Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@@:4]([CH2:1][CH3:3])([OH:12])[CH2:8][CH2:7][N:6]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH3:11]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: COc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(OC)c2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (201 mg), 4-fluoro-2-methoxybenzonitrile (250 mg) and lithium carbonate (180 mg), the title compound was obtained as a colorless solid (yield: 158 mg, yield: 54%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N+:7]([C:10]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[C:33]([N+:40]([O-:42])=[O:41])[C:11]=1[C:12]([NH:14][NH:15][C:16](=[O:32])[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[CH:19][C:18]=1[N+:29]([O-:31])=[O:30])=O)([O-:9])=[O:8]>>[C:11]1([C:12]2[O:32][C:16]([C:17]3[C:18]([N+:29]([O-:31])=[O:30])=[CH:19][C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]=3[N+:23]([O-:25])=[O:24])=[N:15][N:14]=2)[C:33]([N+:40]([O-:42])=[O:41])=[CH:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: O=C(NNC(=O)c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-])c1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(-c2nnc(-c3c([N+](=O)[O-])cc([N+](=O)[O-])cc3[N+](=O)[O-])o2)c([N+](=O)[O-])c1

Procedure:
Stoichiometrically one mole of phosphorus pentachloride (PCl5) should be consumed for each mole of N,N'-bis(2,4,6-trinitrobenzoyl)hydrazine in the reaction to produce 2,5-dipicryl-1,3,4-oxadiazole. However, for better results a molar excess of PCl5 is used. A molar ratio of PCl5 to N,N'-bis(2,4,6-trinitrobenzoyl)hydrazine of from 1.0:1.0 to 3.0:1.0 is preferred, with from 2.0:1.0 to 2.5:1.0 being more preferred.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[I-].[CH3:9][O:10][C:11]([CH2:13][CH2:14][C:15]1[N+:19]([CH3:20])=[CH:18][N:17](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:16]=1)=[O:12]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:20][N:19]1[C:15]([CH2:14][CH2:13][C:11]([O:10][CH3:9])=[O:12])=[CH:16][N:17]=[CH:18]1
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c[n+]1C
Agent: [I-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCc1cncn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
0.5 ml of trifluoroacetic acid is added to a solution of 200 mg (0.37 mmol) of 5-(2-methoxycarbonylethyl)-1-methyl-3-trityl-3H-imidazol-1-ium iodide in 2 ml of dichloromethane. The reaction medium is left to stir overnight at ambient temperature and the solvents are evaporated off. The residue is purified by silica chromatography (eluent 9/1 DCM/MeOH. 80 mg of methyl 3-(3-methyl-3H-imidazol-4-yl)propionate trifluoroacetate are obtained with a yield of 76%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](Cl)=[O:16])=[CH:9][CH:8]=1>ClCCl>[CH3:5][O:6][C:7]1[CH:12]=[C:11]2[C:10]([CH2:13][CH:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]2=[O:16])=[CH:9][CH:8]=1
Reactant: COc1ccc(CC(C(=O)Cl)c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(c1ccccc1)C2

Procedure:
Aluminum chloride (345 mg) and one quarter of the crude 3-(4-methoxyphenyl)-2-phenylpropionyl chloride from the previous step were added to dry dichloromethane (45 ml) at 0° C. After 1 hour aluminum chloride (345 mg) and the second quarter of the acid chloride were added. Stirring was continued and the addition was repeated twice again. After the last addition stirring was continued for half an hour at 0° C. and then 2 hours at room temperature. The reaction mixture was poured into ice-cold diluted acidic water. The organic phase was separated and the water phase was extracted twice with dichloromethane. The combined organic phases were washed with water, 2.5% sodium hydroxide solution in water and again with water. The dichloromethane solution was dried and evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:30]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([C:13]2[C:14]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)[CH3:30])(=[O:10])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncccc2NS(=O)(=O)c2ccc(OC)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncccc2N(C)S(=O)(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
500 mg (1.3 mmol) of the compound of Example 4 was dissolved in 5 ml of dimethylformamide. 60 mg (1.5 mmol) of sodium hydride (60%) was added to the solution. The resulting solution was stirred at room temperature for 30 min and 95 μl (1.5 mmol) of methyl iodide was added thereto.
Reaction SMILES: [CH:1]([Mg:4][Cl:5])([CH3:3])[CH3:2].[Li+].[Cl-].BrC1C=[CH:15][C:12]([C:13]#[N:14])=[CH:11]C=1>C1COCC1>[C:13]([C:12]1[CH:15]=[CH:3][C:1]([Mg:4][Cl:5])=[CH:2][CH:11]=1)#[N:14]
Reactant: CC(C)[Mg]Cl
Reactant: N#Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc([Mg]Cl)cc1
Reaction time: 2 h

Procedure:
A 1.3 M solution of isopropylmagnesium chloride.LiCl in THF [807329-97-1] (19.78 mmol) was added dropwise at 0° C. to a solution of 4-bromobenzonitrile [623-00-7] (16.48 mmol) in THF (8.5 mL) and the mixture was stirred between 0° C. and 5° C. for 2 h. The product was used without further purification. tR: 4.25 min (sample in MeOH) (HPLC 4).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[C@H:17]4[CH2:18][C@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19](=[O:29])[C@@H:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:21]([CH3:23])[CH3:22])=[N:11][C:7]=1[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]3[C:63](=[CH:64][CH:65]=2)[C:47]2[NH:48][C:49]([C@@H:51]4[CH2:55][CH2:54][CH2:53][N:52]4[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:50][C:46]=2[CH:45]=[CH:44]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(OCC)(=O)C>[CH3:27][O:26][C:25]([NH:24][C@@H:20]([CH:21]([CH3:23])[CH3:22])[C:19]([N:13]1[C@H:12]([C:10]2[NH:9][C:8]3[C:30]4[C:4]([CH:5]=[CH:6][C:7]=3[N:11]=2)=[CH:3][C:2]([C:41]2[CH:42]=[C:43]3[C:63](=[CH:64][CH:65]=2)[C:47]2[NH:48][C:49]([C@@H:51]5[CH2:55][CH2:54][CH2:53][N:52]5[C:56]([O:58][C:59]([CH3:61])([CH3:62])[CH3:60])=[O:57])=[N:50][C:46]=2[CH:45]=[CH:44]3)=[CH:32][CH:31]=4)[C@H:17]2[CH2:18][C@@H:14]1[CH2:15][CH2:16]2)=[O:29])=[O:28]
Reactant: COC(=O)N[C@H](C(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.1 %

Procedure:
Methyl (S)-1-((1S,3S,4R)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.300 g, 0.601 mmol), (S)-tert-butyl 2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.334 g, 0.721 mmol), and aqueous potassium phosphate (2M, 0.901 mL, 1.802 mmol) were suspended in 1,2-dimethoxyethane (3.00 mL) and sparged with argon gas for 30 minutes. Palladium tetrakis triphenylphosphine (0.069 g, 0.060 mmol) was added and the reaction mixture was capped and placed in a preheated 80° C. oil bath. The solution was heated for 18 hours and subsequently stirred at room temperature for two days. Upon completion, the reaction was diluted with ethyl acetate and washed with brine. The concentrated organic layer was purified by normal phase chromatography (40-100% ethyl acetate (10% MeOH) in hexanes) to give (S)-tert-butyl 2-(2′-((1S,3S,4R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.305 g, 67%). LCMS-ESI+: calc'd for C44H49N7O5: 755.38 (M+); Found: 756.8 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[Cl:25][C:26]1[C:34]([O:35][C:36]([C:39]#[N:40])([CH3:38])[CH3:37])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(OCC)(=O)C>N1C=CC=CC=1.O>[Cl:25][C:26]1[C:34]([O:35][C:36]([C:39]#[N:40])([CH3:37])[CH3:38])=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)[CH:21]=[CH:22][C:23]=1[Cl:24])=[O:29]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1Cl
Reactant: CC(C)(C#N)Oc1cccc(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C#N)Oc1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)ccc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 16 h
Yield: 24.2 %

Procedure:
N-[5-(3-Amino-4-chlorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.554 mmol) produced in Example C118(ii), 2-chloro-3-(1-cyano-1-methylethoxy)benzoic acid (199 mg, 0.830 mmol) produced in Example C70(i) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (422 mg, 1.11 mmol) were suspended in pyridine (2 mL), and the suspension was stirred at 60° C. for 16 hr. After cooling to room temperature, ethyl acetate (100 mL) and water (80 mL) were added, and the mixture was partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and dried under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→100/0) and basic silica gel column chromatography (ethyl acetate/methanol=100/0→90/10), and triturated with diisopropyl ether to give the title compound (78 mg, 24%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:7])=[CH:4][C:3]=1[B:11]1[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[O:15]1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02 mmol) were dissolved in DMF (20 ml) and stirred at room temperature for 15 mins. 2-Aminothiazole (801 mg, 8.01 mmol) was added and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250 ml) and water (50 ml). The organic phase was washed with hydrochloric acid (2N, 50 ml) and aqueous sodium bicarbonate (1M, 50 ml), then dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane/ethyl acetate (4:1). The solvent was evaporated from the product fractions under vacuum to 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (1.72 g). LCMS: retention time 3.66 min, MH− 345. NMR: δH [2H6]-DMSO 12.65, (1H, b), 8.32, (1H, d), 8.08, (1H, dd), 7.56, (1H, d), 7.35, (1h, d), 7.28, (1H, d), 2.54, (3H, s), 1.34, (12H, s).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:46][CH:47]1[C@H:51]2[C@H:52](OC3CCCCO3)[N:53](C(OC(C)(C)C)=O)[C:54]3[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][C:55]=3[C:56](=[O:57])[N:50]2[CH2:49][CH2:48]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[C@H:19]2[C@H:20](OC3CCCCO3)[N:21](C(OC(C)(C)C)=O)[C:22]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:23]=3[C:24](=[O:25])[N:18]2[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:46][CH:47]1[C@@H:51]2[CH:52]=[N:53][C:54]3[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][C:55]=3[C:56](=[O:57])[N:50]2[CH2:49][CH2:48]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:15]1[C@@H:19]2[CH:20]=[N:21][C:22]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:23]=3[C:24](=[O:25])[N:18]2[CH2:17][CH2:16]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 89.5 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15d (190 mg, 0.19 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16d (99 mg, 0.17 mmol, 90%) as a solid: [α]20D=+474° (c=0.19, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.49-1.65 (m, 4H, 14-H, 14′-H), 1.82-1.97 (m, 4H, 13-H, 13′-H), 1.99-2.13 (m, 4H, 2-H, 2′-H), 2.26-2.41 (m, 4H, 1-H, 1′-H), 3.53-3.65 (m, 2H, 3-H, 3′-H), 3.68-3.76 (m, 2H, 11a-H, 11a′-H), 3.77-3.89 (m, 2H, 3-H, 3′-H), 3.94 (s, 6H, 7-OMe, 7′-OMe), 4.01-4.17 (m, 4H, 12-H, 12′-H), 6.80 (s, 2H, 9-H, 9′-H), 7.52 (s, 2H, 6-H, 6′-H), 7.66 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.7, 28.8, 29.6, 46.6, 53.7, 56.1, 68.8, 110.4, 111.6, 120.1, 140.6, 147.8, 150.8, 162.3, 164.6; IR (neat): 3318, 2943, 1601, 1506, 1454, 1433, 1382, 1262, 1217, 1021 cm−1; MS (FAB) m/z (relative intensity) 639 ([M+2×MeOH]+., 6), 607 ([M+MeOH]+., 23), 575 (M+., 100).
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH3:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16].[Cl-].[NH4+]>C(OCC)C.C(OCC)(=O)C>[CH3:13][CH:14]([CH3:18])[C:15]([C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)([OH:17])[CH3:16]
Reactant: CC(=O)C(C)C
Reactant: Ic1cnccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)C(C)(O)c1cnccn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
2-iodopyrazine (10 g, 48.55 mmol) in dry diethyl ether (100 ml) was cooled to −78° C. n-BuLi (2.5M in hexanes) (20.39 ml of 2.5 M, 50.98 mmol) was added dropwise over 10 minutes. A brown heterogeneous mixture was produced and it was stirred at −78° C. for 10 minutes, then warmed to −50° C. and stirred for an additional 60 minutes. The mixture was then re-cooled to −78° C. and 3-methylbutan-2-one (5.227 g, 6.493 ml, 60.69 mmol) was added. The mixture was stirred for 10 minutes. Further diethyl ether (10 ml) was added. The mixture was then allowed to warm to ambient. A saturated ammonium chloride aqueous solution (40 ml) and ethyl acetate (100 ml) were added and the mixture stirred for 5 minutes. The organic layer was separated and the aqueous extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The crude was purified on silica-gel, eluting with 40% ethyl acetate/petrol to afford the title compound as a pale yellow oil (4.74 g, 60%). 1H NMR (CDCl3) 0.75 (3H, d), 0.99-1.01 (3H, d), 1.58 (3H, s), 2.05-2.09 (1H, m), 4.10-4.40 (1H, m), 8.51-8.52 (2H, m), 8.73 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19](O)(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[C:19]([O:11][CH2:10][CH2:9][CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:2]([F:1])[CH:7]=1)[CH3:12])(=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(CCO)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCC(=O)OCCC(C)c1ccc(-c2ccccc2)c(F)c1

Procedure:
A mixture consisting of 6.11 gm (0.025 mol) of 3-(2-fluoro-4-biphenylyl)-1-butanol, 4.27 gm (0.027 mol) of pelargonic acid, 0.25 gm of p-toluene-sulfonic acid and 50 ml of absolute toluene was refluxed in a vessel equipped with a water trap until no more water separated out. Thereafter, the reaction solution was diluted with ether, the organic solution was extracted with water, dilute ammonia and again with water, dried over sodium sulfate, and the solvent was distilled off. 6.45 gm (67% of theory) of the ester of the formula ##EQU26## having a boiling point of 183°-190°C at 0.1 mm Hg were obtained.
Reaction SMILES: [CH3:1][C@H:2]([NH2:6])[CH:3]([CH3:5])[CH3:4].[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([O:21][CH3:22])[C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12]>>[CH3:1][C@H:2]([NH:6][C:11](=[O:12])[C:10]1[CH:14]=[C:15]([O:21][CH3:22])[C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([F:7])[CH:9]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](C)N
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1OC
Product: C#CCOc1c(F)cc(C(=O)N[C@@H](C)C(C)C)cc1OC

Procedure:
According to the same method as that of Production Example 1, (1S)-1,2-dimethylpropylamine was used in place of 2,2-dimethylpropylamine, 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-((1S)-1,2-dimethylpropyl)-3-fluoro-5-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 49 of the present invention) represented by the formula:
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[NH2:16][CH:17]([CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19].C(OC(N[C@H](C(O)=O)COCC1C=CC=CC=1)=O)(C)(C)C>C(N(CC)CC)C>[CH2:29]([O:28][CH2:27][CH:17]([NH:16][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1)[C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCN(CCC)C(=O)C(N)COCc1ccccc1
Reactant: Cc1nc(-c2ccccc2)nc(Cl)c1C
Agent: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)C(COCc1ccccc1)Nc1nc(-c2ccccc2)nc(C)c1C
Temperature: 150 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
A mixture of 4-chloro-5,6-dimethyl-2-phenylpyrimidine (1.8 g), 2-amino-3-benzyloxy-N,N-dipropylpropanamide (4.6 g), which is prepared from N-(tert-butoxycarbonyl)-O-benzylserine, and triethylamine (1.7 g) is stirred at 150° C. for 5 hours. The reaction mixture is treated in the same manner as in Example 1 to give 3-benzyloxy-2-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylpropanamide (3.5 g) as an oily product.
Reaction SMILES: [N+:1]([CH:4]([CH2:18][CH2:19][CH2:20][CH3:21])[C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.Cl.[N:23]#[C:24][NH2:25]>[Pd]>[CH2:18]([C:4]1[NH:1][C:24]([NH2:25])=[N:23][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:19][CH2:20][CH3:21]
Reactant: N#CN
Reactant: CCCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Product: CCCCc1[nH]c(N)nc1CCCCCc1ccccc1

Procedure:
7-Nitro-1-phenylundecan-6-one (0.049 g, 0.17 mmol) reacted with concentrated HCl (0.85 mmol) and palladium, 5 wt. % on activated carbon (0.072 g, 0.034 mmol) under H2, then reacted with cyanamide (0.035 g, 0.84 mmol) according to the general procedure. Purification by column chromatography gave 0.025 g (52%) over two steps as a yellow oil: 1H NMR (400 MHz, CD3OD) δ 7.22 (m, 2H), 7.15 (m, 3H), 2.60 (t, J=7.2 Hz, 2H), 2.43 (m, 4H), 1.64 (m, 6H), 1.34 (m, 4H), 0.94 (t, J=7.6 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.4, 142.4, 128.2, 128.1, 125.6, 122.1, 121.9, 35.5, 31.2, 31.1, 28.7, 28.2, 23.0, 22.8, 21.9, 12.9 ppm; IR νmax (cm−1) 3166, 2930, 2857, 1680, 1453, 1030, 748, 699; HRMS (FAB) calcd for C18H27N3 (MH+) 286.2278, found 286.2288.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:16]=[C:15]([Si](C)(C)C)[C:13]=2[N:14]=1>C(#N)C.O>[NH2:9][C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19][C:20]([F:23])([F:21])[F:22])[CH:16]=[C:15]([N+:7]([O-:8])=[O:6])[C:13]=2[N:14]=1
Reactant: C[Si](C)(C)c1cc(OC(F)(F)F)cc2sc(N)nc12
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: Nc1nc2c([N+](=O)[O-])cc(OC(F)(F)F)cc2s1
Temperature: 0 °C
Reaction time: 12 h
Yield: 43.3 %

Procedure:
0.68 g of nitronium tetrafluoroborate are added in small portions to a solution of 0.76 g of 2-amino-4-trimethylsilyl-6-trifluoromethoxybenzothiazole in 20 cm3 of acetonitrile cooled to 0° C. Stirring is continued for 12 hours at a temperature close to 20° C. The solution is then diluted with 50 cm3 of water and extracted with 2 times 50 cm3 of ethyl acetate. The organic phases are combined, dried over sodium sulphate and concentrated in vacuum. The residue is purified by flash chromatography on silica gel with a cyclohexane-ethyl acetate mixture (7-3 by volume) as eluent. After recrystallization from a cyclohexane-ethyl acetate mixture (3-2 by volume), 0.3 g of 2-amino-4-nitro-6-trifluoromethoxybenzothiazole melting at 260° C. is obtained.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH:7]1[O:6][C:5]1[CH:16]=[CH:17][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][CH3:28])=[O:26])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OC
Reactant: Brc1ccc(OC2Cc3ccccc3C2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(OC2Cc3ccccc3C2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
To a solution of 2-(4-bromophenoxy)-2,3-dihydro-1H-indene (1.4 g, 4.7 mmol) in N,N-dimethylformamide (4.7 mL) were added sodium hydrogencarbonate (1.0 g, 12 mmol), methyl acrylate (0.86 mL, 9.5 mmol), tetrabutylammonium chloride (2.0 g, 7.1 mmol) and palladium acetate (31 mg, 0.14 mmol), and the mixture was stirred at 100° C. for 24 hrs. The reaction mixture was allowed to return to room temperature and filtered. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.96 g, yield 69%).