Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[N:6][C:7]([CH2:11][CH2:12][CH3:13])=[CH:8][C:9]=1[NH2:10])[CH3:2].C[Al](C)C.CO[C:20](=O)[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[N:28]=1>ClCCCl>[CH2:1]([N:3]1[C:4]2[CH:5]=[N:6][C:7]([CH2:11][CH2:12][CH3:13])=[CH:8][C:9]=2[N:10]=[C:20]1[CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[N:28]=1)[CH3:2]
Reactant: CCCc1cc(N)c(NCC)cn1
Reactant: COC(=O)Cn1ccnc1-c1cccc(F)n1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: CCCc1cc2nc(Cn3ccnc3-c3cccc(F)n3)n(CC)c2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N3-ethyl-6-propyl-pyridine-3,4-diamine (82 mg, ˜0.45 mmol, contaminated with ˜10% of N-(4-amino-6-propyl-pyridin-3-yl)-acetamide) in 1,2-dichloroethane (4 mL) at room temperature under N2 is treated with 2.0 M AlMe3 (0.69 mL, 1.37 mmol). The resulting solution is stirred at room temperature for 30 min and then treated with a solution of [2-(6-fluoro-pyridin-2-yl)-imidazol-1-yl]-acetic acid methyl ester (97 mg, 0.41 mmol) in 1,2-dichloroethane via cannula, followed by a 1 mL rinse. The reaction mixture is then stirred at reflux overnight. After cooling, it is treated with MeOH (˜2 mL) and then further diluted with saturated aq NaHCO3 (˜10 mL) and some H2O. The mixture is stirred vigorously for 15 min and then extracted thrice with CHCl3 containing some (˜5%) MeOH. The combined extracts are dried over K2CO3 and concentrated. The crude material is purified by preparative thin layer chromatography. Developing with 15:1 CHCl3-MeOH yields 3-ethyl-2-{[2-(6-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-6-propyl-3H-imidazo[4,5-c]pyridine as an off-white solid. 1H NMR (CDCl3, 300 MHz) δ 8.70 (d, J=0.9 Hz, 1H), 8.17 (dd, J=8.0, 2.6 Hz, 1H), 7.89 (q, J=7.8 Hz, 1H), 7.47 (s, 1H), 7.22 (d, J=0.9 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H), 6.88 (dd, J=8.6, 2.9 Hz, 1H), 6.27 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 2.86 (m, 2H), 1.78 (sextet, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H) ppm. Electrospray MS: m/z 365 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[NH:12][C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:11])[C:3]=1[NH:12][C:13](=[O:28])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:15]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1OC1CCCC1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cc(N)cc2Cl)cc1OC1CCCC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A solution of N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.5 g) in glacial acetic acid (22 mL) is treated with iron pin dust (1.3 g) and the mixture is heated with stirring at 90° C. for 1 hour. The reaction mixture is cooled, basified to pH 8 by treatment with saturated aqueous sodium carbonate solution, and extracted with ethyl acetate (2×150 mL). The combined organic extract is dried over magnesium sulfate and concentrated in vacuo, to give a white solid. This solid is subjected to flash chromatography, eluting with a mixture of ethyl acetate and pentane (1:1 v/v), to give N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.8 g), m.p. 170-172° C. [Elemental analysis: C, 54.8; H, 5.04; N, 6.5; Cl, 17.4%; calculated: C, 57.7; H, 5.1; N, 7.1; Cl, 17.9%].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.Cl.C(O[C:14](=N)[CH2:15][Cl:16])C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:14]([CH2:15][Cl:16])=[N:9][C:4]=2[CH:3]=1
Reactant: CCOC(=N)CCl
Reactant: Nc1ccc(Br)cc1N
Agent: Cl
Product: ClCc1nc2cc(Br)ccc2[nH]1

Procedure:
Using the procedure for Step D in Example 1 (as described in J. Med. Chem., 1986, 29, 2280), the title compound was prepared from 4-bromo-benzene-1,2-diamine (200 mg, 1.07 mmol) and 2-chloroacetimidic acid ethyl ester hydrochloride salt (168 mg, 1.07 mmol) and was obtained as an off-white solid (240.3 mg, 92% yield). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.75 (d, 1H, J=1.4 Hz), 7.47 (d, 1H, J=8.6 Hz), 7.74 (dd, 1H, J=8.6 Hz, J=1.3 Hz), 4.84 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C18H20ClN3O2S: 247.50 (M+H), Found 247.0.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]=1/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH3:4].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:20][C:19](=[O:21])/[CH:18]=[CH:17]/[C:6]2[CH2:7][CH2:8][C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC1=C(/C=C/C(=O)O)CCc2cc(OC)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC1=C(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)CCc2cc(OC)ccc21

Procedure:
As in Example 113, (E)-3-(1-butyl-3,4-dihydro-6-methoxy-2-naphthalenyl)-2-propenoic acid (1.8 g) was reacted with 4-nitrophenol (0.97 g) in dichloromethane (30 mL) in the presence of 1,3-dicyclohexylcarbodiimide (1.3 g) overnight at room temperature. The normal work up yielded 1.5 g of crude ester. Crystallization from diethyl ether-2-propanol furnished (E)-3-(1-butyl-3,4-dihydro-6-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester, mp 94°-95° C. Anal. Calcd for C24H25NO5 : C, 70.74; H, 6.18; N, 3.44 Found: C, 70.42; H, 6.04; N, 3.29
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=[C:14]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Yield: 100 %

Procedure:
A solution of above tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (4 g) and HCl in dioxane (7.46 ml, 4M) was stirred for 4 hours. Concentration gave 3.58 g of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([P:36](=[O:38])=[O:37])[N:3]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:24][CH2:25][CH2:26][NH:27][C:28]2[C:33](Cl)=[CH:32][N:31]=[CH:30][C:29]=2Cl)[CH:18]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH:14]([CH3:16])[CH3:15])(=[O:6])=[O:5].CP(C)(C(=O)N(C1C=C(C)C=C(OCCNC2C(Cl)=C(Cl)C=NC=2)C=1)S(C1C=CC=CC=1OC(C)C)(=O)=O)=O>>[CH3:39][C:2]([CH3:1])([P:36](=[O:37])=[O:38])[N:3]([C:17]1[CH:18]=[C:19]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:20]=[C:21]([CH3:23])[CH:22]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH:14]([CH3:16])[CH3:15])(=[O:6])=[O:5]
Reactant: Cc1cc(OCCNc2c(Cl)cncc2Cl)cc(N(C(C)(C)P(=O)=O)S(=O)(=O)c2ccccc2OC(C)C)c1
Agent: Cc1cc(OCCNc2cncc(Cl)c2Cl)cc(N(C(=O)P(C)(C)=O)S(=O)(=O)c2ccccc2OC(C)C)c1
Product: Cc1cc(OCCNc2ccncc2)cc(N(C(C)(C)P(=O)=O)S(=O)(=O)c2ccccc2OC(C)C)c1

Procedure:
was produced in a 35% yield analogously to example 5. Oil. MS (m/e)=532. For this 2-isopropyloxy-benzene-sulfonyl chloride was used in step 5c) instead of 2-methoxy-benzenesulfonyl chloride and N-(3-cyanomethoxy-5-methyl-phenyl)-2-(2-propyloxy)-benzenesulfonamide (Fp. 100°-102° C.) was obtained in a 21% yield which was reacted analogously to example 5d) to form N-(dimethyloxophosphinyl-methyl)-N-(3-cyanomethoxy-5-methyl-phenyl)-2-(2-propyloxy)-benzenesulfonamide (65% Fp. 137°-140° C.) and this was reacted analogously to example 5e) to form N-(dimethyloxophosphinyl-methyl)-N-[3-(2-amino-ethoxy)-5-methyl-phenyl]-2-(2-propyloxy)-benzene sulfonamide (75% oil, MS (m/e)=454) which was reacted analogously to example 5f) to form a mixture of N-(dimethyloxophosphinyl-methyl)-N-{3-[2-(3,5-dichloro-pyridin-4-ylamino)-ethoxy]-5-methyl-phenyl}-2-(2-propyloxy)-benzenesulfonamide and N-(dimethyloxo-phosphinyl-methyl)-N-{3-[2-(3,4-dichloro-pyridin-5-ylamino)-ethoxy]5-methyl-phenyl}-2-(2-propyloxy)-benzenesulfonamide (quant., oil, MS (m/e)=601) from which the title compound was obtained analogously to example 5g) by catalytic hydrogenation.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:43]1[CH:48]=CC(C(C)C)=C[C:44]=1B(O)O.[OH-].[K+]>O1CCOCC1.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]>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:43]([CH3:48])=[CH2:44])[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Br)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CC(C)c1ccc(Cl)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: C1COCCO1
Product: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (38 mg, 0.059 mmol) in 1,4-dioxane (0.5 mL) was added (2-chloro-5-isopropylphenyl)boronic acid (10 mg, 0.12 mmol), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (II) (2.4 mg, 5 mol %) and aqueous potassium hydroxide (40 μL, 3M, 2 eq.). The reaction mixture was purged with nitrogen and then sealed in a microwave vessel. The reaction vessel was subject to microwave irradiation at 140° C. for 20 min. Crude mixture was worked up with water and EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude product. This was purified by preparative TLC plate eluted by 20% EtOAc in hexanes to give the titled compound. LC-MS: 610.04 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.84 (s, 1H), 7.64-7.70 (m, 2H), 7.56 (s, 0.5), 7.45-7.50 (m, 1.5H), 7.18-7.23 (m, 1H), 7.02 (d, J=9.0 Hz, 0.5H), 6.99 (d, J=8.5 Hz, 0.5H), 6.67 (d, J=7.0 Hz, 0.5H), 6.64 (d, J=5.5 Hz, 0.5H), 5.52 (d, J=8.0 Hz, 0.5H), 5.43 (d, J=8.5 Hz, 1H), 5.26 (d, J=8.0 Hz, 0.5H), 5.13-5.17 (m, 1H), 4.91 (d, J=15.0 Hz, 0.5H), 4.86 (d, J=15.5 Hz, 0.5H), 4.04 (d, J=15.5 Hz, 0.5H), 3.83 (d, J=15.5, 0.5H), 3.70-3.78 (m, 3H), 3.14-3.25 (m, 1H), 2.18-2.22 (m, 3H), 1.14-1.29 (m, 6H), 0.50 (d, J=6.5 Hz, 1.5H), 0.31 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[C:6]([CH:11]1[CH2:13][CH2:12]1)=[CH:7][N:8](C)C)[CH3:2].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25]N.Cl>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[N:25]([C:19]2[C:18]([Cl:17])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:24])[N:8]=[CH:7][C:6]=1[CH:11]1[CH2:13][CH2:12]1)=[O:15])[CH3:2]
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C1CC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C2CC2)cnn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
To a solution of 3-Cycloproply-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester (6.5 mmol, 1.4 g) in ethanol (25 mL) is added 2,6-dichlorophenyl hydrazine hydrochloride (7.2 mmol, 1.5 g) followed by concentrated HCl (100 μL). The reaction is stirred for 4 h at room temperature followed by heating at 85° C. for 18 h. The reaction mixture is adsorbed onto silica gel and purified using a gradient of 0-20% EtOAc/Hexanes to yield the title compound (0.8 g, 34%). LC-ES/MS m/e 325.0 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1([F:22])[CH2:18][CH2:17][CH:16](C(=O)C)[CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[F:12][C:13]1([F:22])[CH2:18][CH2:17][CH:16]([OH:9])[CH2:15][CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)C1CCC(F)(F)CC1
Solvent: ClC(Cl)Cl
Product: OC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.361 g meta-chloro-perbenzoic acid were added into a solution of 0.262 g 1-(4,4-difluoro-cyclohexyl)-ethanone in 5 ml chloroform. The reaction was stirred at rt for 2 hours when TLC indicated consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone. The solution was poured into saturated sodium hydrogencarbonate solution and extracted with chloroform (3×50 ml). The combined organic phases were passed through a phase separator concentrated in vacuo. The crude product was resuspended in methanol (5 ml) and 10% aq. potassium carbonate solution. (5 ml) and stirred at rt over a weekend. The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution. The organic phases were separated and the aqueous phase was extracted with methylene chloride (3×25 ml). The combined organic phases were passed through a phase-separator, concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 petroleum ether/diethylether).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[C:9](/[CH2:11]P(OCC)(OCC)=O)\[CH3:10])=[O:7].[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C=O)C>[C:20]1(=[CH:11][C:9]([CH3:10])=[CH:8][C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (a 60% liquid paraffin dispersion, 1.8 g, 40 mmol) in DMF (60 mL) was added triethyl 3-methyl-4-phosphonocrotonate (11 g, 41.6 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added cyclohexanone (3.93 g, 40 mmol), and the mixture was stirred for 3 hours. Water was added to the reaction solution and the product was extracted with diisopropyl ether. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain oily crude resultant product of ethyl 4-cyclohexylidene-3-methyl-2-butenoate. To a mixed solution of this compound in THF (160 mL) and methanol (40 mL) was added a 12 N aqueous sodium hydroxide solution (4.0 mL) at room temperature, and the mixture was stirred for 16 hours, and then was concentrated under reduced pressure. To the residue was added water and hydrochloric acid, and the mixture was acidified, which was extracted with ethyl acetate. The organic layer was washed with water, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the crude resultant product of 4-cyclohexylidene-3-methyl-2-butanoic acid. To a mixture of this compound (6.1 g, 33.8 mmol) in acetic acid (150 mL) was added sodium acetate (12 g, 33.8 mmol) at room temperature, and the mixture was heated under reflux under argon atmosphere for 24 hours. The solvent was concentrated under reduced pressure, water was added to the residue, which was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 5.1 g (yield 63%) of the title compound. Oily matter.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6](Cl)[N:5]=1.[OH-:21].[Na+]>>[NH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[CH2:17][C@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]2)=[C:6]([O:21][CH2:17][CH2:13][CH2:14][CH3:15])[N:5]=1
Reactant: [OH-]
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [H-]
Agent: [Na+]
Product: CCCCOc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1

Procedure:
A flask was charged with sodium hydride (60% oil dispersion 300 mg, 7.5 mmol) which was then washed with hexanes before the addition of butanol (10 mL) containing (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (800 mg, 3 mmol) from Example 4. The solution was stirred at reflux for 2 hours and then neutralized by the addition of 1.0 N NaOH. Concentration of the solution afforded the crude product which was purified by elution from a silica gel column with 5% methanol-chloroform; (810 mg, 94%). Crystallization of such a sample from ethanol/acetonitrile gave an off-white powder, m.p. 122-123° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21][CH2:22][C@H:23]4[CH2:25][O:24]4)=[C:16]([CH2:26][CH3:27])[CH:15]=3)[N:10]=2)[CH:6]=[C:5]([CH3:28])[N:4]=1)[CH3:2].[NH3:29]>CO>[NH2:29][CH2:25][C@@H:23]([OH:24])[CH2:22][O:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([C:11]2[N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:28])[N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=3)[O:13][N:12]=2)=[CH:15][C:16]=1[CH2:26][CH3:27]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H]4CO4)c(CC)c3)no2)cc(C)n1
Reactant: N
Solvent: CO
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@H](O)CN)c(CC)c3)no2)cc(C)n1

Procedure:
A solution of (R)-2-ethyl-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (201 mg, 0.531 mmol) in 7 N NH3 in MeOH (20 mL) is stirred at 65° C. for 24 h. The solvent is evaporated and the residue is dried under HV to give (R)-1-amino-3-{2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-propan-2-ol (183 mg) as a pale yellow oil; LC-MS: tR=0.69 min; [M+1]+=397.18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12]C(C3C=CC=C(OC)C=3O[Si](C(C)C)(C(C)C)C(C)C)[N:10]([C:32]([C:34]3[C:39]([F:40])=[CH:38][C:37]([F:41])=[CH:36][C:35]=3[F:42])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[CH2:43]([O:45][C:46]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][O:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([CH:62]=O)[C:57]=2[O:64][CH2:65][C:66]#[N:67])[N:49]=1)=[O:47])[CH3:44]>>[CH2:43]([O:45][C:46]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54][O:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([CH:62]3[N:10]([C:32](=[O:33])[C:34]4[C:35]([F:42])=[CH:36][C:37]([F:41])=[CH:38][C:39]=4[F:40])[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[S:12]3)[C:57]=2[O:64][CH2:65][C:66]#[N:67])[N:49]=1)=[O:47])[CH3:44]
Reactant: COc1cccc(C2SC(c3ccc(F)cc3)=NN2C(=O)c2c(F)cc(F)cc2F)c1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: CCOC(=O)c1cccc(COc2cccc(C=O)c2OCC#N)n1
Product: CCOC(=O)c1cccc(COc2cccc(C3SC(c4ccc(F)cc4)=NN3C(=O)c3c(F)cc(F)cc3F)c2OCC#N)n1

Procedure:
6-{2-Cyanomethoxy-3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-pyridine-2-carboxylic acid ethyl ester is prepared in a similar manner as described for [5-(4-fluoro-phenyl)-2-(3-methoxy-2-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone in example 3 using 6-(2-cyanomethoxy-3-formyl-phenoxymethyl)-pyridine-2-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.1 (d, J=7.9 Hz, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.54-7.58 (m, 3H), 7.05-7.14 (m, 3H), 7.01 (d, J=7.3 Hz, 1H), 6.96 (d, J=8.9 Hz, 1H), 6.76 (t, J=8.5 Hz, 2H), 5.4 (s, 2H), 5.12 (d, J=4.4 Hz, 2H), 4.5 (q, J=7.2 Hz, 2H), 1.45 (t, J=7.3 Hz, 3H); LC/MS (ES+): 651.2 (M+1)+.
Reaction SMILES: C[N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][NH:5][CH2:6]2.[CH2:10](N)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:5]1[CH2:6][CH:7]2[NH:2][CH:3]([CH2:9][CH2:8]2)[CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN1C2CCC1CNC2
Reactant: NCc1ccccc1
Product: c1ccc(CN2CC3CCC(C2)N3)cc1

Procedure:
Was prepared in the same manner as 8-methyl-3,8-diazabicyclo[3.2.1]octane, from benzylamine instead of methylamine.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:5]=1[Br:12].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:12][C:5]1[CH:6]=[C:7]([F:11])[C:8]([F:10])=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1cc(F)c(F)cc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1cc(F)c(F)cc1Br
Temperature: -78 °C
Yield: 120.2 %

Procedure:
A solution of 2-bromo-4,5-difluoro-benzoic acid methyl ester (1.45 g, 5.78 mmol) in toluene (42 mL) was cooled at −78° C. under nitrogen. Diisobutylaluminum hydride (1 M in toluene) (7.51 mL, 7.51 mmol) was added drop-wise over 20 minutes. The reaction mixture was stirred at −78° C. for another hour, and then allowed to warm to room temperature overnight. The reaction mixture was then cooled to 0° C. and quenched with ethyl acetate, followed by addition of saturated Rochelle's salt solution. The biphasic slurry was then allowed to warm to room temperature and stirred for 2 hours. The organic layer was collected, dried over sodium sulfate, filtered, and concentrated to afford crude (2-bromo-4,5-difluoro-phenyl)-methanol (1.55 g, 90%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[N:8]1.[BH4-].[Na+].C(OCC)(=O)C>CO>[CH3:15][Si:2]([CH3:1])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([CH:12]([OH:14])[CH3:13])[CH:9]=[N:8]1
Reactant: CC(=O)c1cnn(COCC[Si](C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)c1cnn(COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-(1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethanone (39.7 mg, 0.17 mmol) in methanol (2 mL) was mixed with sodium borohydride (12.5 mg, 0.34 mmol) and stirred at room temperature for 90 minutes. After completion of the reaction, the reaction solution was mixed with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (43.7 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14][CH2:13]1)#[N:9]>C(Cl)Cl>[NH2:18][CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:8]#[N:9])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCC#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCCN1CCC(N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (1.21 g, 10.62 mmol) was added to a solution of tert-butyl [1-(2-cyanoethyl)piperidin-4-yl]carbamate (0.27 g, 1.06 mmol) in DCM (11 mL), and the mixture was stirred at rt for 2 h. The mixture was evaporated and the product was used without any further purification.