH3:14])[CH3:13]>>[C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][S:7][C:22](=[O:23])[C@@H:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=1)[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CC(C)Cc1ccc([C@@H](C)C(=O)Cl)cc1
Product: CC(=O)N[C@@H](CSC(=O)[C@H](C)c1ccc(CC(C)C)cc1)C(=O)O

Procedure:
By operating in a way similar to that described in the Example 2, and starting from N-acetyl-(R)-cysteine (39.5 g) and (2R)-2-(4-isobutyl-phenyl)-propionyl chloride (45.4 g) the desired product is obtained (18 g) as a solid melting at 102°-104° C.; [α]D20 =-79.6° (c=1%, EtOH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:13]([O:15][CH3:16])[CH3:14])=O.O1CCOCC1>CC(O)=O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:10]([C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:13]([O:15][CH3:16])[CH3:14])=[N:1][C:2]=2[CH:7]=1
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)cc1N
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2[nH]1
Reaction time: 18 h
Yield: 29 %

Procedure:
A solution of tert-butyl {(1S,2R)-1-[(2-amino-4-bromophenyl)carbamoyl]-2-methoxypropyl}carbamate (Preparation 23, 6.5 g, 16.17 mmol) in AcOH (5 mL) was stirred at room temperature for 3 days followed by 40° C. for 18 hours. The reaction was diluted by the addition of dioxane and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-40% acetonitrile in 0.1% formic acid in water to afford the title compound as a white solid (1.8 g, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9](C(OC)=O)([CH3:13])[CH:8]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:7][C:6]=2[CH:26]=1.[I-].[Li+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:9]([CH3:13])[C@@H:8]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH2:7][C:6]=2[CH:26]=1
Reactant: COC(=O)C1(C)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc([C@H]2Cc3cc(Cl)ccc3NC(=O)[C@H]2C)cc1
Yield: 58.6 %

Procedure:
A mixture of 800 mg of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-3-methyl-2H-1-benzazepin-2-one (2.16 mmole), 1.14 g of lithium iodide (8.56 mmoles, 4 equiv.) in 20 ml of pyridine was refluxed for 20 hours. The cooled mixture was diluted with 200 ml of ethyl acetate, then washed with four 30 ml portions of 1N hydrochloric acid, two 30 ml portions of saturated cupric sulfate, 30 ml of water. The organic layer was dried (magnesium sulfate) and concentrated. The residue was triturated with ether to yield 400 mg of (cis)-7-chloro-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-3-methyl-2H-1-benzazepin-2-one as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:20])[N:3]=1>O1CCOCC1.O>[CH2:5]([C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:20])[N:3]=1)[CH:6]([CH3:8])[CH3:7]
Reactant: Cc1cc(-c2noc(-c3cc(C)nc(Cl)c3)n2)ccn1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2noc(-c3cc(C)nc(CC(C)C)c3)n2)ccn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
To a solution of 2-chloro-4-[3-(2-methyl-4-pyridinyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (200 mg, 0.698 mmol) in dioxane (10 mL), Pd(dppf) (11 mg, 14 μmol) and isobutyl zink bromide (2.8 mL, 0.5 M in THF) is added. The mixture is stirred at 80° C. for 3 h before another portion of isobutyl zink bromide (2.8 mL) is added. Stirring is continued at 80° C. for 72 h. The mixture is cooled to rt, diluted with water and extracted with EA. The org. extract is concentrated and the crude product is purified by prep. HPLC to give 2-isobutyl-4-[3-(2-methyl-4-pyridinyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (22 mg) as a beige solid; LC-MS: tR=0.71 min, [M+1]+=309.12.
Reaction SMILES: F[C:2]1[C:7](F)=CC=C[C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1)(=O)=O.[O:29]1C(CS)=CC=[N:30]1>>[OH:26][CH2:25][C@H:24]([NH:23][C:21]1[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=[C:13]([S:10][CH2:9][C:3]2[O:29][N:30]=[CH:7][CH:2]=2)[N:22]=1)[CH3:27]
Reactant: SCc1ccno1
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Product: C[C@H](CO)Nc1nc(SCc2ccno2)nc2[nH]c(=O)cnc12
Yield: 46.8 %

Procedure:
The titled compound (0.038 g) was prepared by the method of Example 13, step (c) using the product from Example 13, step (a) (0.10 g) and 5-isoxazolylmethylmercaptan (0.057 g).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:22])[C:14]1[C:19](Cl)=[CH:18][C:17]([Cl:21])=[N:16][CH:15]=1)[CH3:11]>CN(C)C=O>[CH2:10]([O:12][C:13](=[O:22])[C:14]1[C:19]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:18][C:17]([Cl:21])=[N:16][CH:15]=1)[CH3:11]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)cc1Oc1ccccc1
Yield: 70.4 %

Procedure:
To a solution of 196 mg (ca. 4 mmol) sodium hydride dispersion in mineral oil (ca. 50%) in 15 ml N,N-dimethylformamide a solution of 385 mg (4.09 mmol) phenol in 10 ml N,N-dimethylformamide was added dropwise at room temperature under argon. After 15 min. this solution was slowly added via cannula to a solution of 4,6-dichloro-nicotinic acid ethyl ester in 20 ml N,N-dimethylformamide at room temperature. After 2 h the reaction was quenched with 20 ml water. The mixture was extracted with 3 50-ml portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate and concentrated. After drying in high vacuo at 50° C. and flash column chromatography 800 mg (70.4%) of the title compound was obtained as a white solid. As a side product 130 mg (11.4%) 4-chloro-6-phenoxy-nicotinic acid ethyl ester were also isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[F:11].[CH3:12][C:13](OC(C)=O)=[O:14]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:13](=[O:14])[CH3:12])=[C:3]([F:11])[C:4]=1[F:10])#[N:7]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(N)c(F)c1F
Product: CC(=O)Nc1ccc(C#N)c(F)c1F
Yield: 67 %

Procedure:
A mixture of 9.59 g of 4-amino-2,3-difluorobenzonitrile and 20 mL of Ac2O is heated for 1 hour on a steam bath. The red solution is cooled in an ice bath and the resulting faint pink crystals filtered off, washed with 2×10 mL of Et2O and air dried. In this manner there is obtained 8.26 g (67% yield) of 4'-cyano-2',3'-difluoroacetanilide, m.p. 175°-177° C. with the appropriate NMR and IR spectral data and an ion at 197 in the mass spectrum.
Reaction SMILES: C([O:9][C:10]1[CH:11]=[C:12]([Cl:32])[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)=[C:14]([I:16])[CH:15]=1)(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:32][C:12]1[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=2)=[C:14]([I:16])[CH:15]=[C:10]([OH:9])[CH:11]=1
Reactant: O=C(Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(I)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(I)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.12 g of 5-benzoyloxy-3-chloro-1-iodo-2-[3-(5-trifluoromethylpyrid-2-yloxy)propyloxy]benzene were dissolved in 16 ml of tetrahydrofuran and 7.8 ml of methanol, and 3.9 ml of 2N aqueous sodium hydroxide solution were added. After 30 minutes of stirring at room temperature. 3.9 ml of 2N hydrochloric acid were added, and the reaction mixture was concentrated under reduced pressure. Saturated sodium chloride solution and ethyl acetate were added to the residue, and the mixture was shaken. The ethyl acetate phase was isolated, dried and concentrated. The resulting crude product was purified chromatographically. Yield: 2.03 g (80%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]=[N+:27]=[N-:28])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:29]#[C:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]2[CH:40]=[C:39]([Si:36]([CH3:38])([CH3:37])[CH3:35])[N:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Reactant: C#C[Si](C)(C)C
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](n2cc([Si](C)(C)C)nn2)CC1

Procedure:
A solution of 3-[(trans-4-azido-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (1.0 g, 2.0 mmol) in trimethylsilylacetylene (1.4 ml, 10 mmol) is treated in microwave at 120° C. for 2 h. The mixture is concentrated under reduced pressure and the residue is purified by silica gel column chromatography (5% ethyl acetate/hexane to 100% ethyl acetate) to afford 5-(3,3-dimethyl-but-1-ynyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(4-trimethylsilanyl-[1,2,3]triazol-1-yl)-cyclohexyl]-amino}-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].O>FC(F)(F)C(O)=O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(=O)CC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C(=Cc1ccccc1C(F)(F)F)C(C)=O

Procedure:
To a solution of 2-trifluoromethylbenzaldehyde (8,7 g) and 2,4-pentanedione (5,01 g) in trifluoroacetic acid (10 ml) thionylchloride (4 ml) and catalytic amount of water (0,05 ml) were added at room temperature. The solution was stirred over night at 20°? C. The solvent was evaporated and the residue was distilled in vacuo, bp 110° C./1.5 mbar. Yield 5.3 g (41 %).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56](Br)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(=O)([O-])[O-].[K+].[K+].C(COC)OC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:54][C:53]2[CH:55]=[C:56]([C:26]3[S:25][C:24]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[CH:6]=[O:5])=[N:17][CH:16]=5)=[CH:19][CH:20]=4)=[CH:28][CH:27]=3)[CH:57]=[CH:58][C:52]=2[N:51]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)s3)cc2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C=O)[nH]5)cc4)s3)cc2[nH]1
Temperature: 110 °C
Yield: 66.2 %

Procedure:
A mixture of 2-(5-{4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.110 g), 2-(6-Bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.115 g) and Pd(PPh3)4 (0.012 g) in 2.0M potassium carbonate solution (0.32 mL) and dimethoxyethane (0.64 mL) was heated in microwave at 110° C. for 30 minutes. Reaction mixture was cooled, diluted with ethyl acetate, washed with brine, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) and preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give 2-[6-(5-{4-[2-(1-Formyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-thiophen-2-yl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.085 g) as a bis-TFA salt: LCMS-ESI+: calc'd for C38H45N6O4S: 681.86 (M+H+). Found: 681.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].CC(O)=O>C1COCC1.[Zn]>[CH3:1][O:2][CH2:3][C:4]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)([CH3:6])[CH3:5]
Reactant: COCC(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCC(C)(C)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
1-(2-Methoxy-1,1-dimethyl-ethyl)-4-nitro-benzene (1 eq) was dissolved in THF (40 mL/mmol) at 0° C. and HOAc (20 eq) was added, followed by Zn dust (30 eq). The mixture was stirred at RT until the starting material was consumed and was filtered on silica pad. Solvent was evaporated, the residue was dissolved in CH2Cl2 and washed with NaOH 1M. The organic phase was dried, filtered and evaporated to give the amine.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1>C1COCC1.C(=O)([O-])[O-].[Ag+2]>[CH2:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccnc(O)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Cc1ccnc(OCc2ccccc2)c1
Yield: 94.2 %

Procedure:
A mixture of 13.6 ml (114 mmol, 1.0 eq.) of benzyl bromide and 15.0 g (137 mmol, 1.2 eq.) of 2-hydroxy-4-methylpyridine [CAS No: 13466-41-6] was dissolved in 470 ml of THF. The solution was admixed with 37.9 g (137 mmol, 1.2 eq.) of silver carbonate and the mixture was heated to reflux with exclusion of light overnight. Subsequently, the reaction mixture was filtered through kieselguhr and eluted with ethyl acetate, and the filtrate was concentrated. The crude product was purified by silica gel chromatography (700 g of silica gel, cyclohexane/ethyl acetate 95:5). 21.4 g of the title compound were obtained (94% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([N+:27]([O-])=O)[CH:14]=[C:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:14]=[C:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:16]=1)[NH2:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(C(=O)OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Yield: 90 %

Procedure:
The nitro compound prepared in step c above (3.91 g, 10 mol) was dissolved in ethyl acetate (50 ml) and tin (II) chloride dihydrate (11.27 g, 50 mmol) was added and the mixture stirred and heated at 70° under an atmosphere of nitrogen for 1 h . The mixture was poured carefully onto 5% sodium hydrogencarbonate solution (200 ml) and a further aliquot of ethyl acetate (100 ml) was added. After shaking the organic layer was separated and the aqueous layer was extracted with more ethyl acetate (50 ml). The combined organic layers were washed with brine, and dried, filtered and evaporated to leave a pale yellow solid (3.25 g, 90%).