Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[C:31](I)[C:26]=5[N:25]=[N:24]4)[CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[C:33]([O-:36])([O-])=O.[Na+].[Na+].[C:39]1(C)[CH:44]=CC=C[CH:40]=1.CCO>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:36]1[CH:33]=[CH:44][C:39]([C:31]2[C:26]3[N:25]=[N:24][N:23]([C:21]4[CH:20]=[CH:19][N:18]=[C:17]([NH:16][CH:13]5[CH2:14][CH2:15][CH:10]([C:8]([N:5]6[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]6)=[O:9])[CH2:11][CH2:12]5)[N:22]=4)[C:27]=3[CH:28]=[CH:29][CH:30]=2)=[CH:40]1
Reactant: O=C(C1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1)N1CCC(O)CC1
Reactant: Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(C1CCC(Nc2nccc(-n3nnc4c(-c5ccoc5)cccc43)n2)CC1)N1CCC(O)CC1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of (4-hydroxy-piperidin-1-yl)-{4-[4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl-amino]-cyclohexyl}-methanone (274 mg) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-furan (102 mg) was placed in a screw cap pressure flask, and Na2CO3 (2 M aq, 0.7 mL, degassed), toluene (5 mL, degassed) and EtOH (5 mL) added. To this was added Pd(PPh3)4 (20 mg), the flask sealed, and the mixture stirred overnight at 110° C. The reaction mixture was then cooled to RT, diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a crude solid. The crude product was chromatographed on silica, and eluted with 0-60% Magic Base/DCM, titurated in Et2O overnight, filtered, and evaporated to yield {4-[4-(4-furan-3-yl-benzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-(4-hydroxy-piperidin-1-yl)-methanone (Compound 9, 103 mg). mp=243.0-244.0° C.; M+H=488.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1C=O.[CH3:11][S-:12].[Na+].CN([CH:17]=[O:18])C>O>[Cl:1][C:2]1[CH:3]=[CH:6][C:7]([CH:17]=[O:18])=[C:8]([S:12][CH3:11])[CH:9]=1
Reactant: CN(C)C=O
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Product: CSc1cc(Cl)ccc1C=O
Temperature: 50 °C

Procedure:
The subtitle compound was prepared by using 2-chloro-4-fluorobenzaldehyde (1.16 g) in dry DMF (20 ml). The mixture was treated with sodium thiomethoxide (0.52 g) and heated to 50° C. for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, dried and concentrated under reduced pressure to give a solid. The residue was purified by chromatography on silica eluting with isohexane/diethylether 2:1 to give a white solid, yield 0.70 g.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:23])[CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[CH3:24][N:25]([CH2:27][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:23])[CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH3:26]
Reactant: O=C(COc1ccc2ccccc2c1)N1CCc2ccoc2C1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)COc1ccc3ccccc3c1)CC2
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.230 g (0.748 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-2-(2-naphthoxy)ethan-1-one in 20 ml of acetic acid, 0.10 ml (1.1 mmol) of 50% aqueous dimethylamine and 0.092 ml (1.1 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 45 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate/methanol=9/1 to 6/1) to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([S:13][CH3:14])[N:5]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>CN(C=O)C>[CH3:14][S:13][C:4]1[N:5]=[N:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:3]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: Cc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nnc(SC)nc1Nc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (300 mg, 1.29 mmol) was dissolved in 10 mL dry DMF. To it was added p-toluidine (166 mg, 1.55 mmol) and then DIEA (0.45 mL, 2.58 mmol). The mixture was stirred at RT for 1 h. To the mixture were poured 200 mL EtOAc. The mixture was washed with brine twice, dried in MgSO4, and concentrated in vacuo to afford crude ethyl 3-(methylthio)-5-(p-tolylamino)-1,2,4-triazine-6-carboxylate. It was dissolved in 20 mL “7.0 N ammonia in methanol” (Acros, #133710010) and stirred for overnight. Solid slowly crashed out in the reaction flask and a slurry was yielded. The solid was isolated by filtration, washed with hexane and dried in vacuum oven. It was very pure 3-(methylthio)-5-(p-tolylamino)-1,2,4-triazine-6-carboxamide. Yield was 94 mg (26% for 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:25][N:26]=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CN.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](=[O:15])[NH:26][CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
N-tert-butyloxycarbonyl-4-benzylpiperidine-4-carboxylic acid (3.0 g; 9.0 mmol) was dissolved in methylene chloride (25 ml) and EDAC (1.8 g; 9.0 mmol) and HOAt (1.3 g; 9.0 mmol) was added. The mixture was stirred for 15 min, then methyl amine (33% in ethanol; 2.3 ml; 18 mmol) and DIEA (1.6 ml; 9.0 mmol) was added and the mixture was stirred overnight. Methylene chloride (100 ml) was added and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and a aqueous solution of sodium hydrogensulfate (10%, 50 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica (90 g) using a mixture of aqueous ammonia/ethanol/methylene chloride (1:7:92) as eluent to afford 2.8 g of 4-benzyl-4-methylcarbamoylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.ClCCl>C(O)(=O)C.CC(C)=O>[CH3:12][N:13]1[CH2:18][CH2:17][C:16]([NH:4][C:5]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)([C:1]#[N:2])[CH2:15][CH2:14]1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(N)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1ccc(NC2(C#N)CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
Sodium cyanide (0.318 g, 6.5 mmol) was added to a mixture of p-toluidine (0.535 g, 5 mmol) and 1-methyl-4-piperidinone (0.678 g, 6 mmol) in acetic acid 90% (5 ml). The reaction mixture was stirred at room temperature for 6 h and then 100 ml of dichloromethane was added. The organic layer was washed with a solution NaOH, 2N (2×50 ml), dried over magnesium sulfate, concentrated and chromatographed (DCM and then acetone) to obtained 27a (0.722 g, 3.15 mmol, 63%).
Reaction SMILES: C([N:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]=1[F:21])(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:45]([OH:53])(=[O:52])[CH:46]([CH2:48][C:49]([OH:51])=[O:50])[OH:47].[H][H]>O1CCCC1.CCOCC>[F:21][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:12]=1[NH:11][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:16]([O:52][C:45](=[O:53])[CH:46]([CH2:48][C:49]([OH:51])=[O:50])[OH:47])=[O:17]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(=O)C(O)CC(=O)O)cc1F

Procedure:
A warm solution of N-carbobenzyloxy-3-fluoro-4-(hexadecylamino)benzoyl chloride and 1.3 g. triethylamine in 100 ml. ether is treated with 2 g, malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% Pd(C) at 50 psi until hydrogen uptake stops. The catalyst is filtered, and the solution is evaporated. The residue is crystallized from acetic acid to yield O-[3-fluoro-4-(hexadecylamino)benzoyl]malic acid.
Reaction SMILES: N1CCCC[CH2:2]1.C(O[C:10](=O)[CH2:11][N:12]([C:14](=[O:16])C)C)C.[CH3:18][N:19]([CH3:22])[CH:20]=[O:21]>>[CH3:18][N:19]1[CH2:22][C:14](=[O:16])[NH:12][C:11]([CH3:10])([CH3:2])[C:20]1=[O:21]
Reactant: CCOC(=O)CN(C)C(C)=O
Reactant: C1CCNCC1
Reactant: CN(C)C=O
Product: CN1CC(=O)NC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
Piperidine (867 mL) was added to N-[(α,α-dimethyl-(9H-fluoren-9-ylmethoxy)carbamino] acetylsarcosine ethyl ester (743 mg) in N,N-dimethylformamide (20 mL), followed by stirring at room temperature for 1 hour. N,N-Dimethylformamide (60 mL) was added thereto. The resultant mixture was stirred at 80° C. for 14 hours, and cooled in air. The reaction solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, and then to the resultant solution, hexane was added. The precipitated crystals were recovered by filtration, to thereby give the title compound (162 mg, 59%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=1>N1C=CC=CC=1.[Cu]=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Brc1ccccn1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)Cc1cccc(Oc2ccccn2)c1
Temperature: 90 °C
Yield: 76.1 %

Procedure:
2-Bromopyridine (1.1 ml, 11.5 mmol) and potassium carbonate (2.76 g, 20.0 mmol) were added to a solution of methyl 3-hydroxyphenylacetate (1.66 g, 9.99 mmol) in anhydrous pyridine (12 ml). The vigorously stirred reaction mixture was heated to 90° C. under a nitrogen atmosphere and then copper (II) oxide (1.99 g, 25.0 mmol) was added under a positive nitrogen flush. The reaction mixture was heated under reflux for 16 hours, allowed to cool and diluted with dichloromethane. The mixture was filtered through hyflo and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with 1:3 ethyl acetate/petrol (60°-80° ) then 1:2 ethyl acetate/petrol (60°-80° ) to give methyl [3-(2-pyridyloxy)phenyl]acetate as a pale straw-coloured oil (1.85 g, 78%); δH (360 MHz, CDCl3) 3.63 (2H, s, CH2), 3.69 (3H, s, COOCH3), 6.90 (1H, d, J 8 Hz, ArH), 6.99(1H, m, ArH), 7.06 (2H, m, ArH), 7.11 (1H, d, J 8 Hz, ArH), 7.34 (1H, t, J 8 Hz, 5'-H), 7.67 (1H, m, ArH), 8.19 (1H, m, 6"-H), m/z 243 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]1([CH2:14][CH2:15][C:16](Cl)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:8]1([CH2:14][CH2:15][C:16]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:8]1([CH:14]([CH3:15])[CH2:2][NH:1][C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1ccncc1
Reactant: c1ccncc1
Product: CC(CNc1ccncc1)c1ccccc1
Product: O=C(CCc1ccccc1)Nc1ccncc1

Procedure:
β-(phenyl)-N-(4-pyridyl)propionamide is prepared by reacting 4-aminopyridine with β-(phenyl)propionyl chloride in pyridine at room temperature. The amide is reduced to give the title compound by treating a solution of the amide in dry tetrahydrofuran stirred and cooled to 0° C. with diborane in a stream of nitrogen.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]=[C:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.[NH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[SH:26][CH:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28](O)=[O:29].Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][N:13]1[C:8]2([CH2:9][CH2:10][C:5](=[CH:4][CH2:3][CH:2]([CH3:12])[CH3:1])[CH2:6][CH2:7]2)[S:26][CH:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]1=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)CC(S)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)CC=C1CCC(=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)CC=C1CCC2(CC1)SC(CC(=O)O)C(=O)N2CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To 20 ml of toluene were added 1.90 g of 4-(3-methylbutylidene)-1-cyclohexanone and 2.05 g of benzyl 3-aminopropionate, and the mixture was stirred at ambient temperature for one hour. Then, 1.72 g of mercaptosuccinic acid was added, and the resulting mixture was heated under reflux for one hour under the condition of azeotropic dehydration by means of Dean Stark. The reaction mixture was added to a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography [eluent: chloroform:ethanol=50:1] to obtain 3.10 g of 2-[4-[3-(benzyloxy)-3-oxopropyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-2-yl]-acetic acid as a light yellow oily product.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:11][Si:12]([CH2:15][CH2:16][O:17][CH2:18]Cl)([CH3:14])[CH3:13]>C1COCC1>[CH3:11][Si:12]([CH3:14])([CH3:13])[CH2:15][CH2:16][O:17][CH2:18][O:7][CH:4]1[CH2:5][CH2:6][CH:1]([OH:8])[CH2:2][CH2:3]1
Reactant: OC1CCC(O)CC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOC1CCC(O)CC1
Yield: 24.5 %

Procedure:
Cyclohexane-1,4-diol (4 g, 34.8 mmol) was dissolved in THF (200 mL). To this solution was added 95% NaH (0.922 g, 36.6 mmol). The mixture was heated to reflux for 1 hour. Then 10 the reaction was cooled down. SEMCl (6.44 mL, 36.6 mmol) was added dropwise. The reaction mixture was heated to reflux again overnight. THF was removed. The residue was purified by flash chromatography to give the desired product (2.10 g, 16%). MS (DCI/NH3) m/z 247 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.02 (s, 9H) 0.87-0.95 (m, 2H) 1.30-1.38 (m, 2H) 1.57 (m, 1H) 1.64-1.70 (m, 2H) 1.80 (m, 1H) 1.91-2.01 (m, 2H) 3.50-3.70 (m, 4H) 4.69 (s, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:45]1([C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C.O>[O:21]=[C:19]([N:48]1[CH2:49][CH2:50][N:45]([C:51](=[O:52])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:60])[F:61])[CH2:46][CH2:47]1)[CH2:18][NH:17][C:15]([C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)=[O:16]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
DIPEA (0.130 mL, 0.76 mmol) was added to a stirred solution of [(thiophene-2-carbonyl)-amino]-acetic acid (40 mg, 0.22 mmol) in DMF (1 mL). HOBT (35 mg, 0.26 mmol) and EDCI.HCl (49 mg, 0.26 mmol) were added, followed by the addition of piperazine-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (70 mg, 0.24 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford thiophene-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl}-amide in 54% yield. LC-MS purity: 98% 1H NMR (CDCL3): δ 7.78-7.44 (m, 5H), 7.34 (t, 1H), 7.10 (d, 2H), 4.40-4.18 (m, 2H), 4.08-3.82 (m, 2H), 3.80-3.50 (m, 4H).
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[CH3:8][O:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([S:21][C:22]3[CH:27]=[CH:26][C:25](OC(=O)C)=[CH:24][CH:23]=3)=[CH:17][N:16]2[CH:32]=1)=[O:11].CS(C)([O-])=O>O>[C:1]([C:25]1[CH:24]=[CH:23][C:22]([S:21][C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:32]=[C:13]([NH:12][C:10]([O:9][CH3:8])=[O:11])[N:14]=3)[CH:17]=2)=[CH:27][CH:26]=1)#[N:2]
Reactant: COC(=O)Nc1cn2cc(Sc3ccc(OC(C)=O)cc3)ccc2n1
Reactant: [C-]#N
Agent: C[SH](C)(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Nc1cn2cc(Sc3ccc(C#N)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.7 g. of cuprous cyanide and 2.6 g. of finely powdered sodium cyanide in 20 ml. of dimethyl sulfoxide is treated dropwise with a solution of 4.12 g. (0.01 mole) of the diazonium tetrafluoroborate salt of 6-(aminophenylthio)-2-(methoxycarbonylamino) imidazo [1,2-a] pyridine obtained in Example 15 in 10 ml. of dimethyl sulfinate. An exotherm is observed and external cooling is necessary. The reaction mixture is stirred at room temperature for one hour, diluted with water and the solids collected by filtration. The solids are washed with water, dried and recrystallized from dimethylformamide-ethanol (50/50) to yield 6-(p-cyanophenylthio)-2-(methoxycarbonylamino) imidazo [1,2-a] pyridine.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].O[CH2:19][C:20]1[O:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:19][C:20]3[O:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(CO)o1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(CO)o1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 5-(hydroxymethyl)furfural (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: Cl[C:2]1[C:7](C(C)C)=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.[C:12]([O-])(=O)[CH3:13].[Na+].[CH3:17]O>[Pd]>[CH3:11][C:6]1[CH:7]=[C:2]([CH:12]([CH3:13])[CH3:17])[N:3]=[CH:4][N:5]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ncnc(Cl)c1C(C)C
Reactant: CO
Agent: [Pd]
Agent: [Na+]
Product: Cc1cc(C(C)C)ncn1
Yield: 81 %

Procedure:
4-Chloro-5-isopropyl-6-methylpyrimidine (5.0 g, 29 mmol) and sodium acetate (3.1 g, 38 mmol) were combined in 75 ml methanol and hydrogenated over 500 mg 5 percent palladium on carbon for 20 h. After removal of the catalyst by filtration, the solvent was removed by evaporation. The residue was treated with sat. sodium bicarbonate solution and extracted with diethyl ether. The ether extracts were washed with sat. brine, dried (Na2SO4) and evaporated to give 3.2 g (81 percent yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:13]=2)[N:6]=1
Reactant: CCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.114 g, 0.412 mmol) was reacted with N-(2-azidoethyl)decanamide (0.099 g, 0.412 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-decanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), δ 6.57 (s, 1H), δ 6.43 (s, 1H), δ 6.09 (s, 2H), δ 4.38 (s, 2H), δ 3.67 (s, 2H), δ 2.61 (t, 2H), δ 2.08 (s, 2H), 2.08 (t, 2H), δ 1.42 (m, 15H), δ 1.17 (m, 14H), δ 0.79 (t, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 174.2, 149.7, 148.4, 138.8, 121.9, 106.6, 84.9, 49.5, 39.5, 36.7, 32.1, 31.3, 30.6, 29.9, 29.7, 29.6, 29.5, 29.5, 29.3, 29.0, 28.3, 28.2, 25.9, 25.6, 25.5, 22.9, 14.3 ppm; HRMS (ESI) calcd for C27H47N7O3(M+) 517.3740, found 517.3736, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)decanamide hydrochloride (0.137 g, 73% yield). 1H NMR (300 MHz, CD3OD) δ 8.55 (s, 1H), δ 6.53 (s, 1H), 4.72 (s, 2H), δ 3.75 (s, 2H), 2.89 (s, 2H), δ 2.54 (t, 2H), δ 2.16 (t, 2H), δ 1.81 (s, 2H), δ 1.69 (s, 2H), δ 1.49 (m, 4H), δ 1.28 (s, 12H), δ 0.89 (t, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 175.7, 147.3, 128.5, 127.6, 125.1, 120.8, 108.6, 108.4, 105.6, 63.1, 59.3, 52.5, 48.6, 48.3, 48.1, 47.9, 47.7, 47.5, 57.3, 38.7, 336.6, 35.8, 36.6, 35.8, 31.8, 30.6, 29.4, 29.3, 29.3, 29.2, 28.0, 27.8, 27.7, 25.8, 24.1, 23.9, 23.3, 22.6 ppm; HRMS (ESI) calcd for C22H39N7O (M+) 417.3216, found 417.3209.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:9]2[C:22]3[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][C:11](=O)[C:10]2=3)[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>C(O)C>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([CH:9]2[C:22]3[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=3)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCCC2=C1C(c1cccc(C(F)(F)F)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCCC2=C1C(c1cccc(C(F)(F)F)c1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 52 %

Procedure:
A mixture of 9-(3-trifluoromethylphenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (2.0 g), sodium borohydride (2.1 g) and ethanol (50 mL) was heated at 70° C. overnight and cooled to room temperature. The mixture was partitioned between water and ethyl acetate; the organic layer dried, filtered and concentrated. Chromatography (eluant: methylene chloride/methanol; 98/2) and recrystallization from ethanol/hexane provided the title compound (1.0 g) as a yellow solid, m.p. 250°-251° C.; NMR: 1.47-1.52 (m,3, CH2), 1.66-1.90 (m,5, CH2), 2.10-2.15 (m,4, CH2), 2.40-2.45 (m,2, CH2), 4.28 (s,1, CH), 7.45 (s,4, Ar), 8.44 (s,1, NH); (CI, CH4) MS: m/z=348(M+1). Analysis for C20H20F3NO: Calculated C, 69.15; H, 5.80; N, 4.03; Found: C, 69.01; H, 5.83; N, 3.98.