Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COCCOC[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[CH:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27].Cl.[Cl-].[Na+]>C1COCC1>[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]#[N:21])[C:17]3[N:22]=[CH:23][N:24]([CH3:25])[C:16]=3[CH:15]=2)=[CH:10][C:9]=1[C:26]([F:29])([F:28])[F:27]
Reactant: COCCOCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Temperature: 65 °C

Procedure:
6-(4-(2-Methoxy-ethoxymethoxy)-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (7.5 g) was added to a mixed solvent of THF (300 ml) and 1M HCl (aq). The mixture was heated to 65° C. until the full disappearance of all starting material. After adding saturated sodium chloride solution (200 ml), the mixture was extracted with ethyl acetate (300 ml×3), and the combined organic layers were then dried over sodium sulphate, solvent was removed under reduced pressure, and the residue was triturated in ether. Product, 6-(4-hydroxy-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (5.9 g) was collected by filtration. 1H NMR (CD3OD) δ: 8.45 (s, 1H); 8.34 (s, 1H); 8.29 (s, 1H); 8.20 (m, 1H); 7.09 (m, 1H); 4.04 (s, 3H). MS m/z 319 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:7]([CH3:18])=[N:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)C.[NH2:20][NH2:21]>CCO.[Cl-].[Na+].O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[O:9][N:8]=[C:7]([CH3:18])[C:6]=2[CH2:5][C:4]([NH:20][NH2:21])=[O:3])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1c(C)noc1-c1ccc(Br)cc1
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)NN
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-acetic acid ethyl ester (0.114 g, 0.37 mmol) in EtOH (4 mL) was added hydrazine (1M in THF; 2 mL), and the reaction was sealed and stirred at 80° C. overnight. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were washed with H2O and brine, and then dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH:30]([CH3:32])[CH3:31])=[C:13]([C:15]2[NH:28][C:18]3=[N:19][CH:20]=[C:21]([C:23](OCC)=[O:24])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:29][CH:30]([CH3:32])[CH3:31])=[C:13]([C:15]2[NH:28][C:18]3=[N:19][CH:20]=[C:21]([CH2:23][OH:24])[CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2[nH]c(-c3cc(OCc4ccccc4)ccc3OC(C)C)nc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2cc(CO)cnc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a mixture of ethyl 2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridine-6-carboxylate (0.36 g) in tetrahydrofuran (5 ml) was added lithium aluminum hydride (48 mg) under ice-cooling, and the reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. The obtained crude crystals were washed with diethyl ether to give the title compound (0.12 g, yield 37%) as colorless crystals. melting point 167-168(C. purity 98%. M+H: 390.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[C:35](=O)[NH:36][CH2:37][CH2:38][NH:39]C)(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](=[O:21])[N:36]([CH2:37][CH2:38][NH2:39])[CH3:35])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CNCCNC(=O)OC(C)(C)C
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N(C)CCN)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.8 %

Procedure:
A solution of 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (100 mg, 0.25 mmol) in DMF is added (2-methylamino ethyl)-carbamic acid tert-butyl ester (53 mg, 0.25 mmol), HBTU (140 mg, 0.38 mmol), and DIPEA (0.088 mL, 0.51 mmol). After 48 h stirring at room temperature, the resulting mixture is concentrated and diluted with saturated NaHCO3 solution and extracted with ethyl acetate (3×100 mL). The combine organics are dried over Na2CO3 and concentrated to give a reddish residue. Followed by deprotection using General Procedure A to give 2-{5-[(2-amino-ethyl)-methyl-carbamoyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 77%). MS (ESI) m/z 451.3 (M+H)+
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C@H:9]1[C:17]2[C:16]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:15][CH:14]=[N:13][C:12]=2[CH2:11][CH2:10]1>C(Cl)Cl>[CH3:8][C@H:9]1[C:17]2[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:15][CH:14]=[N:13][C:12]=2[CH2:11][CH2:10]1
Reactant: C[C@@H]1CCc2ncnc(C3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (193 μL, 2.50 mmol) was added to a solution of (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidine-1-carboxylate (32 mg, 0.10 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 1 hour and concentrated to give (R)-5-methyl-4-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine as an oil, which was used further without purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:24])[C@:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([OH:17])[C:12]1S[CH:14]=[CH:15][CH:16]=1)[CH2:2]2.[CH:25]1([C@@](O)(C2C=CC=CC=2)C(O)=O)CCCC[CH2:26]1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:24])[C@:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([OH:17])[C:12]1[CH:26]=[CH:25][CH:14]=[CH:15][CH:16]=1)[CH2:2]2
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCCC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@](O)(c1cccs1)C1CCCCC1
Product: O=C(O[C@H]1CN2CCC1CC2)[C@](O)(c1ccccc1)C1CCCCC1

Procedure:
This compound is prepared analogously to (S)-cyclohexyl-hydroxy-thiophen-2-yl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester by replacing (S)-cyclohexyl-hydroxy-thiophen-2-yl-acetic acid with (R)-cyclohexyl-hydroxy-phenyl-acetic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.O>CN(C)C=O>[CH2:39]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]([CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:22]3=[O:30])[CH2:17][CH2:16]2)=[CH:10][CH:11]=1)=[O:5])[CH3:40]
Reactant: BrCc1ccccc1
Reactant: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)c2cccc(OC)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(CCN2CCC(n3c(=O)n(Cc4ccccc4)c4ccccc43)CC2)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
The 1-[3-(4-diethylcarbamoylphenyl)-3-(3-methoxyphenyl)propyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine (50 mg) obtained in Example 1 was dissolved in N,N-dimethylformamide (1 ml), added with sodium hydride (60% in oil, 7.4 mg) and stirred at room temperature for 1.5 hours. The reaction mixture was added with benzyl bromide (22 μl) and further stirred at 60° C. for 2 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was washed with water (10 ml) and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: ethyl acetate:methanol=10:1) to obtain 33 mg of the title compound. Yield: 57%.
Reaction SMILES: N1CCC([N:7]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)CC1.[C:24]([O-])(=O)[CH3:25].[Na+]>C(OC(=O)C)(=O)C>[N:7]1([C:21]2[CH:20]=[CH:19][C:18]([S:15]([N:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]3=[O:14])(=[O:16])=[O:17])=[CH:23][CH:22]=2)[CH2:25][CH2:24][CH2:10][CH2:9][CH2:8]1
Reactant: CC(=O)[O-]
Reactant: O=C(O)CCCCN(C1CCNCC1)S(=O)(=O)c1ccccc1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCCN1S(=O)(=O)c1ccc(N2CCCCC2)cc1
Temperature: 25 °C
Yield: 185.8 %

Procedure:
5 g of product obtained in Stage B are heated to reflux for 4 hours with 5 g of sodium acetate in 50 cm3 of acetic anhydride. The mixture is cooled to room temperature and evaporated to dryness, the residue is taken up in 50 cm3 of water, filtered off and dried and 4.4 g of expected crude product are obtained. M.p. 140°-145° C. After crystallization in ethanol, 3.4 g of pure product are obtained. M.p. 145°-146° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:14](=[O:25])[N:13]2[CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:15]2[CH:16]=[CH:17][C:12]3=[N:11][C:10]([CH2:9][O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:26][N:13]3[C:14]2=[O:25])=[CH:19][CH:20]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1n(-c2ccc(F)cc2)ccc2nc(COc3ccccc3)cn12
Temperature: 90 °C
Reaction time: 16 h
Yield: 149.1 %

Procedure:
Phenol (40 mg, 0.24 mmol) was added to a stirred suspension of 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one (0.107 g, 0.38 mmol) and K2CO3 (0.160 g, 1.15 mmol) in ACN (3 mL). The mixture was stirred at 90° C. for 16 hours and then the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with diethyl ether to yield 6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (0.12 g, 90% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ ppm 5.20 (s, 2H), 6.70 (d, J=7.8 Hz, 1H), 6.98 (t, J=7.2 Hz, 1H), 7.03 (d, J=8.1 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.19-7.25 (m, 2H), 7.27-7.34 (m, 2H), 7.38-7.45 (m, 2H), 7.83 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ccnc(N)c2)c(F)c1
Reaction time: 144 h
Yield: 107.8 %

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (1.246 g) was dissolved in methanol (20 ml)-tetrahydrofuran (10 ml), and then 10% palladium carbon (1.0 g) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring for 6 days. After replacing with nitrogen inside the system, the catalyst was filtered and washed with ethanol. The filtrate was concentrated under a reduced pressure to provide the titled compound (1.182 g, quantitative) as brown crystals.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:17]=[CH:16][C:9]([C:10](N(OC)C)=[O:11])=[C:8]([CH3:18])[CH:7]=1.[Cl-].[NH4+]>C1COCC1>[Br:5][C:6]1[CH:17]=[CH:16][C:9]([C:10](=[O:11])[CH2:1][CH3:2])=[C:8]([CH3:18])[CH:7]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Br)cc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(=O)c1ccc(Br)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethylmagnesium bromide (2.35 ml of 3M in diethyl ether, 7.05 mmol) is added slowly to a stirred solution of 4-bromo-N-methoxy-N,2-dimethylbenzamide (0.91 g, 3.53 mmol) in dry THF (40 ml) at 0° C. The reaction is stirred at 0° C. for 1 h followed by RT for 18 h. The reaction mixture is poured into saturated ammonium chloride solution to quench the reaction and concentrated in vacuo to remove most of the THF. The product is extracted with diethyl ether and the combined organic extracts are dried (MgSO4). The solvent is removed in vacuo and the resulting oil is purified by chromatography on silica eluting with iso-hexane:ethyl acetate (3:1) give the title product as a colourless oil. MS m/z 227.0 [M+H]+1H NMR (400 MHz, CDCl3) δ 1.18 (3H, t), 2.45 (3H, s), 2.88 (2H, d), 7.40 (1H, d), 7.43 (1H, s), 7.50 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Si](C=[N+]=[N-])(C)(C)[CH3:14]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(F)c1
Reaction time: 1 h
Yield: 64.6 %

Procedure:
2-(3-Fluoro-4-hydroxyphenyl)acetic acid (1.0 g, 5.88 mmol) was diluted with THF:MeOH (3:1) (10 mL) followed by the addition of TMSCHN2 (5.88 ml, 11.8 mmol). After stiffing for 1 hour, the reaction was quenched with 2N HCl and diluted with DCM. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified by silica gel chromatography, eluting with hexanes:ethyl acetate (2:1) to yield methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (700 mg, 64.7% yield) as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:40])[N:5]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]#[N:36])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.C(N(CC)[OH:44])C>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:40])[N:5]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[C:35]([NH2:36])=[O:44])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH3:13])=[N:7]2
Reactant: CCN(O)CC
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#N)c3)c(=O)c12
Solvent: ClCCl
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C(N)=O)c3)c(=O)c12
Temperature: 50 °C
Yield: 97 %

Procedure:
A 100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer and a reflux condenser was purged with nitrogen and charged with compound 141 (219 mg, 0.40 mmol) and anhydrous methylene chloride (15 mL). N,N-Diethylhydroxylamine (146 mg, 1.64 mmol) was added to the resulting solution, and the reaction mixture was heated for 16 h at 50° C., cooled to ambient temperature, and then evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography to give a 97% yield of compound 143 as a white solid. m.p. 195-197° C.; 1H NMR (CDCl3) δ (ppm) 8.34 (d, 1H, J=10.9 Hz), 7.59-8.06 (m, 7H), 7.28 (m, 1H), 6.95 (bs, 1H), 6.00 (bs, 2H), 5.60 (s, 2H), 5.28 (bs, 1H), 3.62 (t, 2H, J=8.4 Hz), 2.85 (s, 3H), 1.53 (dd, 3H, J 6.7, 10.8 Hz), 0.96 (t; 2H, J=8.3 Hz), 0.01 (s, 9H); m/z=571 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:14][CH2:13][C:12]([OH:16])=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S)cc1OC
Reactant: C=CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(SCCC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 22.4 h
Yield: 76.7 %

Procedure:
3,4-Dimethoxythiophenol (5.00 g, 29 mmol) was placed in a flask with acrylic acid (2.27 g, 32 mmol) and stirred at room temperature for 22.4 hours. The reaction mixture solidified, was dissolved in ethyl acetate and extracted with 10% Na2CO3. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, dried over MgSO4, and concentrated in vacuo to give 3-(3,4-dimethoxyphenylthio)propanoic acid (5.39 g , 76%), contaminated with some acrylic acid, as a white solid which was used without further purification in the next step: mp 62°-64° C.; 1H NMR (CDCl3) 300 MHz 9.80 (br s, 1H) 7.01 (d, J=8.3 Hz, 1H) 6.98 (s, 1H) 6.82 (d, J=8.3 Hz, 1H) 3.87 (s, 3H) 3.86 (s, 3H) 3.06 (t, J=7.3 Hz, 2H) 2.63 (t, J=7.3 Hz, 2H). Mass spectrum: M+=242.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:26]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:27])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)C1CCCCC1
Product: CCc1noc(-c2sc(NC(=O)C3CCCCC3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and cyclohexanecarbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[C:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)(=[O:11])[CH3:10].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)([OH:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: COC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(C)(O)c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (8.35 mL, 10.9 mmol) was added to a cooled solution of 1-bromo-4-iodobenzene (3.07 g, 10.9 mmol) in THF (8 mL) and the resultant solution was stirred for 1 hour at 0° C. Methyl trans-4-acetylcyclohexanecarboxylate (1.00 g, 5.43 mmol) in THF (2 mL) was added to the reaction mixture, stirred for 1 hour at 0° C. and saturated aqueous ammonium chloride was added. The reaction mixture was extracted with ethyl acetate (2×), and then the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (ethyl acetate/hexanes) gave methyl trans-4-[1-(4-bromophenyl)-1-hydroxyethyl]cyclohexanecarboxylate as a colorless oil. MS ESI calcd. for C16H22BrO3[M+H]+341 and 343. found 341 and 343. 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 3.63 (s, 3H), 2.16 (tt, J=12.3 Hz, 3.6 Hz, 1H), 2.03-1.91 (m, 2H), 1.84 (m, 1H), 1.60-1.53 (m, 2H), 1.52 (s, 3H), 1.36 (m, 2H), 1.11-0.98 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:26]=[CH:25][C:19]([CH2:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH:8][C:22](=[O:23])[CH2:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:27])([F:28])[F:14])=[CH:26][CH:25]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC
Yield: 70.4 %

Procedure:
3,4-Dimethoxyphenethylamine 42a (3.62 g, 3.4 mL, 20 mmol, 1.0 eq) was added to a solution of 4-(trifluoromethyl)hydrocinnamic acid 43 (4.36 g, 20 mmol, 1.0 eq) in toluene (75 mL). After 5 min a thick suspension formed. The suspension was heated to reflux, giving a clear solution. The mixture was heated at reflux for 24 h using a Dean-Stark trap to remove water that was formed. The mixture was partially cooled, diluted with ethyl acetate (100 mL) and concentrated under reduced pressure to near dryness. The thick slurry was diluted with ethyl acetate (200 mL) and the solution washed sequentially with 1N hydrochloric acid (100 mL), aqueous sodium bicarbonate solution (200 mL), water (100 mL) and brine (100 mL). The organic solution was dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The solid was triturated with heptanes (50 mL), filtered and dried to give 5.37 g (70%) of 44a as a white, fluffy solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:20][C:4]1[CH:3]=[C:2]([NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=1
Reactant: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1
Reactant: NC1CCCC1
Product: O=C(Nc1nc2cc(Cl)cc(NC3CCCC3)n2n1)c1cccnc1
Yield: 4.4 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10), 100 mg; 0.32 mmol; 1.0 eq) and cyclopentylamine (161 μL; 1.62 mmol; 5.0 eq) to give the title compound as a white solid (5 mg, 4%). HPLC, Rt: 3.20 min. (purity 92.3%). LC/MS, M+(ESI): 356.9, M−(ESI): 354.9.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=1[CH3:13].[CH2:14]([CH2:16][NH2:17])[OH:15]>>[OH:15][CH2:14][CH2:16][NH:17][C:6](=[O:8])[C:5]1[CH:4]=[C:3]([CH3:13])[C:2]([OH:1])=[C:11]([CH3:12])[CH:10]=1
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Reactant: NCCO
Product: Cc1cc(C(=O)NCCO)cc(C)c1O

Procedure:
A 270 g quantity of methyl 4-hydroxy-3,5-dimethylbenzoate is heated in 300 ml of ethanolamine for 6 hours at a bath temperature of 160° C. while simultaneously removing the methanol which forms by distillation. The excess ethanolamine is removed under vacuum. The glassy product is ground, screened (1 mm screen), and dried thoroughly at 0.5 torr and 60° C. for a yield of 307 g.