Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][C:13]#[N:14])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>C1COCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3([C:13]#[N:14])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCc1nc(-c2ccccc2)cs1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2nc(-c3ccccc3)cs2)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
A solution of 2-(4-phenylthiazol-2-yl)acetonitrile (0.84 g, 4.19 mmol) in THF (25 mL) was cooled to 0° C. NaH was added (0.5 g, 60% dispersion in oil) portionwise over 10 min. The resulting mixture was allowed to warm up to room temperature and stirred for 20 min. 2-Bromoethyl ether (1.58 mL, 12.5 mmol) was added dropwise. The reaction mixture was further stirred at room temperature for 1 h and then quenched with saturated NH4Cl solution. The reaction mixture was diluted with EtOAc and the organic layer was washed with H2O and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 4-8% EtOAc in petroleum ether) to afford 4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-carbonitrile (0.97 g, yield 85%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.91-7.94 (m, 2H), 7.51 (s, 1H), 7.37-7.48 (m, 3H), 4.07-4.14 (m, 2H), 3.87-3.96 (m, 2H), 2.32-2.43 (m, 4H). MS (ESI) m/z: Calculated for C15H14N2OS: 270.08. found: 271.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([NH2:9])[CH:5]=1.[OH:10][C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14](=[O:22])(=[O:21])[N:13]([CH3:23])[C:12]=1[C:24](OC)=[O:25]>C1(C)C(C)=CC=CC=1>[OH:10][C:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14](=[O:22])(=[O:21])[N:13]([CH3:23])[C:12]=1[C:24]([NH:9][C:6]1[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[O:8][N:7]=1)=[O:25]
Reactant: COCc1cc(N)no1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: COCc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)no1
Reaction time: 8 h
Yield: 22.3 %

Procedure:
A mixture of 0.52 g (4 mmole) of 5-(methoxymethyl)-3-isoxazolamine, 1.08 g (4 mmole) of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide, and 100 ml of xylene is heated at reflux for six hours in a soxhlet apparatus, the thimble of which contains 20 g of Linde type 4A molecular sieve. The reaction mixture is filtered to clarify it and is allowed to stand at room temperature overnight when the product crystallizes out. The product is filtered, washed with methanol-ether mixture, and then recrystallized from methanol to give 0.326 g of white crystals, mp 218°-223° C. dec.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[F:8][C:9]([F:19])([F:18])[O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([O:10][C:9]([F:8])([F:18])[F:19])=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Br)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 4.02 g (23.4 mmol) of 2-bromopropionyl chloride in 10 ml of methylene chloride was added to an ice-cooled solution of 5.0 g (23.4 mmol) of 4-(trifluoromethoxy)aniline hydrochloride, 4.65 g (59 mmol) of pyridine and 30 ml of methylene chloride. The mixture was stirred at ambient temperature for a period of 2.5 hours and then washed with two portions of dilute aqueous HCl and two portions of saturated aqueous sodium bicarbonate, dried over MgSO4, treated with charcoal, filtered and the filtrates evaporated to dryness. The residue was recrystallized from methylcyclohexane to give 5.43 g 74 percent of theoretical) of the above-named product as colorless crystals, m.p. 111°-112° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH3:15].Cl>O>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH2:15])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: N
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Product: NC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 53.1 %

Procedure:
A mixture of methyl 4-hydroxy-3-nitrobenzoate (1.00 g, 5.07 mmol) and concentrated aq ammonia (10.0 mL, 162 mmol) was heated to 100° C. for 90 mins (3×30 mins) in a microwave reactor. The mixture was poured into water (70 mL), acidified with 6N HCl and extracted with EtOAc (4×25 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was triturated with DCM (20 mL) filtered and washed with DCM before drying under vacuum to afford the crude title compound as a yellow solid 0.49 g, 53.0%
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:24]=[CH:23][N:22]=1>C(O)C>[CH3:33][C:31]1[NH:30][N:29]=[C:28]([NH:27][C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH:1][C:2]3[CH:19]=[CH:18][C:5]4[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[S:8][C:4]=4[CH:3]=3)[N:26]=2)[CH:32]=1
Reactant: Nc1ccc2nc(NC(=O)c3ccccc3)sc2c1
Reactant: Cc1cc(Nc2ccnc(Cl)n2)n[nH]1
Solvent: CCO
Product: Cc1cc(Nc2ccnc(Nc3ccc4nc(NC(=O)c5ccccc5)sc4c3)n2)n[nH]1

Procedure:
N-{6-[4-(5-Methylpyrazol-3-ylamino)pyrimidin-2-ylamino]benzothiazol-2-yl}benzamide was prepared by heating a mixture of N-(6-aminobenzothiazol-2-yl)benzamide (IM 2, 35 mg, 0.13 mmol) and (2-chloropyrimidin-4-yl)-(5-methylpyrazol-3-yl)amine (IM 11, 30 mg, 0.143 mmol) in ethanol (3 mL) to 80° C. for 9 h. The precipitate was separated by filtration, washed with ethanol and dried (38 mg, 85 μmol, 66%). LC/ESI-MS: m/z=443 [M+H]+; m/z =441 [M−H]−; Rt=2.80 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[C:8]1[CH:9](OC)[O:10][C:11](=[O:12])[C:7]=1[CH:6]=[CH:5]2.CO.[CH3:20][NH2:21]>C1COCC1>[Br:1][C:2]1[CH:17]=[CH:16][C:15]2[C:8]3[CH:9]([OH:10])[N:21]([CH3:20])[C:11](=[O:12])[C:7]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: COC1OC(=O)c2ccc3cc(Br)ccc3c21
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)c2ccc3cc(Br)ccc3c2C1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-Bromo-1-methoxynaphtho[1,2-c]furan-3(1H)-one (1.03 g) was dissolved in THF (10 mL), and 40% methylamine methanol solution (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hr., and the solvent was evaporated to give the title compound (1.03 g) as pale-yellow crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][NH2:17])C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][NH2:17]
Reactant: [H][H]
Reactant: NCCc1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: NCCc1ccccc1O
Yield: 91.8 %

Procedure:
10% Palladium-carbon catalyst (water content 50%, 42 mg) was added to a solution of 2-(2-benzyloxyphenyl)ethylamine (415 mg, 1.826 mmol, 1.0 eq) in THF (10 ml), and the mixture was stirred for 2 hours at room temperature in a stream of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give 2-(2-hydroxyphenyl)ethylamine (230 mg, 91.8%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[ClH:9].[NH2:10][OH:11]>CO>[ClH:9].[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:10][OH:11])=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1ccncc1
Agent: Cl
Solvent: CO
Product: ON=Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A solution of 4-pyridine carboxaldehyde (25.0 g, 233 mmol) in 100 ml of methanol was treated with hydroxylamine hydrochloride (17.84 g, 250 mmol) and stirred 15 minutes at room temperature. The resulting white solid was collected by filtration and dried in vacuo to provide 27.0 g of 4-pyridine carboxaldehyde oxime, hydrochloride, mp 246°-247° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH:25]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:30]([CH:25]5[CH2:29][CH2:28][CH2:27][CH2:26]5)=[O:31])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: O=C(Cl)C1CCCC1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)C1CCCC1
Yield: 45.8 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol), N,N-dimethylacetamide (3.0 mL) and cyclopentanecarbonyl chloride (90 μL, 0.74 mmol), and in the same manner as in Example 120, the title compound (119 mg, 46%) was obtained as a white powder.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].O>C1COCC1>[O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14]2[C:15]3=[N:20][S:26](=[O:28])(=[O:27])[CH2:25][CH2:24][N:16]3[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)nc3)C2=N1
Temperature: 50 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of 6′-phenoxy-3,3′-bipyridin-2-amine (350 mg) in THF (dry) (15 ml) was added to a mixture of NaH (60%, 266 mg) and 2-chloroethanesulfonyl chloride (542 mg) in THF (dry) (15.0 ml) at room temperature. The mixture was stirred at 50° C. overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (419 mg) as a pale yellow solid. The solid was crystallized from CH3CN-IPE to give a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[F:12][C:13]([F:24])([F:23])[O:14][C:15]1[CH:22]=[CH:21][C:18](C#N)=[CH:17][CH:16]=1>>[F:12][C:13]([F:23])([F:24])[O:14][C:15]1[CH:22]=[CH:21][C:18]([C:1]2[NH:2][C:3](=[O:11])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:17][CH:16]=1
Reactant: CNC(=O)c1ccccc1C
Reactant: N#Cc1ccc(OC(F)(F)F)cc1
Product: O=c1[nH]c(-c2ccc(OC(F)(F)F)cc2)cc2ccccc12
Yield: 24.9 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (5.97 g) and 4-trifluoromethoxybenzonitrile (7.49 g) were reacted, to give 3-(4-trifluoromethoxyphenyl)isoquinolin-1-one (3.04 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1>C(Cl)(Cl)Cl>[Cl:19][C:15]1[CH:16]=[C:17]2[O:18][C:1](=[O:2])[NH:11][C:12]2=[N:13][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ncc(Cl)cc1O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c2ncc(Cl)cc2o1
Temperature: 25 °C
Yield: 85 %

Procedure:
Phosgene is introduced at 40°-50° C., after the addition of 20 parts of pyridine, into a solution of 10 parts of 2-amino-3-hydroxy-5-chloropyridine in 200 parts of chloroform, and stirring is maintained for one hour at room temperature; the chloroform and the pyridine are evaporated off in a water-jet vacuum, and ice-water is added to the residue. The precipitate is filtered off and dried at 40°-50° C. in vacuo. There are obtained 10 parts of 6-chloro-oxazolo[4,5-b]pyridin-2-(3H)-one (85% of theory), m.p. 184°-186° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1F)[C:11]([O:13][CH3:14])=[O:12]>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(F)c(F)c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N2CCNCC2)c(F)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Anhydrous piperazine was added to a THF solution of methyl 3,4-difluorobenzoate, and the mixture was stirred at 60° C. for 18 hours to obtain methyl 3-fluoro-4-piperazin-1-ylbenzoate.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:37](Cl)(=[O:46])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:40]1([CH2:39][CH2:38][C:37]([N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:19][CH:18]=2)=[O:46])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.125 g, 0.34 mmol) and triethylamine (0.18 mL, 1.36 mmol) in 2 mL methylene chloride was added hydrocinnamoyl chloride (0.152 mL, 1.02 mmol), dropwise. The reaction mixture was stirred for 1 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was washed with an additional 2 mL of methylene chloride. The combined organic layers were concentrated to give the title compound of Step A. MS 529.2 (M+1)+
Reaction SMILES: F[C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:3]([C@H:8]3[CH2:13][CH2:12][CH2:11][C@H:10]([OH:14])[CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:24][CH:23]=1
Reactant: O[C@H]1CCC[C@H](c2nccnc2F)C1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@H]1CCC[C@H](c2nccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 150 °C

Procedure:
A mixture of (rac)-trans-3-(3-fluoropyrazin-2-yl)cyclohexanol (35 mg, 0.178 mmol), as prepared according to Scheme 35a, 4-(pyridin-2-ylamino)phenol (66.4 mg, 0.357 mmol), and cesium carbonate (116 mg, 0.357 mmol) in NMP (1 ml) was heated in a Biotage™ microwave reactor at 150° C. for 30 min. The mixture was partitioned between H2O (10 ml) and CH2Cl2 (20 ml), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and the resulting brown oil was purified by reversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95% H2O/MeCN, 0.1% TFA). The product containing fractions were combined, neutralized by the addition of solid Na2CO3, and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to deliver (rac)-trans-3-(3-(4-(pyridin-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol as a tan solid. MS (ESI, pos. ion) m/z: 363.0(M+1). IC50 (uM) 0.01049.
Reaction SMILES: [CH2:1]([C:3]1[C:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)=[N:14][N:15]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]1.CC(O)=O>C(O)C>[CH2:1]([C:3]1[C:10]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=3)=[N:14][N:15]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]1)[CH3:2]
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2cccc(-c3nnc(-c4ccc(OC(C)C)c(C(F)(F)F)c4)s3)c2CC)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a solution of 2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}benzaldehyde (D6) (54 mg) and ethyl 4-piperidinecarboxylate (101 mg) in ethanol (10 mL) stirred at room temperature was added AcOH (0.037 mL). The reaction mixture was stirred at room temperature for 10 min. Then the solvent was removed by evaporation. To the residue was added dichloromethane (DCM) (10 mL) and sodium triacetoxyborohydride (82 mg). Stirring continued for 2 h. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic phases were washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated to afford the crude product ethyl 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)methyl]-4-piperidinecarboxylate (D7) (72.1 mg). MS (ES): C29H34F3N3O3S requires 561. found 562.1 (M+H+).
Reaction SMILES: [CH2:1]1C2C(=CC=CC=2)C[C:2]1=[O:10].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:2]1([OH:10])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:17][CH2:1]1
Reactant: Cc1ccccc1
Reactant: O=C1Cc2ccccc2C1
Product: OC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 3-neck 500 mL round-bottomed flask fitted with a condenser and an addition funnel was charged with 2.62 g (0.11 mol) of Mg turnings and 20 mL of anhydrous diethyl ether. Slow addition of a solution of 25.10 g (0.09 mol) of 3,5-bis(trifluoromethyl) bromobenzene in diethyl ether (100 mL), followed by refluxing for 30 min, gave a brown-grey solution of the aryl Grignard reagent. The solution was cooled to room temperature (RT), filtered over a plug of Celite and evacuated to yield a brown oil. Toluene (40 mL) was added and the suspension cooled to 0° C. whereupon a solution of 2-indanone (9.22 g, 0.07 mol) in toluene (60 mL) was added dropwise to give a tan-brown slurry. This mixture was warmed to room temperature and stirred for an additional 3 hours. After cooling to 0° C. it was quenched with 150 mL of water, hexane (200 mL) added and the reaction mixture neutralized with 5 M HCl. The organic layer was separated, and the aqueous layer was extracted with two 50-mL portions of hexane. The combined organic layers were washed with two 50-mL portions of brine and dried over anhydrous magnesium sulfate. After filtration over Celite, the solvent was removed under vacuo yielding 21.5 g (89% based on 2-indanone) of 2-(bis-3,5-trifluoromethylphenyl) indanol as an off-white solid. 1H NMR (CDCl3, 23 C, 400 MHz): d 8.05 (s, 2H), 7.80 (s, 1H), 7.5-7.0 (M, 4H), 3.41 (m, 4H), 2.21 (s, 1H, OH). Under argon, this alcohol (21.5 g, 0.06 mol) and p-toluene-sulfonic acid monohydrate (800 mg) were dissolved in toluene (250 mL) and the solution was heated to reflux for 6 hours to afford 14.4 g, (70%) of 2-(bis-3,5(trifluoromethyl)-phenyl) indene upon recrystallization from diethyl ether/hexane at −18 C. 1H NMR (CDCl3, 23° C., 400 MHz): d 8.01 (s, 2H), Arf), 7.75 (s, 1H, Arf), 7.52 (d, J=7 Hz, 1H), 7.47 (d, J=7 Hz, 1H), 7.43 (s, 1H), 7.33 (dd, 2J=7 Hz, 1H), 7.27 (dd, 2J=7 Hz, 1H), 2.83 (s, 2H). 13C NMR (CDCl3, 23 C, 100 MHz): L144.3 (s), 143.1 (s), 138.0 (s), 132.1 (q, 2JC—F=33 Hz), 130.1 (d, JC—H=167 Hz), 127.0 (dd), JC—H=160 Hz, 2JC—H=7 Hz), 126.0 (dd, JC—H=159 Hz, 2JC—H=7 Hz)m 125.2 (brd, JC—H=162 Hz), 123.9 (dd, JC—H=156 Hz, 2JC—H=9 Hz), 123.4 (q, JC—F=273 Hz, CF3), 121.8 (dd, Jc-H=160 Hz, 2JC—H=8 Hz), 120.6 (brd, JC—H=167 Hz), 38.9 (td, JC—H=127 Hz, JC—H=7 Hz, CH2). C,H analysis: Anal. Found (Calcd): C, 62.45 (62-20); H 3.01 (3.07).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])([O-])=O>CO>[NH2:2][C:5]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(S(C)(=O)=O)cc1N
Reaction time: 3 h
Yield: 20.4 %

Procedure:
Concentrated hydrochloric acid (90 ml) was added to a stirred suspension of methyl 2-nitro-4-methylsulphonylbenzoate (25 g) in methanol at -5° C. (ice/salt bath). The cooling bath was then removed and iron dust (17.5 g) was added portionwise over a period of 20 minutes. The resulting exotherm was controlled using a cooling bath so that the temperature did not exceed 50° C. After 15 minutes of cooling, the bath was removed and the reaction mixture was allowed to reach room temperature. Stirring was continued for a further 3 hours. The mixture was poured onto ice and then neutralised with sodium carbonate. Dichloromethane was added and the suspension was filtered. The filtrate was extracted with further dichloromethane and the combined organic extracts were dried (magnesium sulphate), filtered and evaporated to yield a crude product which was purified by recrystallisation from ethyl acetate/hexane to give methyl 2-amino-4-methylsulphonylbenzoate (4.5 g) as yellow needles, m.p. 98.3-98.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:19][CH2:20][CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:24](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:19][CH2:20][CH3:21])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:24])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCCC(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Product: CCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-hexanoyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow oil, MS (ESI+): m/z=362 [M+H]+.
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:37])[C@H:24]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:37])=[O:22])[CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc3ccccc3c2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to β-(2-naphthyl)-L-alanine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.