Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1>CO.O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[N:23]=[CH:22][NH:21][N:20]=1
Reactant: Nc1nc[nH]n1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Solvent: O
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(c3nc[nH]n3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde, (uridinedialdehyde), (4.84 g) was dissolved in a mixture of methanol (100 ml) and water (100 ml). To the solution was added 3-amino-1H-1,2,4-triazole (1.68 g). The mixture was stirred at ambient temperature for five hours and evaporated in vacuo. The residue was triturated with acetone to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(1,2,4-triazol-3-yl)morpholin-2-yl]uracil (6.25 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[NH:5][C:6]1[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:19]([O-])=O.N(C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)C1C=CC=CC=1>>[NH2:19][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:15](=[O:18])(=[O:17])[NH2:16])[C:6]=1[NH:5][C:4]1[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[C:10]([OH:12])=[O:11]
Reactant: COc1ccccc1Nc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Nc1ccccc1
Product: COc1ccccc1Nc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
By substituting 4- (o-methoxyanilino)-3-nitro-5-sulphamyl-benzoic acid for the 4-anilino-3-nitro-5-sulphamyl-benzoic acid of Example 9 B, the above compound was obtained after recrystallization from aqueous ethanol.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH:23]([C:25]([CH3:27])=[O:26])=[CH2:24]>C(Cl)(Cl)Cl>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[CH2:22][CH2:21][N:20]([CH2:24][CH2:23][C:25](=[O:26])[CH3:27])[CH2:19][CH2:18]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(C)=O
Reactant: CC(C)(C)C1CCC(c2ccccc2N2CCNCC2)CC1
Solvent: ClC(Cl)Cl
Product: CC(=O)CCN1CCN(c2ccccc2C2CCC(C(C)(C)C)CC2)CC1
Yield: 81.1 %

Procedure:
A mixture of the 1-[2-(4-t-butylcyclohexyl)phenyl]piperazine (30 mg, 0.0998 mmol) produced in Example (10a) and chloroform (0.5 mL) was cooled in an ice bath and stirred. Methyl vinyl ketone (0.017 mL, 0.200 mmol) was added to the mixture, followed by stirring for 2 hours under the same conditions. The reaction mixture was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 30 mg of the title compound as a colorless oil, as a mixture of diastereomers at the position of t-butylcyclohexyl.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[O:11]1
Reactant: O=Cc1ccncc1
Reactant: CC1=CC(=O)C(C)(c2ccccc2)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CC1(c2ccccc2)OC(C=Cc2ccncc2)=CC1=O
Temperature: 60 °C
Yield: 37 %

Procedure:
To a solution of 4-pyridinecarboxaldehyde (1.4 mL, 14.9 mM) and 2,5-dimethyl-2-phenyl-3(2H)-furanone (2.0 g, 10.6 mm) in ethanol (50 mL), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 323 mg, 2.1 mM). The reaction solution was heated at 60° C. for 4 hours. After the reaction solution cooled to room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a red gummy product. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to give a white crystalline solid (1.1 g, 37% yield), m.p. 165°-166° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH:14]=[O:15])[CH3:9].O.Cl>CCOCC.C([Li])CCC.C1COCC1>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:15])[CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[CH3:9]
Reactant: Brc1ccccn1
Reactant: CCOc1cc(C=O)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(O)c2ccccn2)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 2-bromopyridine (4.0 g) in dry ether (50 ml), n-butyl lithium (19.2 ml, 1.6M hexane solution) was added dropwise under argon atmosphere at −78° C. After finishing the dropping, the mixture was stirred for 1 hour, and a solution of 3-ethoxy-4-nitrobenzaldehyde (5.0 g) in dry ether (100 ml) and dry THF (50 ml) was added dropwise to the mixture. After finishing the dropping, and the mixture was allowed to be at room temperature and the mixture was stirred overnight. Water was added to the mixture, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), to give (3-ethoxy-4-nitrophenyl)(2-pyridyl)methanol (3.4 g) as dark brown oil.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH3:9])[C:5](=[O:7])[N:6]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>O>[C:25]([NH:1][C:2]1[O:3][CH:4]([CH:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH3:9])[C:5](=[O:7])[N:6]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(c1c[nH]c2ccccc12)C1OC(N)=NC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NC1=NC(=O)C(C(C)c2c[nH]c3ccccc23)O1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-amino-5-[1-(indol-3-yl)ethyl]-2-oxazolin-4-one (100 mg) was dissolved into pyridine (0.5 ml). Acetic anhydride (117 μl) was added. The mixture was stirred for 2 hours at 80° C. To the reaction mixture was added water. The mixture was made acidic using 4N hydrochloric acid. The whole was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentration of the solution gave a residue, which was subjected to the silica gel chromatography. The eluent with hexane-acetone (1:1) was collected and concentrated to provide the titled compound (16 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][N:6]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]1[CH2:12][CH2:13][NH2:14].Cl[C:20]1[NH:21][C:22]2[C:27]([C:28](=[O:30])[CH:29]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH2:5][N:6]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]1[CH2:12][CH2:13][NH:14][C:20]1[NH:21][C:22]2[C:27]([C:28](=[O:30])[CH:29]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: O=c1cc(Cl)[nH]c2ccccc12
Reactant: NCCC1CC=CCN1Cc1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(NCCC2CC=CCN2Cc2ccc(Cl)c(Cl)c2)[nH]c2ccccc12
Temperature: 110 °C

Procedure:
A mixture of 2-[1-(3,4-dichlorobenzyl)-1,2,3,6-tetrahydropyridin-2-yl]ethylamine (284 mg, 1 mmol), 2-chloro-1H-quinolin-4-one (184 mg, 1.03 mmol) and diisopropylethylamine (0.18 mL, 1.03 mmol) was heated at 110° C. After 56 h the mixture was cooled and the residue chromatographed over silica gel eluting with dichloromethane and increasing amounts of methanol containing 10% concentrated aqueous ammonia to yield the title compound as a pink foam. δH (CD3OD) 1.59-1.69 (1H, m), 1.83-2.10 (2H, m), 2.21-2.42 (1H, m), 2.90-3.15 (4H, m), 3.67 (2H, s), 5.55-5.64 (1H, s), 5.66 (1H, s), 5.72-5.87 (1H, m), 7.18-7.58 (6H, m), 8.10 (1H, d, J=6.67 Hz); MS (ES+) 426 (100%) MH+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][O:25][C@H:24]([CH2:28][OH:29])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:35]=[CH:36][C:31]([N:30]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([N:22]6[CH2:27][CH2:26][O:25][C@H:24]([CH2:28][OH:29])[CH2:23]6)[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:32][CH:33]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCO[C@H](CO)C6)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CCO[C@H](CO)C4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.3 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[(2S)-2-(hydroxymethyl)morpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (4.60 mg, 0.00710 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 15 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (3.42 mg, 73.3%) as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([CH3:25])[CH:17]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(Cl)(Cl)Cl>CO>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:14][CH2:13]2)=[O:21])=[C:18]([CH3:25])[CH:17]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a mixture of 1-(3,5-dimethylpyridin-2-yl)piperazine (3.8 g) described in Preparation Example 47, 4-bromo-2-methylbenzoic acid (4.3 g) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (8.8 g) were added chloroform (30 mL) and methanol (30 mL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, ethyl acetate was added, and insoluble materials were filtered off. The solvent in the filtrate was evaporated, and the residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (7 g).
Reaction SMILES: [Mg].C(Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][C:11]1([CH3:24])[C:16]2[CH:17]=[CH:18][C:19]([C:21](=O)[CH3:22])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.C(O)(=O)C.O>[CH3:10][C:11]1([CH3:24])[C:16]2[CH:17]=[CH:18][C:19]([C:21]([CH3:25])=[CH:22][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc2c(c1)OCCC2(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: CC(=Cc1ccccc1)c1ccc2c(c1)OCCC2(C)C
Temperature: 25 °C
Yield: 593.8 %

Procedure:
1.7 g of magnesium shavings were covered with 10 ml of ether. A solution of 7.7 g of benzyl chloride in 80 ml of ether was added dropwise thereto under slight reflux and the mixture was subsequently held at boiling for an additional hour until the magnesium had dissolved completely. After cooling to room temperature, a solution of 7 g of 3,4-dihydro-4,4-dimethyl-7-acetyl-2H-1-benzopyran in 50 ml of ether was added dropwise and the reaction mixture was heated under reflux for an additional 2.5 hours. After cooling, the mixture was poured on to ice/2N hydrochloric acid and extracted with ether. The organic phase was washed with water and dilute sodium bicarbonate solution, dried and evaporated. The thus-obtained slightly yellow oil was dissolved in 10 ml of acetic acid and, after the addition of 0.5 g of p-toluenesulfonic acid, heated under reflux for 2 hours. The reaction solution obtained was diluted with water and extracted several times with ether. The combined extracts were diluted with water, washed with sodium bicarbonate solution and water, dried and evaporated. The crude product was chromatographed (silica gel, eluting agent hexane/0.5% ethyl acetate) and recrystallized from hexane. There were obtained 4.8 g of 3,4-dihydro-4,4-dimethyl-7-(α-methylstyryl)-2H-1-benzopyran, melting point 44°-46° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:20])=O.[NH2:21][C:22]([NH2:24])=[S:23]>CCO>[CH3:20][C:6]1[CH:7]=[C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:21]=[C:22]([NH2:24])[S:23][CH:2]=1
Reactant: Cc1ccc(Sc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 100 %

Procedure:
A reaction mixture containing 2-bromo-1-(2,6-dimethyl-4-(p-tolylthio)phenyl)ethanone (394.8 mg, 1.1 mmol, 1.0 equiv) and thiourea (86.04 mg, 1.1 mmol, 1.0 equiv) in EtOH (10.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(2,6-dimethyl-4-(p-tolylthio)phenyl)thiazol-2-amine (371.9 mg, 1.1 mmol) as yellow solids in >99% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.27 (d, J=8.0 Hz, 2 H), 7.21 (d, J=8.0 Hz, 2 H), 6.97 (s, 2 H), 6.87 (s, 2 H), 6.36 (s, 1 H), 2.30 (s, 3 H), 2.05 (s, 6 H); ESI-MS: m/z 327.0 (M+H)+.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1CCC(N=C=NC2CCCCC2)CC1>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21]([C@@H:22]([O:6][C:5](=[O:7])[CH2:4][CH:3]=[C:2]([CH3:1])[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: CC1=C(CC/C(C)=C/CC(=O)O)C(C)(C)CCC1
Reactant: COC(=O)[C@@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H](OC(=O)CC=C(C)CCC1=C(C)CCCC1(C)C)c1ccccc1
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of 10.0 g (40 mmol) (E)-4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid [H. S. Corey, J. R. D. Cormick, W. E. Swensen, J. Am. Chem. Soc. 1964, 86, 1884], isomeric purity of 95%, in 100 ml MTBE were added at r.t. 6.64 g (40 mmol) (S)-(+)-mandelic acid methyl ester [α]D=+144.9 (c=1.04, MeOH) and 1.0 g DMAP. Then a solution of 8.24 g (40 mmol) DCC in 100 ml MTBE was added and the reaction mixture stirred for 2 h. After addition of 1 ml MeOH and 1 ml HTDNF the mixture was stirred for 30 min, filtered and the residue washed with MTBE. The combined organic phases were concentrated in vacuo and the residue (18.0 g) was purified by flash chromatography (silicagel, hexane/MTBE 9:1) affording 14.0 g (88%) 4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid (S)-methoxycarbonyl-phenyl-methyl ester (11) in form of a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[C:28](Cl)=[O:29].C(=O)(O)[O-].[Na+]>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:28]([C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)=[O:29])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a mixture of 3-nitroaniline (2.07 g) and triethylamine (2.3 ml) in 1,4-dioxane (40 ml) was added 2-naphthoyl chloride (3.00 g) and the mixture was stirred at room temperature for 30 minutes. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate three times. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give N-(3-nitrophenyl)-2-naphthalenecarboxamide (3.02 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([S:14](Cl)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1.Cl.[F:19][C:20]1([F:24])[CH2:23][NH:22][CH2:21]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([S:14]([N:22]3[CH2:23][C:20]([F:24])([F:19])[CH2:21]3)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:4]2[CH:3]=1
Reactant: CC(C)c1nc2cc(Br)ccn2c1S(=O)(=O)Cl
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1nc2cc(Br)ccn2c1S(=O)(=O)N1CC(F)(F)C1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
7-Bromo-2-isopropylimidazo[1,2-a]pyridine-3-sulfonylchloride (500 mg, 1.481 mmol) obtained in step 1 was dissolved in acetonitrile (5.0 mL), and the solution was stirred at 50° C. for 30 minutes after adding 3,3-difluoroazetidine hydrochloride (230 mg, 1.78 mmol) and triethylamine (0.413 ml, 2.96 mmol). The reaction mixture was allowed to cool to room temperature, and a sodium hydrogen carbonate aqueous solution was added. The precipitated solid was collected by filteration to give 7-bromo-3-(3,3-difluoroazetidin-1-ylsulfonyl)-2-isopropylimidazo[1,2-a]pyridine (546 mg, yield 94%).
Reaction SMILES: CC(O)=O.[CH3:5][C:6](=O)[CH2:7][C:8](=O)[CH3:9].C([O-])(=O)CO.[NH2:17][C:18]1[NH:22][N:21]=[C:20]([CH2:23][OH:24])[N:19]=1>CC(OC)(C)C>[CH3:5][C:6]1[CH:7]=[C:8]([CH3:9])[N:22]2[N:21]=[C:20]([CH2:23][OH:24])[N:19]=[C:18]2[N:17]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1nc(CO)n[nH]1
Agent: O=C([O-])CO
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(CO)nc2n1
Temperature: 100 °C
Reaction time: 0.38 h
Yield: 58.6 %

Procedure:
To a 10L reactor was charged HOAc (4.7 L), 2,4-Pentanedione (543 mL, 5.29 mol), and the glycolate salt of (5-amino-1H-1,2,4-triazol-3-yl)methanol (944 g, 4.96 mol). The mixture was heated to 100° C. until the solution was homogeneous. After reaching 100° C., the solution should be nearly homogeneous. The time at 100° C. should be ˜15-30 min. After this time, if the solution remains cloudy heating should be discontinued. The resulting solution was cooled to ambient temperature, and MTBE (16 L) was added and the mixture stirred for 30 min. The mixture was filtered through a 14″ Buchner, rinsed with MTBE (7 L), and dried in a vacuum oven overnight at 50° C. to provide 518 g (59%) of (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol as a white solid. The filtrate contained significant product, so a second crop was isolated by charging the MTBE filtrates to a 22L reactor and cooling to 0° C. MTBE (8 L) was added and stirred for 2 hours. The resulting slurry was filtered and dried to yield an additional 173.7 g (20%) of (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol as a grey solid. Both crops were carried forward. 1H NMR (300 MHz, d6-DMSO): 2.57 (s, 3), 2.71 (d, 3, J=0.8), 4.63 (uneven d, 2, J=5.7), 5.49 (t, 1, J=6.2), 7.13 (d, 1, J=0.8).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:25][C:26](OC(C)=O)=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][N:4]([C:26](=[O:27])[CH3:25])[CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1Cc2cc([N+](=O)[O-])ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-(dimethylamino)pyridine (0.125 g, 1.02 mmol), 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-isoquinoline (0.21 g, 1.02 mmol), DIEA (0.53 mL, 3.06 mmol), and Ac2O (0.19 mL, 2.04 mmol) in 7 mL of CH2Cl2 was stirred at RT under N2 for two days. The volatiles were removed under vacuum. The residue was partitioned between EtOAc and brine, and the organic portion was dried with Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (2-3% MeOH in CH2Cl2), to yield the desired compound as a light yellowish solid. MS (ES+): 249.3 (M+H)+. Calc'd for C13H16N2O3-248.28.
Reaction SMILES: CC(OP(C1C=CC(N)=CC=1)(=O)OC(C)C)C.[CH3:18][C:19]1([CH3:35])[CH2:24][O:23][P:22](=[O:34])([C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)[O:21][CH2:20]1>>[CH3:18][C:19]1([CH3:35])[CH2:20][O:21][P:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)(=[O:34])[O:23][CH2:24]1
Reactant: CC1(C)COP(=O)(c2ccc([N+](=O)[O-])cc2)OC1
Agent: CC(C)OP(=O)(OC(C)C)c1ccc(N)cc1
Product: CC1(C)COP(=O)(c2ccc(N)cc2)OC1
Yield: 41 %

Procedure:
Prepared according to the procedure described for dipropan-2-yl(4-aminophenyl)phosphonate using 5,5-dimethyl-2-(4-nitrophenyl)-1,3,2-dioxaphosphinane 2-oxide. Yield: 41%. 1H-NMR (DMSO-d6, 400 MHz): δ=0.97 (s, 3H), 1.02 (s, 3H), 3.78 (m, 2H), 4.08 (m, 2H), 5.91 (s, br, 2H), 6.61 (dd, J=3.6, 8.4 Hz, 2H), 7.34 (m, 2H). MS: m/z 242.10 [MH+].
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]#[N:32])[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:36].[NH4+].OO.O>CO>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]([NH2:32])=[O:36])[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: [OH-]
Agent: OO
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: NC(=O)c1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
3-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile (45 mg, 0.097 mmol) was dissolved in hot methanol (2 mL). Subsequently, the solution was cooled down to room temperature and 30% ammonium hydroxide (2 mL) was added. The reaction mixture was then cooled to 0° C., and 30% hydrogen peroxide was added. After stirring at room temperature for 8 hours, water was added and the resulting mixture extracted with ethyl acetate. The organics were dried over magnesium sulfate. Filtration and concentration, followed by purification with flash chromatography (95:5 dichloromethane:methanol), gave 3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzamide (18 mg, 39% yield) as a yellow solid. 1H NMR (CDCl3): δ 8.12 (s, 1H), 7.99 (d, 1H), 7.92 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.51 (t, 1H), 7.32 (t, 1H), 6.28 (d, 1H), 6.18 (broad, 1H), 6.05 (d, 1H), 6.02 (d, 1H), 5.82 (broad, 1H), 5.25 (d, 1H), 4.30 (m, 1H), 4.00 (m, 1H), 2.15 (m, 2H), 2.03 (m, 2H), 1.81–1.50 (m, 12H). MS m/z 482 (M+1).