Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=1)(=[O:5])=[O:4].[ClH:24]>CN(C=O)C.O.[Pd]=O>[ClH:24].[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3=CCN(C)CC3)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 18.5 h

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indol-5-yl]ethenesulphonamide (10 kg) and 10% palladium oxide on charcoal (10 kg, 50% wet paste, added as two charges) in DMF (50 L), water (20 L) and 2N hydrochloric acid (15 L) was hydrogenated at atmospheric pressure over 18.5 hr. The catalyst was removed by filtration. The filter cake was washed with water (20 L). The filtrate was concentrated in vacuo to approximately 30 L and cooled to 20°. Ethyl acetate (70 L) was added over 1 hr and the resulting suspension cooled to 5° and aged for 30 min. The product was collected by filtration, washed with ethyl acetate (20 L) and dried in vacuo at 40°-50° overnight (9.34 kg, 81.6% of theory). A portion (2.0 kg) of the solid was recrystallised from hot water (6.0 L) and obtained as white crystals (1.40 kg, 70% of theory).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>>[CH3:9][C:4]1[CH:5]=[C:6]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[CH:16]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2cc(C)nc(N)n2)c1

Procedure:
The title compound is synthesized according to general procedure GP4 starting from 2.0 g (14 mmol) 2-amino-4-chloro-6-methylpyrimidine and 2.5 g (18 mmol) 3-methyl-phenyl boronic acid. Yield after extraction and re-crystallization from diethylether: 4.1 g (>100%, approximately 70% pure).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O.O.CSC>[OH:8][C:9]1[CH:10]=[C:11]([CH:30]=[CH:31][CH:32]=1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(OCc2ccccc2)c1
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 68 h
Yield: 70 %

Procedure:
1-(3-Benzyloxybenzyl)-5-methoxy-2-phenylindole (200 mg) was dissolved in trifluoroacetic acid-water-dimethyl sulfide (95/5/10, 4.8 mL), and the solution was stirred at room temperature for 68 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (110 mg).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:10]([F:17])=[CH:11][C:12]=3[C:13]2=O)=[CH:4][CH:3]=1.[CH3:24][Mg]Br.C(OCC)C.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH:8]=[C:9]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])[C:10]([F:17])=[CH:11][C:12]=3[C:13]2=[CH2:24])=[CH:4][CH:3]=1
Reactant: O=c1c2cc(Br)ccc2oc2cc(OCC(F)(F)F)c(F)cc12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2Oc2cc(OCC(F)(F)F)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-bromo-2-fluoro-3-(2,2,2-trifluoroethoxy)-9H-xanthen-9-one (2.00 g, 5.11 mmol) in THF (25 mL) at 0° C. was added methylmagnesium bromide 3.0 M in diethyl ether (3.41 mL, 10.23 mmol) slowly. After addition, the mixture was stirred at room temperature for overnight. Then, the mixture was cooled to 0° C. and saturated ammonium chloride (50 mL) was added slowly. The mixture was then stirred at RT for 15 min. Then, the organic layer was collected and the aqueous layer was extracted with EtOAc (1×50 mL). The combined organic extracts were dried over MgSO4, concentrated, and dried in vacuo to give 7-bromo-2-fluoro-9-methylene-3-(2,2,2-trifluoroethoxy)-9H-xanthene as a brown solid. MS (ESI, positive ion) m/z: 388.9, 390.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([CH:21]=[O:22])[CH:18]=[C:17]([CH3:23])[C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[C:17]([CH3:23])[C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(Oc1c(C)cc(C=O)cc1C)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Oc1c(C)cc(CO)cc1C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To a solution of 1.260 g (3.79 mmol) of the product of Step A in 8 mL methanol was added 0.072 g (1.90 mmol) of sodium borohydride and the reaction mixture was stirred at room temperature for 15 minutes. Excess borohydride was quenched with water, and the reaction mixture was extracted into EtOAc. The organic layer was dried (MgSO4), filtered, evaporated, and then purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 0.790 g (63%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[C:6]([CH:19]=1)[C:7]([N:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14](OCC)=[O:15])=[O:8].[BH4-].[Na+]>CO>[OH:15][CH2:14][CH:10]1[N:9]([C:7]([C:6]2[CH:19]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:20]2[N:24]=[CH:23][CH:22]=[N:21]2)=[O:8])[CH2:13][CH2:12][O:11]1
Reactant: CCOC(=O)C1OCCN1C(=O)c1cc(C)ccc1-n1nccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCOC2CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-ethyl 3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,3-oxazolidine-2-carboxylate obtained in Reference Example 1 (4.0 g, 12.1 mmol) in MeOH (60 mL), NaBH4 (4.6 g, 121 mmol) was added gradually under cooling with ice water and stirred for 1 hour. The resulting mixture was heated to room temperature and stirred for 1 hour. The solvent was distilled off under reduced pressure, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was extracted with CHCl3. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, hexane/EtOAc=88/12 to 0/100) to obtain the title compound (3.6 g) (colorless oil).
Reaction SMILES: [Na].[C:2]1([C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][O:4]1)=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.Cl>C(O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]2[C:2](=[O:3])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:4])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C1OCc2ccccc21
Reactant: COc1cccc(C=O)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: COc1cccc(C2C(=O)c3ccccc3C2=O)c1
Yield: 44.1 %

Procedure:
Sodium (1.1 g) was dissolved in anhydrous Ethanol (90 ml). This solution was added with Phthalide (4.43 g, 33.04 mmol) and m-Methoxy benzaldehyde (3.00 g, 22.03 mmol). The reaction mixture was heated for 3 hrs under reflux. The reaction mixture was concentrated in a vacuum. White solid was obtained by adding conc.HCl. And then the white solid was recrystalized in ethylacetate:hexane (=1:2) to afford the title compound (2.45 g, 44%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH2:7][C:6](=[O:10])[N:5]([CH3:11])[C:4]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:3]1=2>[Pd].C(O)(=O)C>[NH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:3]2[N:2]([CH3:1])[C:8](=[O:9])[CH2:7][C:6](=[O:10])[N:5]([CH3:11])[C:4]=2[CH:12]=1
Reactant: CN1C(=O)CC(=O)N(C)c2cc(C#N)ccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1C(=O)CC(=O)N(C)c2cc(CN)ccc21
Yield: 55.7 %

Procedure:
10% Palladium on carbon(0.1 g) was added to an acetic acid solution (20 ml) of 1,5-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile(0.3 g), and catalytic reduction was carried out at room temperature under 4 atm. The catalyst was removed by celite filtration, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=9:1→5:5). The purified product was condensed under reduced pressure to give the title compound(0.17 g) as a yellowish white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH3:21][OH:22].C[O-].[Na+]>CO>[CH3:21][O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC(OCCCCCBr)CC1
Agent: C[O-]
Agent: [Na+]
Product: COCCCCCOC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
To a solution of 4-(5-bromopentyloxy)-1-N-t-butoxycarbonylpiperidine (2.44 g) in methanol (13 ml) was added 28% sodium methoxide methanol solution (14.2 ml), and the mixture was stirred under reflux for 4 hours. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (250 ml) eluting with a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractions containing the object compound were collected and evaporated under reduced pressure to give 4-(5-methoxypentyloxy)-1-N-t-butoxycarbonylpiperidine (1.97 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:28][CH2:29][O:25][C:26]3=[O:30])=[CH:3][C:4]=2[CH3:24])=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3C)CC2)c(C)c1
Yield: 28.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (775 mg) described in Preparation Example 6 and oxazolidin-2-one (174 mg), the title compound (224 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:3]([NH:13][CH:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH:14]1[NH:13][C:3]1[CH:2]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(NC2Cc3ccccc3C2)c(Cl)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1ccc(NC2Cc3ccccc3C2)nc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 29.5 %

Procedure:
To a mixture of ethyl 5-chloro-6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (395 mg) and ammonium formate (472 mg) in ethanol (10 mL) was added 10% palladium on carbon (40 mg), and the mixture was stirred at 100° C. for 10 hours. The catalyst in the reaction mixture was removed by filtration. The solvent was evaporated in vacuo. The residual solid was collected with hexane and ethyl acetate (2/1 v/v) to give ethyl 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (104 mg). The mother liquid was concentrated in vacuo, and the residue was purified by preparative thin layer column chromatography (hexane/ethyl acetate=2/1) to give ethyl 6-(2,3-dihydro-1H-inden-2-ylamino)nicotinate (209 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([O-])(O)=[O:19].[Na+].C1C(=O)N(Br)C(=O)C1.N1C=CC=CC=1>CC(C)=O.O>[O:19]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])/[CH:17]=[CH:16]/[CH:15]=[O:14]
Reactant: CCCCCCCCCCCCc1ccco1
Reactant: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC(=O)/C=C/C=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
A mixture of 2-dodecylfuran (1.00 g, 4.24 mmol) and NaHCO3 (712 mg, 8.48 mmol) in acetone/H2O (10:1, 2 ml) was treated at −20° C. with NBS (905 mg, 5.11 mmol) dissolved in acetone/H2O (10 ml). After the mixture had been stirred for 1 h at −20° C., it was treated with pyridine (0.69 ml, 8.48 mmol). Thereafter, the reaction mixture came to RT, and stirring was continued for 2 h. The solution was washed with 1 N HCl, followed by extraction with ethyl acetate (2×50 ml). The organic phase was dried over NaSO4 and concentrated in order to obtain the crude product. The latter was purified by column chromatography (DCM) to give the product as a pale yellow oil (642 mg, 2.55 mmol, 60%). 1H NMR (300 MHz, CDCl3) δ 1H ppm: 0.88 (t, 3H, J=6.7 Hz, H-16), 1.19-1.36 (m, 18H), 1.59-1.71 (m, H-5), 2.69 (t, 2H, J=7.8 Hz, H-5), 6.73-6.92 (m, 2H, H-2.3), 9.78 (d, CHO, J=7.0 Hz, H-1); 13C NMR (75.5 MHz, CDCl3) δ 13C ppm: 14.2 (C-16), 22.8, 23.7, 29.2, 29.3, 29.4, 29.5, 29.5, 29.6, 29.7, 32.0, 41.3 (C-5), 137.2 (C-2), 144.8 (C-3), 193.2 (C-1), 199.9 (C-4); (−)-ESI-CID-MS: 251 [M−H]−; ESI-FT-ICR-MS: m/z 251.20137 (calculated for C16H27O2−, m/z 251.20165).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([N+:33]([O-:35])=[O:34])[CH:25]=3)(=[O:30])=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1

Procedure:
Prepared from 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethylamine and 4-chloro-3-nitro-benzenesulphonic acid chloride analogously to Example 2.
Reaction SMILES: C([O:4][CH2:5][C:6]#[C:7][CH2:8][N:9]1[C:13]([CH2:16][F:17])([CH2:14][F:15])[C:12](=[O:18])[N:11]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)[C:10]1=[O:31])(=O)C.CO.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:15][CH2:14][C:13]1([CH2:16][F:17])[C:12](=[O:18])[N:11]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)[C:10](=[O:31])[N:9]1[CH2:8][C:7]#[C:6][CH2:5][OH:4]
Reactant: CC(=O)OCC#CCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CF)CF
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#Cc1ccc(N2C(=O)N(CC#CCO)C(CF)(CF)C2=O)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
1 g of the product obtained in Stage 3 above, 18 ml of methanol and 4.5 ml of 2N hydrochloric acid are introduced then left for one hour 30 minutes at 50° C. The reaction medium is then returned to ambient temperature, poured into 30 ml of sodium bicarbonate, extraction is carried out with ethyl acetate 3 times, the extracts are washed with salt water and dried. After chromatography on silica eluting with methylene chloride-acetone: 85-15, 780 mg of expected product (white crystals) is obtained. M.p.=131-132° C.
Reaction SMILES: Br[C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][N:3]=1.C(S)CC1C=CC=CC=1>CO>[SH:4][C:5]1[N:9]([C:2]#[N:3])[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]=1
Reactant: Brc1nsc2nc3ccccc3n12
Agent: SCCc1ccccc1
Solvent: CO
Product: N#Cn1c(S)nc2ccccc21
Yield: 85.9 %

Procedure:
To a suspension of 500 mg of 3-bromo-1,2,4-thiadiazolo [4,5-a]benzimidazole in 50 mL methanol was added 790 μL of phenethyl mercaptan. The solid rapidly dissolves. After completion of the reaction, the solvent was evaporated and the residue purified by chromatography to give 296 mg of 2-mercapto-1-benzimidazolecarbonitrile:=H NMR (DMSO-d6) δ12.85 (br s, 1H, SH), 7.5-7.2 (m, 4H, 4×ArH) ppm; IR (KBr) ν2259, 1509, 1459, 1303, 1189, 752 cm-1 ; MS m/z 175 (M+), 150 (M+ -CN).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([O:26][CH3:27])[N:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12](F)[CH:11]=1)=[O:8])#[N:3].C(OC(N1CCO[C@@H](C2C=CC(N)=C([F:48])C=2)C1)=O)(C)(C)C>>[ClH:1].[C:2]([C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([O:26][CH3:27])[N:25]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][C:11]=1[F:48])=[O:8])#[N:3]
Reactant: COc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)c(F)c2)cc(C#N)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(F)c2)C1
Agent: Cl
Product: COc1cc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2F)cc(C#N)n1

Procedure:
In analogy to example 83, step a) using 2-Cyano-6-methoxy-isonicotinic acid (described in example 107) instead of 2-(trifluoromethyl)-4-pyridinecarboxylic acid (CAS 131747-41-6) and (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (described in example 1 h) instead of (+)-(R)-2-(4-Amino-2-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].CCOC(C)=O.CO>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH:15][C:25](=[O:26])[C:24]4[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=4)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Solvent: c1ccncc1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)cc3)cn2c1
Yield: 79.6 %

Procedure:
Prepared as described in the Amide Coupling section using 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.20 g, 0.897 mmol) and 4-nitrobenzoyl chloride (0.166 g, 0.897 mmol) in dry pyridine (13 ml) to give the title compound (0.266 g, 80%) as a pale yellow solid after work-up and flash chromatography (1:1 EtOAc/MeOH).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12][CH:13]([OH:26])[C:14]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[OH:17])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[C:33]1([C:11]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:10]3[CH:15]([CH2:16][NH:8][CH2:9]3)[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH:13]([OH:26])[CH2:12]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Temperature: 65 °C

Procedure:
A mixture of 2 g of (3aRS, 4RS, 5RS, 7aRS)-2-benzyl-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol and 50 cm3 of ethanol is heated to 65° C. with stirring; 0.65 g of 20% palladium hydroxide on charcoal is added, and the reaction mixture is then hydrogenated, with stirring, at a temperature of 65° C. and at atmospheric pressure. After reaction for 1 hour, the theoretical volume of hydrogen has been absorbed; the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 10. cm3 of isopropyl ether. 1.45 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydro-4,5-isoindolediol are obtained, melting at 230° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[C:26]1[CH3:37]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]([CH3:24])[C:26]=3[CH3:37])=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
Product: Cc1c(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)c2ccccc2n1C

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1,2-dimethyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.83 min; [M+H]+=504.2.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH3:36][C:37]1[CH:41]=[C:40]([CH2:42][NH:43][C:44]2[CH:53]=[CH:52][CH:51]=[CH:50][C:45]=2[C:46](OC)=[O:47])[O:39][N:38]=1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:14]2[NH:15][N:16]=[C:12]([NH:11][C:46](=[O:47])[C:45]3[CH:50]=[CH:51][CH:52]=[CH:53][C:44]=3[NH:43][CH2:42][C:40]3[O:39][N:38]=[C:37]([CH3:36])[CH:41]=3)[CH:13]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1ccccc1NCc1cc(C)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3ccccc3NCc3cc(C)no3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 10.5 %

Procedure:
NaHMDS (1M solution in THF, 0.83 ml, 0.828 mmol, 2.5 eq) was added dropwise to a solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (90 mg, 0.364 mmol, 1.1 eq) and methyl 2-{[(3-methylisoxazol-5-yl)methyl]amino}-benzoate (115 mg, 0.331 mmol, 1 eq), stirred in THF (4 ml) under nitrogen. The solution was stirred at room temperature for 50 mins. The solution was quenched with satd. aq. NH4Cl, diluted with water (5 ml) and extracted with ethyl acetate (3×8 ml). The crude product was purified by silica column chromatography, eluting with a gradient of 0-1.5% MeOH in DCM. Fractions containing product were evaporated and further purified by reverse phase prep. HPLC purification, eluting with a gradient of MeCN/H2O+0.1% TFA to afford the title compound as an off-white solid (16 mg, 10% yield); 1H NMR (399.902 MHz, DMSO) δ 2.20 (s, 3H), 2.88 (s, 4H), 3.73 (s, 6H), 4.57 (s, 2H), 6.21 (s, 1H), 6.33 (t, 1H), 6.41 (bs, 1H), 6.43 (d, 3H), 6.65 (t, 1H), 6.77 (d, 1H), 7.28-7.34 (m, 1H), 7.75-7.79 (m, 1H), 8.10 (bs, 1H), 10.50 (s, 1H). MS: m/z 462 (MH+)