Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)N.[OH:14]S(O)(=O)=O.N([O-])=O.[Na+]>O>[F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:14])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(S(F)(F)(F)(F)F)c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
5.0 g of 3-pentafluorosulfanylaniline were suspended in 50 ml of a 35% aqueous H2SO4 solution. Then, at 0° C., a solution of 1.57 g of NaNO2 in 5 ml of water was added dropwise over the course of 10 minutes. The mixture was stirred at 0° C. for 40 minutes. Then a solution, cooled to 0° C., of 8.56 g of Cu(NO3)2 in 50 ml of water was added to this suspension. Immediately thereafter, 3.26 g of Cu2O was also added, whereupon marked evolution of gas was observable. 3 extractions each with 100 ml of CH2Cl2 were carried out, the org. phase washed with 100 ml of a saturated aqueous NaCl solution and dried over MgSO4, and the solvent was removed in vacuo. Chromatography with DIP on a short silica gel column afforded 3.5 g of the phenol as colorless oil.
Reaction SMILES: [CH:1]1([C:4]([O:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]3[O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[CH:11][CH:10]=2)=[O:5])[CH2:3][CH2:2]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH:1]1([C:4]([O:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH:16]3[O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)=[CH:13][CH:14]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)C3CC3)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCCc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1)C1CC1

Procedure:
In an analogous manner to that described in Example 22(l), by cleavage of the BOC group from tert-butyl (3RS,4RS)-4-[4-(2-cyclopropylcarbonyloxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate using trifluoroacetic acid in methylene chloride there was obtained (3RS,4RS)-2-[4-(3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-ethyl cyclopropanecarboxylate trifluoroacetate as a white solid; MS: 430 (M+H)+.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[Cl:11].C([Li])CCC>C1COCC1>[Cl:11][C:5]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:4]=1[C:3]#[CH:2]
Reactant: Clc1ccc(C=C(Br)Br)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1,1-dibromo-2-(2,4-dichlorophenyl)ethene (14 g, 42.4 mmol) in THF (100 ml) at −78° C. under nitrogen was treated with butyllithium (1.6 M solution in hexane, 28 ml, 44.8 mmol). after being stirred for 1 hour at −78° C., the reaction mixture was warmed to room temperature and stirred for another hour. The reaction was quenched with water and the product was extracted with hexanes. The extract was dried over MgSO4, filtrated and concentrated in vacuo to give the product. (Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769)
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:16]1([NH:15][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[NH:7][C:6]([C:2]2[S:1][CH2:5][CH2:4][N:3]=2)=[CH:14]3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1cccc2cc(C3=NCCS3)[nH]c12
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: c1cc(NC2CCCC2)c2[nH]c(C3=NCCS3)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.5 %

Procedure:
[2-(4,5-Dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-amine (15 mg, 0.07 mmol) prepared in Step A was dissolved in 1,2-dichloroethane (10 mL). Cyclopentanone (12 mg, 0.14 mmol) and sodium triacetoxyborohydride (29 mg, 0.14 mmol) were added thereto, and the mixture was stirred for 3 h at room temperature. The reaction was quenched by water, and the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (6.7 mg, Yield 34%).
Reaction SMILES: [C:1]([CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18](=O)[CH2:19][CH2:20][CH3:21])(=[O:6])=[O:5])#[N:2].Cl>[OH-].[Na+]>[CH2:19]([C:18]1[NH:17][C:8]2[CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=[CH:12][C:7]=2[S:4](=[O:6])(=[O:5])[C:3]=1[C:1]#[N:2])[CH2:20][CH3:21]
Reactant: CCCC(=O)Nc1cc(C(F)(F)F)ccc1S(=O)(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCC1=C(C#N)S(=O)(=O)c2ccc(C(F)(F)F)cc2N1
Temperature: 0 °C
Yield: 85.1 %

Procedure:
N-(2-Cyanomethylsulfonyl-5-trifluoromethylphenyl)butyramide (0.41 g) in 0.5 M aqueous NaOH (5 ml) was stirred at room temperature for 2 h. The mixture was cooled to 0° C. and 1M HCl (4 ml) was added. After 30 min the precipitate was collected by filtration and dried to give 0.33 g (85%) of the title compound; mp 199.5-200.5° C.; El SP/MS: 316 (M+); 1H-NMR(CD3OD) δ (ppm): 8.16 (d, 1H); 7.73 (d+s, 2H); 4.88 (br, H2O+NH); (dd, 2H), 1.88 (sextet, 2H), 1.06 ppm (t, 3H).
Reaction SMILES: [C:1]([C@@:4]12[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([OH:14])[CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:3])[CH3:2].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20]Cl.C(N(CC)CC)C>C1COCC1>[C:1]([C@@:4]12[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:3])[CH3:2]
Reactant: COCCOCCl
Reactant: CC(=O)[C@]12CCCC[C@@]1(O)CCCC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOCO[C@]12CCCC[C@@]1(C(C)=O)CCCC2

Procedure:
A mixture of 100 mmol of 4a-acetyl-8a-hydroxy-cis-decalin, 110 mmol of 2-methoxyethoxymethyl chloride, 110 mmol of triethylamine, and 200 ml of THF was refluxed for 3 hours. The resulting reaction mixture was subjected to column chromatography on a silica gel to yield 4a-acetyl-8a-(2-methoxyethoxymethoxy)-cis-decalin represented by the following formula (yield: 90.3%). The conversion rate from 4a-acetyl-8a-hydroxy-cis-decalin was 95%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][C:13]2[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=2[CH3:23])=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (0.70 g, 4.093 mmol, see preparation 1) in CH2Cl2 (6 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (0.74 g, 4.093 mmol, see preparation 12), and triethylamine (0.83 g, 8.187 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 2.60 g, 8.187 mmol) is added via syringe and stirred at ambient temperature. After 12 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes to give the title compound as an off-white solid (1.10 g, 81%). Mass spectrum (m/z): 333.2 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].C(N(CC)CC)C.[C:40]([CH2:44][C:45](Cl)=[O:46])([CH3:43])([CH3:42])[CH3:41]>C1COCC1.C(OCC)(=O)C>[CH3:17][CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:6]=1[NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:45](=[O:46])[CH2:44][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:21][CH:20]=1)[CH3:16]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a cooled (0° C.) solution of (S)-α-amino-N-[2,6-bis(1-Methylethyl)phenyl]-4-(phenylmethoxy)benzenepropanamide (1.15 g, 2.67 mmol) and triethylamine (0.37 mL, 2.67 mmol) in THF (50 mL) was added tert-butylacetylchloride (0.39 mL, 2.80 mmol) dropwise. The resulting slurry was warmed to 25° C. and stirred (1 hour, 25° C.). The resulting slurry was diluted with ethyl acetate (200 mL). The organic layer was washed with 1.0N aqueous HCl (1×65 mL), with brine (1×65 mL), with saturated aqueous sodium bicarbonate (1×65 mL), with brine again (1×65 mL), then dried (MgSO4) and concentrated. The resulting oil was triturated with ether, and cooled. The resulting solid was collected by filtration, washed with cold ether, and dried in a vacuum oven at 40° C. to yield 1.2 g (85.1%) of the title compound as a white solid, melting point 209°-211.5° C.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC)=O.CCN(CC)CC.[F:30][C:31]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:32]=1[C:33](=[NH:36])[NH:34][NH2:35]>C1COCC1>[F:30][C:31]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:32]=1[C:33](=[NH:36])[NH:34][NH:35][C:14](=[O:16])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:10]([CH3:11])([CH3:12])[CH3:13]
Reactant: N=C(NN)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)NNC(=N)c1cc(F)ccc1F)C(C)(C)C
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
The N-Boc-D-tert-butylglycine (7.5 g, 32.4 mmol) was converted to a mixed anhydride by adding ethyl chloroformate (3.41 mL, 35.6 mmol), Et3N (6.8 mL, 48.6 mmol) in anhydrous THF (65 mL, 0.5 M) at −5° C. to 0° C. The mixture was stirred at −5° C. for 30 min. The resulting solid was filtered off and additional anhydrous THF was added to wash the precipitate. The resulting reaction solution was then added to a THF solution of 2,5-difluorobenzimido-hydrazide (5.53 g, 32.4 mmol) at −5° C. Then the reaction was gradually warmed to room temperature and stirred for overnight. Once the reaction was complete, the mixture was partitioned between EtOAc and H2O. The organic layer was separated and washed with H2O, brine, then dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give the crude product, which was purified on silica gel column (50% EtOAc in Hexanes) to afford (R)-tert-butyl 1-(2-((2,5-difluorophenyl)(imino)methyl)hydrazinyl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (67%). Rf=0.4 (50% EtOAc in Hexanes). LC/MS (uplc): MH+ 385.3, 0.65 min.
Reaction SMILES: [OH:1][Li].O.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:17][C:14]3([CH2:16][CH2:15]3)[N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2=[O:25])=[CH:7][CH:6]=1>O.CO.C1COCC1>[C:21]([O:20][C:18]([NH:13][C:14]1([CH2:17][CH:11]([C:8]2[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=2)[C:12]([OH:25])=[O:1])[CH2:16][CH2:15]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(c2ccc(Cl)cc2)CC12CC2
Reactant: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CC(C(=O)O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A solution of LiOH hydrate (0.24 g, 5.7 mmol) in water (2 mL) was added to a stirred solution of tert-butyl 6-(4-chlorophenyl)-5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (0.46 g, 1.4 mmol) in MeOH (2 mL) and THF (2 mL). The reaction was stirred at room temperature overnight. The solvents were evaporated in vacuo. The residue was taken up in water and extracted with ether (2×). The aqueous phase was acidified by 2N HCl and extracted with EtOAc. The combined organic phases were washed with brine, dried and concentrated to give 3-(1-(tert-butoxycarbonylamino)cyclopropyl)-2-(4-chlorophenyl)propanoic acid (0.41 g, 84%) as a white solid. LCMS (APCI+) [M-Boc+H]+ 240.0; Rf: 2.38 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[N:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To a solution of 3-hydroxy-6-methylpyridine (5.00 g, 45.8 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (2.02 g, 50.4 mmol, 60% in oil) at 0° C., and the solution was stirred for 15 minutes at 0° C. Then, benzyl bromide (5.99 mL, 50.4 mmol) was added at 0° C., and the solution was stirred for 3.5 hours at room temperature. The reaction solution was partitioned in water and ethyl acetate. This organic layer was separated, washed with water and brine and dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=2/1), and the title compound (5.99 g, 66%) was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:20][O:21][C:22](=[O:29])[C@H:23]([C@H:25]([CH2:27][CH3:28])[CH3:26])[NH2:24]>C(Cl)(Cl)Cl.CO>[CH3:20][O:21][C:22](=[O:29])[C@H:23]([C@H:25]([CH2:27][CH3:28])[CH3:26])[NH:24][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)OC

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example D11 above) and L-isoleucine methyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.15 in 97:3 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:17]=[N:18][NH:19][CH:20]=4)=[CH:14][N:13]([CH2:21][O:22]CC[Si](C)(C)C)[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[N:1]1([C:7]2[C:8]3[C:15]([C:16]4[CH:20]=[N:19][NH:18][CH:17]=4)=[CH:14][N:13]([CH2:21][OH:22])[C:9]=3[N:10]=[CH:11][N:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2cn[nH]c2)c2c(N3CCOCC3)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: OCn1cc(-c2cn[nH]c2)c2c(N3CCOCC3)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
4-(Morpholin-4-yl)-5-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C20) (0.13 g, 0.32 mmol) was dissolved in trifluoroacetic acid (10 mL) and stirred at room temperature for 2 hours. Removal of solvent in vacuo provided the product (100 mg) as a brown solid; this was used in the next step without further purification. LCMS m/z 301.2 [M+H+].
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CN(C=O)C>[CH:1]1([NH:9][C:15]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[C:12]=2[C:13]#[N:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1c(F)cccc1F
Reactant: NC1CCCCCCC1
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1NC1CCCCCCC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.2 %

Procedure:
Cyclooctylamine (1.4 mL; 10 mmol) was added dropwise to a solution of 2,6-difluorobenzonitrile (1.39 g, 10 mmol) in DMF (6 ml) at 0° C. The reaction mixture was stirred at room temperature for 4.5 hours. The reaction mixture was added to vigorously stirred ice water (40 ml) and extracted with ethyl acetate. Solvent was removed to yield 1.63 grams of 2-cyclooctylamino-6-fluorobenzonitrile.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([Br:15])=[CH:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]1[CH2:21][O:22]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1N(COCC[Si](C)(C)C)C(COC)=C(C(OCC)=O)C=1>>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([Br:15])=[CH:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]1[CH:21]=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(Br)n(COCc2ccccc2)c1COC
Agent: CCOC(=O)c1cc(Br)n(COCC[Si](C)(C)C)c1COC
Product: CCOC(=O)c1cc(Br)n(COCc2ccccc2)c1C=O
Yield: 95 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 15-(f) except for using 895 g (purity: 85.1%, 1.99 mol) of ethyl 1-benzyloxymethyl-5-bromo-2-methoxymethyl-1H-pyrrol-3-carboxylate obtained in Reference example 17-(b) in place of ethyl 5-bromo-2-methoxymethyl-1-(2-trimethylsilylethoxymethyl)-1H-pyrrol-3-carboxylate, whereby 805 g (purity: 86.3%) of the title compound was obtained as a brownish oil. (Yield: 95%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:16][C:13]([NH:17]C(=O)OC(C)(C)C)([CH2:14][CH2:15]1)[CH2:12][CH2:11][CH2:10]2.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]12[CH2:16][C:13]([NH2:17])([CH2:14][CH2:15]1)[CH2:12][CH2:11][CH2:10]2
Reactant: CC(C)(C)OC(=O)NC12CCCC(C#Cc3ccccn3)(CC1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC12CCCC(C#Cc3ccccn3)(CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a solution of tert-butyl 5-(pyridin-2-ylethynyl)bicyclo[3.2.1]octan-1-ylcarbamate (1.1 g, 3.37 mmol) in DCM (5.0 mL) was added 2,2,2-trifluoroacetic acid (2.0 mL). After stirring at room temperature for two hours, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with ethyl ether (10 mL) to remove non-amine organic impurity. The aqueous layer was basified with NaOH to pH=12 and then extracted with DCM (3×10 mL). The combined DCM layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 600 mg (78%) of the title compound, 5-(pyridin-2-ylethynyl)bicyclo[3.2.1]oct-1-ylamine. 1HNMR (500 MHz, CDCl3): δ 8.51 (d, J=5.0 Hz, 1H), 7.59-7.56 (m, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.16-7.13 (dd, J=7.0, 5.0 Hz, 1H), 2.42 (s, 2H), 2.15-1.54 (m, 12H); ESI-MS m/z: 227 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH:31][C:11](=[O:13])[C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3cccc(Oc4ccccc4)c3)cc2s1

Procedure:
The title compound is prepared by following General Method A, using 3-phenoxy-benzoic acid (0.22 g, 1.04 mmol), and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.20 g, 0.80 mmol) to afford an off-white solid (0.19 g, 53%). LC/MS: Retention time=4.45 nm in; (m/z): calcd for C25H2(N4O2S (M+H)+: 447.6; found: 447.3.
Reaction SMILES: [C:1]1([C:7]2[C:16]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]([O:28]C)=[O:27])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:32]I.Cl>C1COCC1>[CH3:32][N:17]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[C:16]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:26]([OH:28])=[O:27])=[CH:11][CH:10]=2
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N[C@H](C)c3ccccc3)nc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (R)-methyl 2-phenyl-3-(1-phenylethylamino)quinoxaline-6-carboxylate (141 mg, 0.37 mmol, 1.00 equiv) in THF (20 mL), sodium hydride (294.5 mg, 7.36 mmol, 20.00 equiv, 60%). The resulting solution was stirred for 1 h at room temperature in an ice/salt bath. This was followed by the addition of a solution of CH3I (522.8 mg, 3.68 mmol, 10.00 equiv) in THF (1 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 20° C. The pH value of the solution was adjusted to 3-4 with 1N aqueous hydrogen chloride. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 57 mg (39%) of (R)-3-(methyl(1-phenylethyl)amino)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[CH2:8][CH2:7][O:6][CH:5]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:2]2[S:10][C:9]3[CH2:8][CH2:7][O:6][CH:5]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=3[CH:3]=2)[CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NCC1OCCc2sc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCC1OCCc2sc(-c3cccnc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of tert-butyl (2-bromo-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl)methylcarbamate (500 mg, 1.44 mmol), pyridine-3-boronic acid (351 mg, 2.88 mmol), Pd(OAc)2 (33 mg), PPh3 (170 mg, 0.65 mmol) in 1,4-dioxane was purged with nitrogen. After stirring at room temperature for 0.5 hr, 457 mg of Na2CO3 in 3 mL of H2O was added. The reaction mixture was stirred at 100° C. for 2 hr. After cooling to room temperature, the reaction mixture was poured into 100 mL of water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography to give the desired product.
Reaction SMILES: [F:1][C:2](=[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[O:17][C:16]([CH3:24])([CH3:23])[CH:15]=[C:14]2[CH3:25])[CH2:9][CH3:10])[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C>>[F:1]/[C:2](=[C:8](/[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[O:17][C:16]([CH3:24])([CH3:23])[CH:15]=[C:14]2[CH3:25])\[CH2:9][CH3:10])/[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)=C(CC)c1cc2c(cc1OC)OC(C)(C)C=C2C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC/C(=C(\F)CO)c1cc2c(cc1OC)OC(C)(C)C=C2C

Procedure:
Following General Procedure L, ethyl 2-fluoro-3-(7-methoxy-2,2,4-trimethyl-2H-chromen-6-yl)-pent-2-enoate (Compound 77, 195 mg, 0.56 mmol) and a diisobutylaluminum hydride (1 M in hexanes, 1.68 mL, 1.68 mmol) were reacted to give the title compound as yellow solid after purification by flash chromatography (silica gel, 1:4 ethyl acetate/hexane).