Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[C:13]2[NH:14][CH:15]=[CH:16][C:12]=2[C:11]([C:17]2[CH:18]=[N:19][N:20]([C@@H:22]3[CH2:27][CH2:26][C@H:25]([CH2:28][S:29]([C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[C:33]#[N:34])=[O:30])[CH2:24][CH2:23]3)[CH:21]=2)=[N:10][CH:9]=1.C1C=C(Cl)C=C(C(OO)=[O:47])C=1.CC#N.O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[C:13]2[NH:14][CH:15]=[CH:16][C:12]=2[C:11]([C:17]2[CH:18]=[N:19][N:20]([C@@H:22]3[CH2:27][CH2:26][C@H:25]([CH2:28][S:29]([C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[C:33]#[N:34])(=[O:47])=[O:30])[CH2:24][CH2:23]3)[CH:21]=2)=[N:10][CH:9]=1
Reactant: N#Cc1ccccc1S(=O)C[C@H]1CC[C@@H](n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1S(=O)(=O)C[C@H]1CC[C@@H](n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-[(cis-4-[4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl)sulfinyl]-benzonitrile (prepared as in Example 687A, 17.2 mg, 0.0000400 mol) (21 mg TFA salt), was dissolved in DCM (10 mL) and cooled to 0° C. To this mixture was added MCPBA (18 mg, 0.0000800 mol). The resulting mixture was stirred for 1 h at 0° C., and then for 16 h at rt. HPLC and LCMS showed 80 area % product, and 3 area % sulfoxide. The MCPBA was removed using a sat'd NaHCO3 wash, and the resulting washed mixture was concentrated by roto-evaporation. The product was isolated by prep HPLCMS using a 19 mm×100 mm C18 column; 23% CH3CN—H2O (0.1% TFA), 1.0 min, to 43% at 6 min; 30 mL/min; detector set at m/z 447 nm; retention time, 5.1 min. The product was isolated from the eluent by freeze-drying. The yield was 5 mg of the TFA salt. 1H NMR (d6-DMSO) δ 12.70 (br s, 1H, NH); 8.83 (s, 1H); 8.82 (s, 1H); 8.41 (s, 1H); 8.21 (dd, 1H); 8.16 (dd, 1H); 8.01 (td, 1H); 7.95 (td, 1H); 7.78 (s, 1H); 7.19 (s, 1H); 4.34 (m, 1H, NCH); 3.62 (d, 2H); 2.28 (m, 1H); 2.10 (m, 2H); 1.90 (m, 2H); 1.72 (m, 4H). MS (ES) 447 (M+1).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:3]=1[CH:4]=[O:5].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:20][CH:21]=2)[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2C=O)cc1
Temperature: 90 °C

Procedure:
2,6-Dichloro-4-(trifluoromethyl)benzaldehyde (406 mg, 1.7 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (150 mg, 0.8 mmol), Pd(dppf)Cl2 (81 mg, 0.1 mmol) and K3PO4 (769 mg, 3.3 mmol) were dissolved in wet 1,4-dioxane (20 mL) and the resulting mixture was heated to 90° C. After 10 h the resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1)(=[O:23])[CH3:22]
Reactant: COC(=O)CCc1cccc(Oc2ccnc(N)c2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CCc1cccc(Oc2ccnc(NC(C)=O)c2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 772.6 %

Procedure:
Methyl 3-{3-[(2-aminopyridin-4-yl)oxy]phenyl}propanoate (390 mg, 0.14 mmol) was dissolved in pyridine (5 mL) and the reaction mixture was cooled at 0° C. and stirred for 1 h. Acetic anhydride (135 μL, 0.14 mmol) was added dropwise and the reaction mixture was allowed to stir for 1 h. The reaction mixture was allowed to warm to rt and to stir overnight. The reaction was quenched with water and extracted with EtOAc. The organic solutions were dried (MgSO4), filtered and concentrated. The residue was purified column chromatography to give the title compound (340 mg, 76%) as a white solid. LCMS: (FA) ES+ 315.29 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:22])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13](Br)[CH:14]=1)#[N:2].[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:22])[N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[C:13]([CH:24]=[CH:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:14]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1cc(Br)cn(-c2ccccc2)c1=O
Reactant: C=Cc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1-c1cc(C=Cc2ccccn2)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 15 %

Procedure:
A mixed liquid of 100 mg of 3-(2-cyanophenyl)-1-phenyl-5-bromo-1,2-dihydropyridin-2-one, 100 mg of 2-vinylpyridine, 6 mg of palladium acetate, 17 mg of tri-(o-tolyl)phosphine and 3 ml of triethylamine was stirred at 130° C. for 2 hours in nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added thereto. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 16 mg of the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[C:17]([O:19][CH:20]([CH3:22])[CH3:21])[C:16]([Cl:23])=[CH:15][C:14]=2[F:24])[C:4](=[O:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[Na]>C(O)CC>[Cl:23][C:16]1[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:18][C:13]([N:3]2[C:4](=[O:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=[C:2]2[O:12][CH2:4][CH2:5][CH3:6])=[C:14]([F:24])[CH:15]=1
Reactant: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: [Na]
Solvent: CCCO
Product: CCCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 2-chloro-1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone and sodium propylate in n-propanol there is obtained 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-2-propoxy-4-trifluoromethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.31 ppm (d,1H), 6.80 ppm (d,1H), 6.59 ppm (s,1H), 4.31-4.51 ppm (m,3H), 1.67 ppm (m,2H), 1.38 ppm (d,3H), 1.37 ppm (d,3H), 0.85 ppm (t,3H);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH3:15])[CH:9]=1)=[O:6].[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5]([N:7]([CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH3:15])[CH:9]=1)=[O:6])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CSc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2cccc(N)c2)c1
Product: CSc1cccc(N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)C(=O)c2cccc(NC(C)=O)c2)c1
Yield: 80.7 %

Procedure:
Using 3-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(3-methylthiophenyl)benzamide (196.7 mg, 0.40 mmol) and acetic anhydride (0.046 ml, 0.48 mmol), the procedure of Inventive Example 94 was repeated to obtain 172.2 mg (80.7%) of the title compound in a light brown amorphous form.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][N:7]=[CH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[C:12]([O:14][CH3:15])=[O:13]>C(OCC)(=O)C.[Fe]>[NH2:19][C:18]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[CH:8]=[N:7][O:6][CH3:5]
Reactant: CON=Cc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CON=Cc1cc(C(=O)OC)ccc1N

Procedure:
In a 5-liter three-necked round-bottomed flask was placed 0.9 l of 5% aqueous acetic acid and 157 g (2.8 moles) of iron. To the resulting well-stirred mixture was added 166.6 g (0.7 moles) of the previously prepared methyl 3-methoxyiminomethyl-4-nitrobenzoate dissolved in 0.9 l of ethyl acetate followed by dropwise addition of 0.9 l of acetic acid while keeping the temperature below 35° C. The resulting mixture was stirred at 35° C. for 30 minutes and filtered through diatomaceous earth. The filtrate was poured into 5 l of water. The aqueous phase was separated and washed with ethyl ether (2×500 mL). The combined organic layers were washed sequentially with water (4×500 mL), saturated aqueous sodium bicarbonate (2×500 mL), water (2×500 mL), and brine (1×400 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent removed using a rotary evaporator yielding 130 g of the expected methyl 4-amino-3-methoxyiminomethylbenzoate.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5].[O:23]([CH2:30][CH2:31][NH2:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[O:23]([CH2:30][CH2:31][NH:32][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:4]#[N:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(-c3cccnc3)c(C#N)c(NCCOc3ccccc3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h

Procedure:
Compound D (150 mg, 483 μmol), 2-phenoxyethylamine (127 μl) and sodium hydrogencarbonate (400 mg) were added to DMSO (3 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate to give the object compound of 2-(2-phenoxyethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-(pyridin-3-yl)nicotinonitrile (82 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.CCN(C(C)C)C(C)C.N.CO>CN(C=O)C>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: Cc1cccc(C(=O)O)c1N
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cccc(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To solution of 2-amino-3-methylbenzoic acid (4.0 g, 26.5 mmol) in degassed DMF (40 mL) were added HOBt (4.28 g, 31.7 mmol), DIEA (5.52 mL, 31.7 mmol), and 2N NH3/MeOH (19 mL, 37.1 mmol). The solution was stirred at rt for 16 h, then the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 10-60% EtOAc/hexanes to afford 2-amino-3-methylbenzamide as a solid (2.52 g, 63%). 1H NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 6.40-6.47 (m, 3H), 7.06 (m, 2H), 7.42 (d, 1H), 7.72 (br d, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19]CC([O:23][CH2:24][CH3:25])=O.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C.C(O)(C)C>[ClH:19].[C:13]1([CH2:12][N:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:25][C:24]2=[O:23])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCO
Product: O=C1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
A mixture of N,N'-dibenzylethylenediamine (24.0 g., 0.1 mole), ethyl chloroacetate (V, 24.51 g., 0.2 mole), anhydrous sodium carbonate (10 g., 0.094 mole) in ethanol (250 ml.) is heated under reflux for 20 hours. The ethanol is removed under reduced pressure and the residue is partitioned between chloroform and water. Evaporation of the chloroform gives an oil which is dissolved in isopropanol (200 ml.) and acidified with ethereal hydrogen chloride. The precipitate of 1,4-bis(phenylmethyl)piperazinone hydrochloride is filtered off and recrystallized from isopropanol, m.p. 209°-212°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[C:16](Cl)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)(C)(C)C.[ClH:27]>>[Cl:27][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[CH:21]2)=[CH:16][C:15]=1[O:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccc3cnccc3c2Cl)CC1
Reactant: Cl
Product: N[C@H]1CC[C@H](Oc2cc3ccncc3cc2Cl)CC1
Reaction time: 48 h

Procedure:
18 mg (0.05 mmol) trans-[4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (10) were stirred in 2 M HCl at room temperature. After 2 days, the solvent was removed i. vac. and the residue was purified by preparative HPLC. 8 mg of the title compound could be obtained as trifluoro acetate. Rt=0.69 min (Method #1). Detected mass: 277.2/279.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](OCC)=[O:34].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:32]([CH2:31][CH2:30][CH2:29][CH2:28][C:20]3[S:19][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[C:33]2=[O:34])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCCc1nc2ccccc2s1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCc2nc3ccccc3s2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 6-(benzothiazol-2-yl)hexanoate (1.5 eq., prepared according to the procedure of Example 13 in JP, A, 8-208631 (1996)) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(benzothiazol-2-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 167.5 to 169.5° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]1(=[O:13])[O:12][CH2:11][CH2:10]1.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1CCO1
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCSc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
p-Fluorothiophenol (5 g, 40 mmol) and β-propiolactone (2.8 g, 40 mmol) were dissolved in THF (36 mL of freshly distilled) and then placed in an ice bath. 95% sodium hydride (1 g, 42.9 mmol) was added in small portions over 1 hour. The reaction was allowed to stir at 0° C. for 2 hours, then placed in the freezer overnight. The reaction was quenched with ice chips and then acidified with concentrated hydrogen chloride until a pH of 2. The product was extracted with ethyl acetate (1×200 mL) and dichloromethane (2×200 mL), dried (sodium sulfate) and concentrated to give 3-[(4-fluorophenyl)sulfanyl]propanoic acid (7.08 g, 89%). 1H NMR (CDCl3, 300 MHz): δ 7.42–7.35 (m, 2H), 7.02 (t, 2H, J=8.6 Hz), 4.35 (t, 1H, J=6.2 Hz), 3.10 (t, 2H, J=7.3 MHz), 2.63 (t, 2H, J=7.3 Hz) ppm.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH:6]2[CH2:10][NH2:11])[CH2:3][CH2:2]1.[CH3:12][O:13][C:14]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([S:26](=[O:29])(=[O:28])[NH2:27])=[C:19]([CH3:30])[C:15]=1[C:16](Cl)=[O:17]>CC(CC)=O>[CH:1]1([CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH:6]2[CH2:10][NH:11][C:16](=[O:17])[C:15]2[C:19]([CH3:30])=[C:20]([S:26](=[O:29])(=[O:28])[NH2:27])[CH:21]=[C:22]([CH:23]([CH3:25])[CH3:24])[C:14]=2[O:13][CH3:12])[CH2:2][CH2:3]1
Reactant: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)Cl
Reactant: NCC1CCCN1CC1CC1
Solvent: CCC(C)=O
Product: COc1c(C(C)C)cc(S(N)(=O)=O)c(C)c1C(=O)NCC1CCCN1CC1CC1
Temperature: 10 °C
Yield: 23.6 %

Procedure:
4.3 g of 1-cyclopropylmethyl-2-aminomethylpyrrolidine (0.028 mole) and 40 ml of methylethyl ketone are placed in 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The mixture is cooled to about 10° C. and a solution of 7.6 g of 2-methoxy-3-isopropyl-5-sulphamoyl-6-methyl benzoyl chloride (0.025 mole) in 50 ml of methyl-ethyl-ketone is poured in drop by drop. The mixture is reacted for 1 hour at room temperature then evaporated dry under vacuum, and the residue is dissolved in 100 ml of water and 10 ml of hydrochloric acid (density 1.18). The solution is sucked up under vacuum to eliminate the last traces of solvent, an insoluble component is filtered off and the filtrate is made alkaline with 15 ml of ammonia (density=0.91). The precipitate formed is filtered, washed with water and re-crystallised moist in 50 ml of ethyl acetate. 2.5 g (24%) of product is obtained, melting at about 125° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[N:13]([CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:12]=[C:11]([NH:21][C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([F:32])[CH:23]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.S1C=CC=C1>C1COCC1.[Ni]>[F:32][C:24]1[CH:23]=[C:22]([NH:21][C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][N:3]=[CH:2][C:7]=3[CH3:8])[N:13]([CH2:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:12]=2)[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=1
Reactant: Cc1c(-c2cc(Nc3cc(F)cc(C(F)(F)F)c3)nn2CCC(=O)N(C)C)ccnc1Cl
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: Cc1cnccc1-c1cc(Nc2cc(F)cc(C(F)(F)F)c2)nn1CCC(=O)N(C)C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
E1 (0.40 g; 0.85 mmol) was dissolved in THF (50 ml) and then Et3N (0.5 ml), 10%, RaNi (0.1 g) and thiophene solution (0.1 ml) were added. The reaction mixture was stirred under H2 pressure overnight. The solvent was evaporated in vacuo and then H2O (10 ml) was added. The water phase was extracted by EtOAc (3×30 ml), the combined organic layers were washed by brine, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by reversed-phase high-performance liquid chromatography (Shandon Hyperprep® C18 BDS (Base Deactivated Silica) 8 μm, 250 g, I.D. 5 cm). A gradient with 2 mobile phases was applied. Phase A: a 0.25% NH4HCO3 solution in water; phase B: CH3CN). The fractions were collected and worked-up. The desired fraction yielded 0.25 g of E9 (67.55%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:11]([C:14]1[O:15][CH2:16][C@@H:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=1)[CH2:12][CH3:13])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1>ClCCl.[Cu](Br)Br>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:11]([C:14]1[O:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=1)[CH2:12][CH3:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](C1=N[C@H](C(=O)OC)CO1)[C@@H](C)NC(=O)OC(C)(C)C
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC[C@@H](c1nc(C(=O)OC)co1)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.4 %

Procedure:
A solution of (S)-methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)-4,5-dihydrooxazole-4-carboxylate (1.62 g, 5.14 mmol) in anhydrous dichloromethane (15 mL+15 mL+6 mL washing) was added via a glass Pasteur pipette to a stirred suspension of copper(II) bromide (4.60 g, 20.61 mmol), hexamethylenetetramine (2.89 g, 20.61 mmol) and DBU (3.11 ml, 20.61 mmol) in anhydrous dichloromethane (20 mL). The thick suspension was stirred at room temperature for 1.5 hours-HPLC analysis (at 220 nm) indicated complete consumption of starting material and desired product formation. The reaction was partitioned between dichloromethane (20 mL) and a mixture of 10% NH4OH solution and saturated aqueous ammonium chloride solution (1:1, 30 mL). The aqueous phase was extracted with dichloromethane (3×25 mL). The combined organic phase was then washed with 10% NH4OH solution and saturated aqueous ammonium chloride solution (1:1, 30 mL), and a mixture of 1N HCl:brine (1:1, 30 mL). The organic layer was then dried (MgSO4) and evaporated in vacuo to give the crude product which was purified by column chromatography using ethyl acetate-hexane as eluent to give methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylate (711 mg, 2.28 mmol, 44.2% yield) as an oil. 1H NMR (400 MHz, CCl3D) δ 8.20 (s, 1H), 5.00 (d, J=9.0 Hz, 1H), 4.17-3.99 (m, 1H), 3.92 (s, 3H), 2.94 (dt, J=9.6, 5.4 Hz, 1H), 1.95-1.70 (m, 2H), 1.42 (s, 9H), 1.10 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.4 Hz, 3H). LC/MS: M+H+313.08, ret. time=0.93 min. Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(N)nc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
To a solution of 5-trimethylsilanylethynyl-pyridin-2-ylamine (32.1 g, 169 mmol) in THF (150 mL) and methanol (350 mL) at 0° C. was added potassium carbonate (2.33 g, 16.9 mmol) and the mixture was stirred at 0° C. for 5 h. It was diluted with ice water (500 mL), extracted with tert-butylmethylether (3×500 mL), washed the combined organic layers with brine and dried over magnesium sulfate. Concentration left a dark brown solid, which was dissolved in hot ethyl acetate and precipitated with n-heptane trituration to give the 5-ethynyl-pyridin-2-ylamine (14.61 g, 73%) as a light brown solid. MS: m/e=118.1 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][C:20]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[CH2:13][CH2:12]2)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([CH2:19][C:20]1([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[CH2:13][CH2:12]2
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(OCc4ccccc4)ccc3C2)COC(C)(C)OC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(CN2CCc3cc(O)ccc3C2)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of the product of Example 38, Step E, (0.13 g; 0.27 mmol) and 10% Pd/C (0.3 g) in EtOAc (15 ml) was vigorously stirred at room temperature for 3 h under H2 (balloon). The catalyst was removed by filtration through the Celite pad, washed with CH2Cl2 (2×10 ml) and combined filtrates were evaporated to dryness under reduced pressure to give the title compound (0.105 g; 99%) as colourless solid. 1H-NMR (CDCl3) 1.4 (s, 3H); 1.42 (s, 9H); 1.44 (s, 3H); 2.7-2.85 (m, 4H); 2.91 (s, 2H); 3.8 (s, 2H); 3.82 (d, 2H, J=11.6 Hz); 4.05 (d, 2H, J=11.6 Hz); 4.98 (broad s, 1H); 5.5 broad s, 1H); 6.52-6.6 (m, 2H); 6.76 (d, 1H, J=8.2 Hz).