Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:28])[C:7]([CH3:27])([CH3:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([OH:25])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])C>O.C(O)C>[OH:25][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([OH:20])=[O:19])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:27])([CH3:26])[C:6]([OH:28])=[O:5]
Reactant: CCOC(=O)C(C)(C)CCCCC(O)CCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCC(O)CCCCC(C)(C)C(=O)O)C(=O)O
Yield: 94.8 %

Procedure:
To a homogeneous solution of potassium hydroxide (3.45 g, 61 mmol) in water (3.3 mL) and ethanol (11.1 mL) was added 7-hydroxy-2,2,12,12-tetramethyltridecanedioic acid diethyl ester (8.2 g, 22 mmol) and the mixture was heated at reflux for 4 h. The mixture was concentrated in vacuo and the residue was extracted with diethyl ether (3×50 mL). The water layer was acidified with concentrated hydrochloric acid (6 mL) to pH 1. The product was extracted with diethyl ether (3′100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica, dichloromethane:methanol=90:10) to give the pure product (6.6 g, 95%) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 8.10 (br., 3H), 3.58 (br., 1H), 1.62-1.22 (m, 16H), 1.18 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 184.3, 71.8, 42.1, 40.5, 36.9, 25.9, 25.0, 24.9. HRMS (LSIMS, gly): Calcd. for C17H33O5 (MH+): 317.2328. found 317.2330. HPLC: 90.4% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([CH3:22])=[CH:19][CH2:20]O>>[CH3:17][C:18]([CH3:22])=[CH:19][CH2:20][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Reactant: CC(C)=CCO
Product: CC(C)=CCOC(=O)[C@H](C)NC(=O)Cc1cccc(Cl)c1

Procedure:
Following General Procedure C above and using N-(3-chlorophenylacetyl alanine (from Example D above) and 3-methylbut-2-en-1-ol (Aldrich), the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 30% EtOAc/hexane as the eluant.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:21])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=1)([CH3:23])[CH3:24]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CN(C)c1ccc(CNc2ccc(C(F)(F)F)cc2)cc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(F)(F)F)cc1
Yield: 13.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using [(4-dimethylaminophenyl)methyl](4-trifluoromethylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.83 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-trifluoromethylphenyl)urea (0.23 g) was obtained. melting point: 129–130° C.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C:13]([CH3:49])([CH3:48])[C:14]([N:16]([CH3:47])[C:17]2[C:18]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3[CH3:46])=[CH:19][C:20]([C:23]#[C:24][CH2:25][C@H:26]([NH:31]C(OC(C)(C)C)=O)[C:27]([O:29][CH3:30])=[O:28])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClCCl>C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[F:50][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:49])([CH3:48])[C:14]([N:16]([CH3:47])[C:17]2[C:18]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3[CH3:46])=[CH:19][C:20]([C:23]3[CH2:24][CH2:25][C@@H:26]([C:27]([O:29][CH3:30])=[O:28])[N:31]=3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)[C@H](CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of methyl (2S)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 2, 750 mg, 1.036 mmol) in dry Dichloromethane (10 ml) trifluoroacetic acid (3 ml, 1.036 mmol) was added and the reaction mixture was stirred for 1 h at r.t. The solvent and the excess of trifluoroacetic acid were removed under vacuum and the residue was purified by SPE-SCX cartridge (10 g). The obtained light yellow solid was dissolved in acetonitrile (10 ml) and AgOTf (26.6 mg, 0.104 mmol) was added and the reaction mixture was stirred overnight at r.t. The solvent was evaporated and the residue was dissolved in ethyl acetate and filtered. The organic layer was collected and evaporated to afford the title compound (645 mg, 1.034 mmol, 100% yield) as a pale yellow solid. UPLC: Rt 0.95 min, m/z 624 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.4 %

Procedure:
To a solution of 4-nitroimidazole (7.28, g, 64.4 mmol) in 60 mL of dry DMF at 0° C. was added triethylamine (9.87 mL, 70.8 mmol), then chlorotriphenylmethane (17.95 g, 64.4. mmol). After 5 minutes, the solution was warmed to room temperature. After 30 minutes, the reaction mixture was poured over ice, filtered, and washed with ice water. The resulting product was dried in vacuo next to P205 to provide the titled product as a white powder (22.29 g, 97% yield) which was sufficiently pure for use in the next step.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH:24]1[CH:29]=[C:28]([CH:30]=O)[C:27]([OH:32])=[CH:26][CH:25]=1>C(O)C>[O:32]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:29][C:28]=2[CH:30]=[C:2]1[C:3]([C:5]1[CH:6]=[C:7]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: O=Cc1ccccc1O
Reactant: CCOC(=O)C(C)c1cccc(C(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)c1cccc(C(=O)c2cc3ccccc3o2)c1
Yield: 25 %

Procedure:
Ethyl 2-[meta-(α-bromo-acetyl)-phenyl]propionate (0.1 mole) is mixed with dry potassium carbonate (0.2 mole), salicylic aldehyde (0.1 mole) and ethanol (200 cc). The mixture is refluxed for 5 hours, with vigorous stirring. The initially yellow reaction medium turns brown during the heating step. The reaction mixture is then allowed to cool and the resulting precipitate is suction filtered. The alcohol is removed in vacuo. The resulting material is taken up into ethyl acetate, after which it is washed to neutral pH, dried and evaporated. The distilled residue gives a thick oil, b.p.0.05 = 210°-220°C. A second distillation gives the pure product (Yield: 25%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:37](=[O:44])([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH2:38].CC(C)([O-])C.[K+]>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:8]2[C:5]3[CH:6]=[N:7][C:2]([NH:38][C:37](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:3][C:4]=3[N:10]([C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]=2)=[CH:35][CH:34]=1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cc(Cl)ncc23)cc1
Reactant: CC(C)(C)OC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc2c(cn1)c(-c1ccc(F)cc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
6-Chloro-3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.48 g, 3.02 mmol), tert-butyl carbamate (1.062 g, 9.06 mmol), and chloro(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (0.249 g, 0.362 mmol) was dissolved in THF (30 mL) then potassium tert-butoxide (6.65 mL, 6.65 mmol, 1 M in THF) was added. The reaction mixture was purged under argon for five minutes then heated to 80° C. and stirred overnight. The reaction mixture was diluted with DCM and washed with NaOH (1 N) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo while loading onto silica gel. The residue was purified by flash chromatography (2-20% EtOAc/isohexane) to give tert-butyl (3-(4-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)carbamate (403 mg, 0.706 mmol, 23%). MS ESI calc'd. For C36H31FN4O2 [M+1]+ 571, found 571.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([NH2:18])=[C:8]([NH2:19])[N:7]=1.[CH2:20](OC(OCC)OCC)C.[OH-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]=[C:8]2[NH:19][CH:20]=[N:18][C:9]2=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(-c2ccncc2)c(-c2ncco2)nc1N
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: c1cc(-c2cc3nc[nH]c3nc2-c2ncco2)ccn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
A mixture of 2-(1,3-oxazol-2-yl)-3,4′-bipyridine-5,6-diamine (Intermediate 10, 0.100 g, 0.39 mmol) and triethylorthoformate (0.117 g, 0.79 mmol) in glacial acetic acid (2 mL) was heated in a sealed tube to 140° C. After stirring for 2 hours, the mixture was cooled and taken to pH 7 with 6N aqueous sodium hydroxide solution. Ethyl acetate was added to the mixture and, after stirring for 30 minutes, the separated solid was filtered, washed with diethyl ether and dried in vacuo to give the title compound (0.047 g, 49%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[CH3:18][C:19]([CH3:26])([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH2:20]>>[CH3:18][C:19]([NH:20][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:6]=1)=[O:17])([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[CH3:26]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (LC/MS): 392.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[CH:18]1>>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:17][CH:18]=1)(=[O:5])=[O:4]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ccccc13)C(=O)N2

Procedure:
5-Dimethylaminosulfonyl-2-oxindole was condensed with indole-3-carboxaldehyde to give the title compound.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:25][C:26]#[N:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C(N(CC)CC)C.[CH:41](=O)[CH2:42][CH3:43].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(=O)(O)[O-].[Na+].CCOC(C)=O>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:25][C:26]#[N:27])[CH2:20][CH2:21][N:22]([CH2:41][CH2:42][CH3:43])[CH2:23][CH2:24]4)[CH:18]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: CCC=O
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCNCC4)c3)n2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCN1CCC(CC#N)(n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)CC1
Reaction time: 0.5 h
Yield: 27 %

Procedure:
2-(4-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-4-yl)acetonitrile hydrochloride (Example 28, Step A; 30.0 mg, 0.0604 mmol) was suspended in acetonitrile (604 μL, 0.0604 mmol). To this was added triethylamine (33.7 μA, 0.242 mmol), followed by propionaldehyde (43.6 μL, 0.6043 mmol). After 30 minutes, NaBH(OAc)3 (64.0 mg, 0.302 mmol) was added. After stirring for 30 minutes, the reaction mixture was diluted in saturated sodium bicarbonate and EtOAc. The aqueous layer was back-extracted with DCM. The combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated. Purification of the resulting crude material by reverse phase HPLC using a 0-100% acetonitrile/water gradient afforded afford 2-(4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-propylpiperidin-4-yl)acetonitrile (7.0 mg, 23% yield). MS (apci) m/z=430.3 (M+H).
Reaction SMILES: [Cl-].C[SiH](C)C.[F:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10]Br.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[N:19]=[CH:18][N:17]=1.O>O1CCCC1.BrC(Br)C.[Zn]>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:10][C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([F:6])[CH:8]=2)[N:19]=[CH:18][N:17]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Fc1cccc(CBr)c1
Agent: CC(Br)Br
Agent: C[SiH](C)C
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(Cc2cc(Cl)ncn2)c1
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
In 10 ml of tetrahydrofuran was suspended 1.3 g of zinc (powder), to which dibromoethane (2 drops) was added. The mixture was heated under reflux for 5 minutes, to which trimethylsilane chloride was added. The mixture was further heated under reflux for 5 minutes, to which a solution of 1.5 g of 3-fluorobenzyl bromide dissolved in 20 ml of tetrahydrofuran was slowly added with heating under reflux, followed by stirring for 20 minutes. (The solution thus obtained is referred to as solution I). In 10 ml of tetrahydrofuran were suspended 1.5 g of 4,6-dichloropyrimidine and 0.1 g of dichlorobistriphenylphosphine palladium, to which the above solution I was added, followed by heating under reflux for 3 hours and further stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.62 g of 4-chloro-6-(3-fluorobenzyl)pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:12]([C:13]([C:15]2[S:19][C:18]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])=[CH:17][CH:16]=2)=[O:14])[N:11]=[C:10]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:9]1.N>CO.[Ni]>[NH2:24][CH2:23][C:22]1[CH:21]=[C:20]([C:18]2[S:19][C:15]([C:13]([N:12]3[CH:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH2:9][C:10]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[N:11]3)=[O:14])=[CH:16][CH:17]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1cccc(-c2ccc(C(=O)N3N=C(c4cccnc4)CC3c3ccccc3O)s2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cccc(-c2ccc(C(=O)N3N=C(c4cccnc4)CC3c3ccccc3O)s2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(5-{[5-(2-hydroxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-1-yl]carbonyl}-2-thienyl)benzonitrile in 7M mixture of ammonia in MeOH was added Raney nickel (3 mL). The reaction mixture was allowed to stir at rt under an atmosphere of hydrogen for 2 days. The resulting solution was filtered over a pad of celite and the filtrate was concentrated. The crude product was purified via HPLC to give 2-[1-({5-[3-(aminomethyl)phenyl]-2-thienyl}carbonyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl]phenol (I-2) (0.073 g, 0.138 mmol) as a white solid. LCMS: (FA) ES+ 455.4, ES-453.4. 1H NMR (400 MHz, d6-DMSO) δ: 9.05-9.08 (m, 1H), 8.66-8.70 (m, 1H), 8.35 (s, 1H), 8.26-8.31 (m, 1H), 8.05 (d, 1H), 7.78-7.82 (m, 1H), 7.64-7.68 (m, 1H), 7.53-7.59 (m, 2H), 7.36-7.47 (m, 2H), 7.08 (t, 1H), 6.92-6.97 (m, 1H), 6.81-6.86 (m, 1H), 6.72 (t, 1H), 5.85 (dd, 1H), 3.89-3.95 (m, 1H), 3.88 (s, 2H), and 3.16-3.24 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.I[CH3:20].[H-].[Na+]>C1COCC1>[CH3:20][N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (330 mg, 1.298 mmol) and iodomethane (0.085 mL, 1.362 mmol) in THF (10 mL) was cooled in an ice bath. Sodium hydride (78 mg, 1.946 mmol) was added and the ice bath was removed. The reaction was stirred at room temperature for 4 hrs. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3; the aqueous layer was extracted with EtOAc. Then the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel, Hexanes/EtOAc gradient 0 to 100% EtOAc) to give tert-butyl 2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (315 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N+:21]([O-:23])=[O:22])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[N+:21]([C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1)([O-:23])=[O:22]
Reactant: C#CCCn1nc2cccc([N+](=O)[O-])c2n1
Reactant: Brc1ccccn1
Product: O=[N+]([O-])c1cccc2nn(CCC#Cc3ccccn3)nc12
Yield: 31.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (76 mg, 0.48 mmol) and 2-but-3-ynyl-4-nitro-2H-benzo[d][1,2,3]triazole (95 mg, 0.44 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.14 mmol, 31%) of 4-nitro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as an orange oil.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.C(O[C:14](=[O:29])[CH2:15][CH2:16][C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[N:19][CH:18]=1)C.O>O1CCCC1>[CH2:22]([N:21]1[C:17]([CH2:16][CH2:15][C:14]([C:3]2[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=2)([C:3]2[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=2)[OH:29])=[CH:18][N:19]=[CH:20]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CCc1cncn1Cc1ccccc1
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)cc(C(O)(CCc2cncn2Cc2ccccc2)c2cc(C)cc(C)c2)c1
Temperature: 25 °C

Procedure:
1,06 g of magnesium turnings are covered with 30 ml of dry tetrahydrofuran. To the mixture is then added dropwise a solution of 5-bromo-m-xylene (8,14 g) in 10 ml of dry tetrahydrofuran at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of 1-benzyl-5-imidazole propionic acid ethyl ester (5,0 g) in 40 ml of tetrahydrofuran at 60° C. After the addition is complete, the reaction mixture is refluxed for 2 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and to the solution is added conc. hydrochloric acid. The solution is cooled, some ether is added and the precipitate which contains the product as hydrochloride salt is removed by filtration, washed and dried. Yield 4,1 g. M.p. 120°-124° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[CH:13][N:14]=2)=[CH:5][CH:4]=1.Cl.[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32](Cl)(=[O:34])=[O:33])[CH:31]=1.CCN(CC)CC>C(Cl)Cl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([S:32]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10]3[S:11][C:12]([C:15](=[O:16])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:23])=[CH:13][N:14]=3)=[CH:7][CH:8]=2)(=[O:34])=[O:33])[CH:31]=1
Reactant: Cc1ccccc1C(=O)c1cnc(Nc2ccc(CN)cc2)s1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1cnc(Nc2ccc(CNS(=O)(=O)c3cc(F)ccc3C)cc2)s1

Procedure:
A mixture of 35.8 mg (0.1 mmol)[2-(4-aminomethyl-phenylamino)-thiazol-5-yl]-o-tolyl-methanone; hydrochloride, 25 mg (0.12 mmol) 5-fluoro-2-methyl-benzenesulfonyl chloride (commercially available) and 69 ul (0.5 mmol) NEt3 in 3 ml DCM was stirred at 60° C. for 16 h. After evaporation of the volatiles the residue was taken up in 1.5 ml MeOH/formic acid 2/1 and subjected to reversed phase HPLC purification eluting with a gradient of acetonitrile/water. After evaporation of the product fractions 10 mg (21%) of the title compound was obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([O:31][CH2:32][CH3:33])[C:25]=1[O:34][CH2:35][CH3:36])(=[O:3])[CH3:2].[Br:37]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[C:28]([CH2:30][Br:37])[CH:27]=[C:26]([O:31][CH2:32][CH3:33])[C:25]=1[O:34][CH2:35][CH3:36])(=[O:3])[CH3:2]
Reactant: CCOc1cc(C)cc([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1OCC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(CBr)cc([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A suspension of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(2,3-diethoxy-5-methylphenyl)-D-glucitol (500 mg) and N-bromosuccinimide (209 mg) in carbon tetrachloride (10 ml) was refluxed with heating and 2,2′-azobis(isobutyronitrile) (80 mg) was added. The mixture was stirred for 30 minutes under refluxing and the reaction mixture was allowed to be cooled to room temperature. After evaporating the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate-n-hexane) to obtain (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2,3-diethoxyphenyl]-D-glucitol (464 mg).