Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[C:21]([CH3:22])=[C:20]([N:23]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[O:25])[N:19]3[N:40]=[CH:41][C:42]([C:43]([OH:45])=O)=[C:18]3[N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C([N:49]=C=NCCCN(C)C)C.C(N(CC)CC)C.N>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16]2[C:21]([CH3:22])=[C:20]([N:23]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)=[O:25])[N:19]3[N:40]=[CH:41][C:42]([C:43]([NH2:49])=[O:45])=[C:18]3[N:17]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOc1ccc(C(=O)N(OC(C)(C)C)c2c(C)c(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c(C(=O)O)cnn23)cc1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(=O)N(OC(C)(C)C)c2c(C)c(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc3c(C(N)=O)cnn23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.25 g) in N,N-dimethylformamide (20 mL) were added ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g), N-hydoroxybenzotriazole monohydrate (0.31 g), triethylamine (2.8 mL) and ammonia (5.0 mL, 2.0 mol/L in methanol). The resulting mixture was stirred at room temperature for 24 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH2Cl2, the combined organic layer was washed with water, dried over MgSO4, and the solvent was removed in vacuo to give the crude title compound (1.25 g) as a white solid. This crude product was used in the next reaction without further purification. ESI/MS data for this compound are shown below.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCCCC.[Cl:17][CH2:18][C:19]([CH2:21][Cl:22])=[O:20]>C(OCC)C>[Cl:17][CH2:18][C:19]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1)([OH:20])[CH2:21][Cl:22]
Reactant: O=C(CCl)CCl
Reactant: Fc1ccc(Br)cc1F
Agent: [Li]CCCCCC
Solvent: CCOCC
Product: OC(CCl)(CCl)c1ccc(F)c(F)c1

Procedure:
Preparation according to Preparation 1: 1-bromo-3,4-difluorobenzene (5 g, 25.9 mmol), dry diethyl ether (100 mL), n-hexyllithium (2.3 M in hexane, 11.2 ml, 25.9 mmol) and 1,3-dichloroacetone (3.29 g, 25.9 mol). Yield: 4.54 g (73%). MS m/z (rel. intensity, 70 eV) 241 (M+, 1), 193 (32), 191 (bp), 141 (14), 127 (64).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CO[C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18]C(C)(C)C(C)(C)[O:15]2)=[CH:10][CH:9]=1.Cl>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[OH:23][C:7]1([C:8]2[CH:9]=[CH:10][C:11]([B:14]([OH:15])[OH:18])=[CH:12][CH:13]=2)[CH2:2][CH2:1]1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Product: OB(O)c1ccc(C2(O)CC2)cc1
Temperature: -78 °C
Reaction time: 12 h

Procedure:
A 3.0 M solution of ethylmagnesium bromide in diethylether (7.6 mL) is added to a stirred solution of titanium(IV) isopropoxide (2.2 mL) in diethylether (70 mL) chilled to −78° C. The resultant solution is stirred at −78° C. for 1.5 h, before 4-(4,4,5,5-tetramethyl-[1,3,2]dioxa borolan-2-yl)-benzoic acid methyl ester (2.0 g) is added. The reaction mixture is warmed to ambient temperature and stirred for an additional 12 h. Then, 1 M aqueous hydrochloric acid is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The residue is dissolved in acetone (60 mL) and 0.1 M aqueous NH4OAc solution (50 mL) followed by NalO4 (2.3 g) is added. The resulting reaction mixture is stirred at room temperature for 18 h. After removal of the acetone, the residue is extracted with ethyl acetate. The combined extracts are dried (sodium sulphate) and the solvent is evaporated. The residue is purified by chromatography on silicagel (cyclohexane/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]1[C:15]([C:16]2[C:17]([NH2:31])=[N:18][CH:19]=[C:20](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)=[N:14][N:13]=[N:12]1.Br[C:33]1[S:37][C:36]([CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[C:35]([CH3:51])[CH:34]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=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]>[NH2:31][C:17]1[N:18]=[CH:19][C:20]([C:33]2[S:37][C:36]([CH:38]3[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[CH2:42][CH2:43]3)=[C:35]([CH3:51])[CH:34]=2)=[CH:21][C:16]=1[C:15]1[N:11]([C:3]2[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([F:8])[C:2]=2[F:1])[N:12]=[N:13][N:14]=1
Reactant: Cc1cc(Br)sc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(-n2nnnc2-c2cc(B3OC(C)(C)C(C)(C)O3)cnc2N)c(F)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-n2nnnc2-c2cc(-c3cc(C)c(C4CCN(C(=O)OC(C)(C)C)CC4)s3)cnc2N)c(F)c1F
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
To a solution of 3-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (Compound 1106, 200 mg, 0.4649 mmol) and tert-butyl 4-(5-bromo-3-methylthiophen-2-yl)piperidine-1-carboxylate (Compound 1054, 167.5 mg, 0.4650 mmol) in DMF (8 mL) was added a solution of NaHCO3 (2.509 g, 1.162 mL of 1.2 M, 1.395 mmol). The mixture was degassed under a nitrogen stream for 20 minutes. PdCl2(dppf) (34.02 mg, 0.04650 mmol) was added and the reaction was stirred for 10 minutes at 120° C. under microwave irradiation. The mixture was diluted with EtOAc, filtered, and the filtrate was washed with water. The organics were dried over magnesium sulfate, concentrated, and the resulting residue purified via silica gel chromatography to give tert-butyl 4-(5-(6-amino-5-(1-(2,3-difluoro-4-methoxyphenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-3-methylthiophen-2-yl)piperidine-1-carboxylate (Compound 1107, 230 mg, 83%) as a yellow solid.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([Br:15])[CH:7]=1)([CH3:5])[CH2:3][OH:4].C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C.[Cl:31][CH2:32][C:33](Cl)=[O:34]>CN(C=O)C.C1(C)C=CC=CC=1.O>[Br:15][C:8]1[CH:7]=[C:6]([C@:2]([NH:1][C:33](=[O:34])[CH2:32][Cl:31])([CH3:5])[CH2:3][OH:4])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@](N)(CO)c1cc(Br)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@](CO)(NC(=O)CCl)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
(R)-2-Amino-2-(3-bromo-5-nitro-phenyl)-propan-1-ol (6.27 g, 22.79 mmol) was dissolved in DMF (230 ml) under N2 and K2CO3 (7.87 g, 57 mmol) and DIPEA (3.98 ml, 22.79 mmol) were added. The mixture was cooled to 0° C. and chloro-acetylchloride (2.83 g, 25.07 mmol) was added dropwise. The reaction was stirred at 0° C. for 19 hrs. After completion, the reaction was put between water (2.3 liter) and toluene (2.3 l). The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure. The crude product was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as colorless oil. 1H-NMR (360 MHz, DMSO-d6): 8.51 (1H, NH), 8.28 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 5.25 (t, 1H), 4.15 (d, 2H), 3.62 (m, 2H), 1.62 (s, 3H); MS: 351 [(M+H)+].
Reaction SMILES: Cl.NO.Cl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](=[O:14])[N:11]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([N:24]=CC(C)C)[CH2:20][CH2:19]3)=[O:17])[C:10]=2[CH:29]=1>C(#N)C>[ClH:5].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](=[O:14])[N:11]([CH2:15][C:16]([N:18]3[CH2:19][CH2:20][N:21]([NH2:24])[CH2:22][CH2:23]3)=[O:17])[C:10]=2[CH:29]=1
Reactant: CC(C)C=NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Agent: Cl
Agent: NO
Solvent: CC#N
Product: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.9 %

Procedure:
To a solution of hydroxylamine hydrochloride (5.48 g) in a mixed solvent of acetonitrile (60 ml) and 6N-hydrochloric acid (30 ml) was added 5-chloro-3-[(4-isobutylideneamino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (3.0 g). The resulting solution was stirred overnight at room temperature. After stirring for five hours under ice cooling, the crystalline precipitates were filtered, and washed successively with water (6 ml) and methylene chloride (15 ml). This product was further washed by suspending in water (6 ml) and filtered to give 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hydrochloride (1.93 g).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C.CN(C)C=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>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(I)ccc1O
Reactant: C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (950 mg, 2 mmol) and trimethylsilylacetylene (246 mg, 2.5 mmol) were dissolved in triethylamine (2 mL) and N,N-dimethylformamide (4 mL). Tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and cuprous iodide (4 mg, 0.02 mmol) were added under argon atmosphere, and the mixture was stirred at 40° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (100 mL) and 1 N citric acid (100 mL), stirred, and filtered through celite. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=19:1) to give a light orange solid. This was crystallized by n-hexane to give the title compound (286 mg, 32.1%) as a white crystal.
Reaction SMILES: [N:1]1([CH2:10]O)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C2C=CC=CC=2N=N1>CCO>[CH2:20]([N:19]([CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: OCn1nnc2ccccc21
Agent: c1ccc2[nH]nnc2c1
Solvent: CCO
Product: c1ccc(CN(Cc2ccccc2)Cn2nnc3ccccc32)cc1
Reaction time: 24 h
Yield: 99.7 %

Procedure:
1H-Benzotriazole-1-methanol (51.0 g, 0.342 mol) was weighed into a round bottom flask and solubilized in EtOH (800 mL). Dibenzylamine (67.5 g, 0.342 mol) was added slowly (over 5 min) to the rapidly stirred solution. Formation of a white precipitate was observed shortly after starting addition. The solution was abandoned to stir for 24 h. At this time the reaction is judged complete by NMR (product fragments on LCMS to show only benzotriazole). The majority of the solvent was removed by rotovap and diethyl ether (1 L) was added to the residue with vigorous stirring. This mixture was filtered, the filtrand washed with ether and dried under vacuum to yield the desired product as a fluffy white solid (112 g, quat. yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.80 (s, 4H) 5.48 (s, 2H) 7.21 (d, J=8.34 Hz, 1H) 7.34-7.43 (m, 11H) 7.49 (d, 1H) 8.09 (d, J=7.83 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].CC(C)([O-])C.[K+].Cl[C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24]3)[C:18]=2[N:17]=[C:16]([NH2:28])[N:15]=1>C1COCC1.C(Cl)Cl.O>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][O:5][C:14]1[C:23]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24]3)[C:18]=2[N:17]=[C:16]([NH2:28])[N:15]=1
Reactant: CN(C)CCO
Reactant: Nc1nc(Cl)c2c(n1)C1(CCCC1)CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCOc1nc(N)nc2c1CCCC21CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(dimethylamino)ethanol (63.9 μL, 0.631 mmol) in THF (5 mL) was treated with potassium tert-butoxide (78 mg, 0.694 mmol) at 0° C., and the reaction mixture was stirred for 30 minutes at ambient temperature. It was then treated with a solution of the product from Example 14A (30 mg, 0.126 mmol) in THF (2 mL) at ambient temperature, and the whole was stirred for 2 hours. The mixture was diluted with CH2Cl2 (20 mL) and H2O (10 mL), then the organic layer was separated, dried with MgSO4, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel, eluting with NH4OH/MeOH/CH2Cl2 (0.8/7.2/92), to afford the title product. 1H NMR (300 MHz, CDCl3) δ 4.56 (s, 2 H), 4.37 (t, 2 H), 2.68 (t, J=5.93 Hz, 2 H), 2.43 (t, J=6.10 Hz, 2 H), 2.32 (s, 6 H), 2.01-2.13 (m, 2 H), 1.79-1.90 (m, 2 H), 1.59-1.74 (m, 6 H), 1.47-1.57 (m, 2 H). MS (DCI+) m/z 291 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[N:9]=[CH:10][C:3]=12.[NH2:18][CH2:19][C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+].C(O)=O>O>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[C:3]2[CH:10]=[N:9]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: O=C(O)CNc1ncnc2c1cnn2-c1ccccc1Cl
Yield: 82.7 %

Procedure:
4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (1.3 g, 4.90 mmol) was added to a stirred solution of glycine (0.72 g, 9.59 mmol) and anhydrous sodium carbonate (0.58 g, 5.48 mmol) in water (10 mL). The reaction was refluxed for 2 hrs. The reaction mixture was acidified by the addition of formic acid. The precipitate was filtered, washed with water and dried in vacuo to give the title compound as a colourless solid (1.23 g), 1H NMR (300 MHz, CD3OD) δ 8.32 (s, 1H), 8.24 (s, 1H), 7.66 (m, 1H), 7.54 (m, 3H), 4.34 (s, 2H).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>C[O-].[Na+].CO>[OH:21][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(-c3cccnc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3cccnc3)sc2c1O
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A mixture of 7-hydroxy-2-pyridin-3-yl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (27 mg, 0.09 mmol) and glycine (169 mg, 1.80 mmol) in 0.5 M sodium methoxide/methanol (4.5 mL) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (15 mL) and extracted twice with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.3 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (17 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.56 (br s, 1H), 9.34 (s, 1H), 8.94 (s, 1H), 8.80 (d, 1H), 8.53 (m, 1H), 7.66 (m, 1H), 4.03 (d, J=5.8 Hz, 2H); MS: (+) m/z 331.00 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: Clc1ccccn1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCO[C@@H]1CN(c2ccccn2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 3.5 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 2-chloropyridine (0.035 mL, 0.37 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMF (1 mL), and the suspension was heated using a microwave reactor at 180° C. for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=7/3→1/0) to obtain 3.9 mg of the title compound as a white amorphous solid (3%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:9]([N:8]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C@H:5]1[CH2:6][CH2:7][C@H:2]([N:1]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:3][CH2:4]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCCCC3)CC2)cc1

Procedure:
2.0 g (6.8 mmol) of trans-1amino-4-dibenzylaminocyclohexane (see Example 2) is dissolved in 50 mL DMF and stirred for 48 h at RT with 1.6 g (7 mmol) of 1,5-dibromopentane and 2 g of potassium carbonate. The mixture is cooled, combined with water, extracted twice with 100 mL of dichloromethane, dried and the solvent is eliminated in vacuo. The residue is purified over a column (about 100 mL silica gel, about 500 mL ethyl acetate 80/methanol 20+1% concentrated ammonia). The desired fractions are evaporated down in vacuo and crystallised from petroleum ether. Yield: 1.2 g (49%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:37][CH:36]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.[C:56]1([CH2:62][CH2:63][CH:64]=O)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:22][C:23]1[CH:32]=[C:31]([CH2:33][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3([N:50]4[CH2:55][CH2:54][N:53]([CH2:64][CH2:63][CH2:62][C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)[CH2:52][CH2:51]4)[C:46](=[O:47])[NH:45][C:44](=[O:48])[NH:43][C:42]3=[O:49])=[CH:39][CH:40]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1
Reactant: Cc1cc(COc2ccc(C3(N4CCNCC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Reactant: O=CCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(C3(N4CCN(CCCc5ccccc5)CC4)C(=O)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 69.6 %

Procedure:
Using a procedure analogous to Example 15, the product from example 14 (100 mg, 0.125 mmol) was treated with 3-phenylpropionaldehyde (25.1 mg, 1.5 eq) to provide the title barbituric acid (80.0 mg, 70%). MS found: (M+H)+=578.
Reaction SMILES: [CH2:1]([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:12]([C:14]1[CH:15]=[C:16]([N+:20]([O-])=O)[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>[Pd].C(OCC)(=O)C.C1COCC1>[CH2:23]([N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:12]([C:14]1[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1)=[O:13])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCN(CCCCCCCCCC)C(=O)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCN(CCCCCCCCCC)C(=O)c1cccc(N)c1
Yield: 107.2 %

Procedure:
To an ice bath cooled solution of 0.80 g (2.69 mmol) of di-decylamine and 0.75 mL (5.4 mmol) of triethylamine in 10 mL of anhydrous methylene chloride was added dropwise a solution of 0.50 g (2.69 mmol) of 3-nitrobenzoyl chloride in 5 mL of methylene chloride with stirring. The mixture was stirred at room temperature for 4 hours. Water was added, the organic layer was separated and dried. The solvent was removed at reduced pressure and the residual oil was purified by chromatography on 30 g of silica gel using 12.5% ethyl acetate-hexane to give 1.0 g of 3-(di-decylaminocarbonyl)-1-nitrobenzene as an oil. The nmr and mass spectra were consistent with the structure. A mixture of 1.0 g of 3-(di-decylaminocarbonyl)-1-nitrobenzene and 0.2 g of 10% palladium on carbon in 20 mL of ethyl acetate and 20 mL of THF was stirred under a hydrogen atmosphere at room temperature for 2 hours when hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated to give 1.0 g of 3-(di-decylaminocarbonyl)benzenamine as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH2:20]([OH:23])[C:21]#[CH:22].Cl>O1CCCC1.CCOCC.O.[Cu]I.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>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]#[C:21][CH2:20][OH:23])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C#CCO)cc1
Temperature: 55 °C
Reaction time: 20 h

Procedure:
To a degassed solution of 4-bromotoluene (4.27 g, 25 mmol) in tetrahydrofuran (30 mL) was added in the following order: copper(I) iodide (143 mg, 0.75 mol), tetrakis(triphenylphosphine)palladium (0.85 g, 7.5 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.55 g, 30 mmol). The resulting mixture was degassed one more time, cooled in an ice bath and a solution of propargyl alcohol (1.68 g, 30 mmol) in tetrahydrofuran (5 mL) was added over period of 10 min. The reaction mixture was slowly heated up to 55° C. and then stirred at this temperature for 20 h. This mixture was then cooled to ambient temperature, diluted with ether (150 mL) and water (50 mL) and acidified with 5% hydrochloric acid. The ethereal layer was separated and the aqueous layer was extracted with ether (3×30 mL). The combined organic portions were washed with 5% hydrochloric acid (2×30 mL), saturated aqueous solution of sodium hydrogen carbonate (2×30 mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, chloroform) affording 3-(4-methylphenyl)prop-2-yn-1-ol as oil.