Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19]([C:21]2[C:26]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH3:33]C1C(N[C@H]2CCC[C@@H]2N)=NC=C(C(F)(F)F)C=1.N1N(C2C(C(O)=O)=NC=CC=2)N=CC=1>>[CH3:33][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19]([C:21]2[C:26]([N:27]3[N:28]=[CH:29][CH:30]=[N:31]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Cl)c1ncccc1-n1nccn1
Reactant: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Agent: Cl
Agent: O=C(O)c1ncccc1-n1nccn1
Product: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-chloro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 122) from (1S,2S)-1-N-[3-methyl-5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 35; 100 mg, 0.34 mmol) and 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 71 mg, 0.37 mmol) to afford the title compound.
Reaction SMILES: O[C:2]1[C:3]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[O:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:20]([C:16]1[CH:15]=[C:14]([C:12]2[O:13][C:2]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:11]=2)[CH:19]=[CH:18][CH:17]=1)([O-:22])=[O:21]
Reactant: O=C(Nc1c(O)cccc1C(=O)O)c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)c1cccc2oc(-c3cccc([N+](=O)[O-])c3)nc12
Yield: 83.3 %

Procedure:
3-Hydroxy-2-(3-nitrobenzeneamido)benzoic acid (1.8 g, 6.0 mmol) and 4-methylbenzenesulfonic acid (2 g, 12.0 mmol) were added to toluene (36 mL) and the mixture was stirred under reflux for 10 hr. The solvents was evaporated under reduced pressure and the residue was washed with water (100 mL×3), filtered, the solid was dried in vacuum at 50° C. to obtain 2-(3-nitrophenyl)benzo[d]oxazole-4-carboxylic acid as a yellow solid (1.42 g, yield 83%). LC-MS (ESI) m/z 285 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]([CH:12]=1)[C:10]1[CH2:13][CH2:14][CH2:15][CH2:16][C:9]=1[N:8]=2)([O-])=O.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[CH:12]1[N:11]2[C:7](=[N:8][C:9]3[CH2:16][CH2:15][CH2:14][CH2:13][C:10]=32)[CH:6]=[CH:5][C:4]=1[NH:1][C:31]([C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:34])[F:35])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)=[O:32]
Reactant: O=[N+]([O-])c1ccc2nc3c(n2c1)CCCC3
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: O=C(Nc1ccc2nc3c(n2c1)CCCC3)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Conducting the operations similar to those of Example 1 using 2-nitro-6,7,8,9-tetrahydropyrido[1,2-a]benzimidazole and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH2:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOCC.O>[N:30]([CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH3:12])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCC(O)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC(N=[N+]=[N-])c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 54.6 %

Procedure:
A solution of 1-[4-(trifluoromethyl)phenyl]butan-1-ol (1.4 g, 6.4 mmol) and diphenylphosphoryl azide (2.8 ml, 12.8 mmol) in THF (6 mL) cooled to −10° C. under N2 was treated with DBU (1.9 mL, 12.8 mmol). The resulting solution was stirred at room temperature for 20 hours and then diluted with a mixture of ether and H2O. The organic phase was dried and concentrated and the residue purified by column chromatography using hexane:ethyl acetate (10:1) as eluent to furnish pure azide (0.85 g, 54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C

Procedure:
To a solution of (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (20.0 g) in dichloromethane (500 ml) were added triethylamine (13.5 ml) and methanesulfonyl chloride (7.4 ml) with stirring in an ice bath and the mixture was stirred at the same temperature for 4 hours. The solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4S)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (27.7 g) as a pale brown oil.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:31]3[NH:32][CH2:33][CH:34]([CH3:36])[N:35]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:26]=[C:27]([C:31]3[NH:32][CH:33]=[C:34]([CH3:36])[N:35]=3)[CH:28]=[C:29]([CH3:30])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(C3=NC(C)CN3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)cc(-c3nc(C)c[nH]3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1

Procedure:
A solution of 0.35 g (0.7 mMol) of methyl 4'-[[2-n-propyl-4-methyl-6-(4-methyl-imidazolin-2-yl)-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate in 10 ml of toluene is mixed with 0.16 g palladium (10% on activated charcoal) under nitrogen and the mixture is refluxed for 66 hours. Then the toluene is evaporated off, the residue is taken up in methylene chloride, filtered and evaporated down. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant methylene chloride to start with, later followed by methylene chloride/ethanol/ammonia (50:1:0.05, 20:1:0.02, 10:1:0.01 and 5:1:0,005). The uniform fractions are combined and evaporated down.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:28])[CH2:6][CH:7]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:28])[CH2:6][CH:7]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2([Br:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1
Reactant: COC(=O)CC(c1ccccc1)c1ccc(C(=O)C2CCCCC2)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CC(c1ccccc1)c1ccc(C(=O)C2(Br)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
A solution of 7.32 g (44.5 mmol) of bromine in 10 ml of methylene chloride is added dropwise at room temperature to a mixture of 10.18 g (37.10 mmol) of methyl3-phenyl-3-[4-(cyclohexylcarbonyl)phenyl]propionate in 250 ml of methylene chloride. The mixture is stirred for 16 hours at room temperature after which the reaction mixture is poured into a 5% aqueous sodium thiosulfate solution and stirred for 10 minutes. The organic layer is washed twice with 5% aqueous sodium thiosulfate solution, once with 10% sodium bicarbonate solution, dried over sodium sulfate, and concentrated to give 8.19.0 g (62.5%) of methyl3-phenyl-3-[4-((1-bromocyclohexyl)carbonyl)phenyl]propionate. Mass spectrum: m/z 429.1 (M+H)+.
Reaction SMILES: [C@@H:1]12[C:9](=[O:10])[NH:8][C:7](=[O:11])[C@@H:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2.[N:12]#[C:13]Br.CC(C)=O.C(N(CC)CC)C>C(OCC)(=O)C>[C:13]([N:8]1[C:7](=[O:11])[C@@H:2]2[CH2:3][CH:4]=[CH:5][CH2:6][C@@H:1]2[C:9]1=[O:10])#[N:12]
Reactant: O=C1NC(=O)[C@@H]2CC=CC[C@H]12
Reactant: N#CBr
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: N#CN1C(=O)[C@H]2CC=CC[C@H]2C1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Using a 250 mL round-bottomed flask equipped with a magnetic stir bar and an ice/salt bath, a suspension of cis-4-cyclohexene-1,2-dicarboximide (15.1 g, 100 mmol), cyanogen bromide (11.7 g, 110 mmol), and 100 mL of acetone was cooled to 0° C. Triethylamine (16.0 mL, 115 mmol) was added via syringe over a 12 minute period. The resulting peach slurry was allowed to stir for 15 minutes. The mixture was diluted with ethyl acetate and filtered to remove solid triethylamine hydrobromide. The filter cake was rinsed with ethyl acetate and the filtrate was concentrated using a rotary evaporator. The crude paste was partitioned between water and a 2:1 mixture of ethyl acetate/hexanes. The organic phase was washed with brine, dried (MgSO4), and concentrated to give a light brown solid. The crude product was purified by recrystallization using ethyl acetate/pet ether or ethyl acetate/hexanes to afford 11.5 g (65%) of a glossy off white solid, mp 136°-138° C.: IR (nujol) 2256 (nitrile), 1749 (carbonyl) cm-1 ; 1H NMR (200 MHz, CDCl3) δ 2.30 (ddd, 2, J=15, 4.4, 2.75 Hz), 2.64 (ddd, 2, J=15, 3.8, 2.75 Hz), 3.35 (dd, 2, J=3.5, 2.75 Hz), 5.98 (ddd, 2, J= 3.9, 1.7, 1.5 Hz); 13C NMR (50 MHz, CDCl3) δ 173.48, 127.52, 100.72, 40.08, 23.26; GC/MS m/e (relative intensity) 176 (29.5), 147 (11.1), 107 (20.0), 105 (23.3), 80 (44.0), 79 (100), 78 (35.1).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8](OCC)=O)[C:5]2[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:4]=2[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH2:25].[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[N:6]([CH:7]([OH:25])[CH3:8])[C:5]2[CH:13]=[C:14]([CH3:18])[C:15]([CH3:17])=[CH:16][C:4]=2[N:3]=1
Reactant: O
Reactant: CCOC(=O)Cn1c(C)nc2cc(C)c(C)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2nc(C)n(C(C)O)c2cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution of ethyl 2-(2,5,6-trimethylbenzimidazol-1-yl)acetate (6.15 g) in dry tetrahydrofuran (20 ml) was added to a suspension of lithium aluminium hydride (0.95 g) was dry tetrahydrofuran (60 ml) at 0° C. The reaction was allowed to warm to room temperature and stirred at room temperature for 1 hour. Water (1 ml) was added dropwise to the reaction followed by 15% sodium hydroxide (3 ml) and water (3 ml). The suspension was filtered and the solvent removed under reduced pressure. The product was dissolved in dichloromethane, dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was triturated with acetone, the solid filtered and dried under reduced pressure to yield the title compound (1.9 g, 37%), m.p. 191°-2° C. Found: C, 70.17; H, 8.07; N, 13.56. C12H16N2O requires: C, 70.59; H, 7.84; N, 13.72%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13](Cl)[N:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH2:17]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([NH:17][CH3:16])[N:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: COC(=O)c1cc(Cl)nc(C(C)(C)C)c1
Product: CNc1cc(C(=O)O)cc(C(C)(C)C)n1
Temperature: 130 °C

Procedure:
1.0 g (4.39 mmol) of methyl 2-tert-butyl-6-chloroisonicotinate [lit.: O. Isler et al., Helvetica Chimica Acta 1955, 38 (4), 1033-1046] and 3.8 ml (43.9 mmol) of a 40% strength aqueous methylamine solution were heated in a microwave oven (Biotage Initiator, with Dynamic Field Tuning) at 160° C. for 6 h. After cooling, the volatile components were removed on a rotary evaporator. The residue was taken up in 4 ml of semiconcentrated hydrochloric acid and once more heated in the microwave at 130° C. for 1 h. The product was then isolated directly by preparative HPLC (Method 12). Evaporation of the product fractions and drying of the residue under high vacuum gave 180 mg (92% pure, 18% of theory) of the title compound.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([NH2:23])=[CH:21][C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:19]2)[CH:15]=[CH:16][CH:17]=1)C1C=CC=CC=1.O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:23][C:22]1[N:18]([C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][C@H:10]([CH3:28])[CH2:9][OH:8])[N:19]=[C:20]([C:24]([CH3:25])([CH3:27])[CH3:26])[CH:21]=1
Reactant: C[C@H](COCc1ccccc1)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 78.4 %

Procedure:
A solution of Intermediate 151a (0.37 g, 0.97 mmol) in ethanol (IMS grade, 8 mL) was treated with water (1 mL) and ammonium formate (0.61 g, 9.7 mmol). The mixture was purged with N2 then 10% Pd/C (0.31 g, 0.29 mmol Pd) was added. The mixture was heated to reflux for 16 h then filtered through celite and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC, using 0-75% EtOAc in cyclohexane to give the title compound (0.22 g, 79%) as a pink gum. LCMS (Method 3): Rt 2.44 min, m/z 290.3 [MH+].
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[F:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][N:15]=[N+:16]=[N-:17].FC1C=CC=CC=1CN1C(C(N)=O)=C(C(N)=O)N=N1>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][N:15]1[C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:1]([C:7]([O:9][CH3:10])=[O:8])[N:17]=[N:16]1
Reactant: [N-]=[N+]=NCc1ccccc1F
Reactant: COC(=O)C#CC(=O)OC
Agent: NC(=O)c1nnn(Cc2ccccc2F)c1C(N)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1nnn(Cc2ccccc2F)c1C(=O)OC
Temperature: 90 °C
Reaction time: 5 h

Procedure:
The starting material may also be prepared as follows: A solution of 40 g (0.282 mole) of dimethyl acetylenedicarboxylate in 500 ml of toluene is added dropwise to a solution of 41.5 g (0.255 mole) of o-fluorobenzyl azide in 50 ml of toluene, which solution has been heated to 90° C. After a further 5 hours at 90° C., the toluene is stripped off, the reaction mixture is cooled and the crystalline product is filtered with suction. Recrystallisation from a 1:1 mixture of diethyl ether/petroleum ether yields dimethyl 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylate with a melting point of 49°-51° C.
Reaction SMILES: C([C:3]1[N:7]([CH:8]([CH3:12])[C:9]([NH2:11])=[O:10])[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30]N)[CH3:26]>O>[CH2:25]([N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][CH2:30][NH:11][C:9](=[O:10])[CH:8]([CH3:12])[N:7]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6]1)[CH3:26]
Reactant: CCN(CC)CCCN
Reactant: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1C(C)C(N)=O
Solvent: O
Product: CCN(CC)CCCNC(=O)C(C)n1cc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
A mixture of 27.3 g (0.085 mol) of ethyl 3,4-diphenyl-α-methyl-1H-pyrazole-1-acetamide of example 9 and 120 mL of 3-(diethylamino)propanamine was heated 5 hr on a steambath. The reaction was poured into water and extracted into ethyl acetate. The ethyl acetate layer was dried and stripped to an oil in which a solid slowly crystallized. The crystals were removed and recrystallized from cyclohexane to yield 6.2 g of N-[3-(diethylamino)propyl]-3,4-diphenyl-α-methyl-1H-pyrazole-1-acetamide, mp 87°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=2[N:14]=1.[CH2:25](N(CC)CC)[CH3:26].C(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH2:25]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:6]1[CH:5]=[CH:4][C:3]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=3[N:14]=2)=[C:2]([F:1])[CH:7]=1)[CH3:26]
Reactant: CCN(CC)CC
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCN4)cc3F)nc12
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 50F (150 mg) in methanol (6 mL) was added triethylamine (125 mL) and 32 wt/v % acetaldehyde in water (210 mL). The solution was stirred for 1 hour, treated with sodium cyanoborohydride (95 mg), stirred for 3 hours at ambient temperature and at 50° C. for 18 hours and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (CD3OD) δ 1.31-1.36 (m, 3H), 2.30-2.42 (m, 2H), 2.61-2.70 (m, 1H), 3.17-3.29 (m, 2H), 3.34-3.41 (m, 1H), 3.52-3.62 (m, 1H), 3.94-4.01 (m, 1H), 4.64-4.73 (m, 1H), 7.75 (t, J=7.98 Hz, 1H), 7.87 (d, J=7.67 Hz, 1H), 7.93 (d, J=11.35 Hz, 1H), 8.07 (d, J=7.98 Hz, 1H), 8.13 (d, J=7.67 Hz, 1H), 8.28 (t, J=7.52 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])(=[O:3])[CH3:2].O1[CH:15]2[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH:14]12.Cl[Si](C)(C)C.[I-].[Na+]>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:20][CH2:21]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH3:19])(=[O:3])[CH3:2]
Reactant: C=CCCCCCCOC(C)=O
Reactant: C1=CCCC2OC2CC1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Product: CCCC/C=C\CCCCCCCCCCOC(C)=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
This example is designed to produce Z-11-hexadecenyl acetate through the reaction shown in FIG. 3. To a dry 50-mL round-bottomed flask is added 4.5 g (0.026 mol) 7-octenyl acetate, 3.3 g (0.026 mol) 1,2-epoxy-5-cyclooctene and a magnetic stir bar. The solution is cooled to 0° C. and sparged with nitrogen for 10 minutes. Grubbs catalyst 848 (1.10 g, 1.30 mmol) is added and the reaction is stirred at 0° C. for 24 hours. The reaction is quenched by addition of 15 ml of 2M THP in IPA solution, warmed to 60° C. with stirring for 24 hours. Water (5 mL) is added and stirred vigorously for 10 minutes. The aqueous layer is separated, and the product washed with brine solution and dried over sodium sulfate. The product is purified by vacuum distillation, and then hydrogenated using 10% palladium on carbon (Pd/C) with a 5 psi overpressure of hydrogen. The catalyst is filtered off without further purification. The epoxide is converted to the cis olefin as described in (Tetrahedron Lett. 22, 3551 (1981)). There is sufficient detail to run the reaction 11,12-Epoxy-hexadecyl acetate is treated with 2.87 g (0.026 mol) chlorotrimethylsilane and 3.96 g (0.026 mol) sodium iodide. The reaction is slowly heated from room temperature to 60° C., until the starting materials are consumed. The mixture is then quenched with water and the organic phase was washed with an aqueous solution of sodium bicarbonate, and finally water. The organic phase is dried over sodium sulfate, acetylated with acetic anhydride and acetic acid and vacuum distilled to yield Z-11-hexadecenyl acetate.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19]([O:20]CC)=[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:17]=[N:16][C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:28](I)[CH3:29]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][N:16]([CH2:28][CH3:29])[C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C(C)=O)CC3)ncc2c1OCC
Reactant: CCI
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O

Procedure:
Following the procedure described in Example 37 using ethyl 2-(4-acetyl-1-piperazinyl)-5-ethoxypyrido[2,3-d] pyrimidine-6-carboxylate with ethyl iodide, there is obtained the product, m.p. 208° - 210°C with decomposition.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.C[O:23][C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:32](=[O:36])[CH2:31][CH2:30][CH2:29][C:28]=2[CH:27]=1)=O.CO>C1(C)C=CC=CC=1.C1COCC1>[OH:23][CH2:24][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C@@H:32]([OH:36])[CH2:31][CH2:30][CH2:29]2
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccc2c(c1)CCC[C@@H]2O
Temperature: -10 °C

Procedure:
To an oven-dried 2 L round-bottomed flask equipped with an argon inlet/outlet and magnetic stirring was added (R)-2-methyl-CBS-oxazaborolidine (7.4 mL of a 1 M solution in toluene, 7.4 mmol, Aldrich). Toluene (190 mL) was added and the reaction mixture was cooled in an ice-salt bath (bath temp.=−10° C). BH3—SMe2 was added (17 mL, 180 mmol, Aldrich), then 5-oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (30 g, 150 mmol, Albany Molecular) in 200 mL of THF was added over 5 h using a syringe pump. After the addition was complete, the reaction mixture was stirred for an additional 1 h. The reaction mixture was allowed to stir for 72 h at RT. The reaction mixture was poured into an addition funnel, and the mixture was added to 200 mL of MeOH, cooled in a ice-salt bath, over 30 min at such a rate that the internal temperature was kept below 0° C. The mixture was concentrated in vacuo to get a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.35-1.50 (m, 2H), 1.55-1.75 (m, 2H), 2.30 (s, 1H), 2.35-2.60 (m, 2H), 4.22 (s, 2H), 4.33 (s, 1H), 6.78 (s, 1H), 6.87 (d, 8.0 Hz, 1H), and 7.12 (d, 8.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][C@H:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1.C1(C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(Cl)Cl.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][C:11]1[CH:10]=[N:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:26]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH3:21])[CH2:27]3)=[CH:3][CH:4]=2)=[N:13][CH:12]=1
Reactant: C[C@H]1CNCCN1
Reactant: Cc1cnc(-c2ccc(Br)cc2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1cnc(-c2ccc(N3CCN[C@@H](C)C3)cc2)nc1

Procedure:
A mixture of 2-(4-bromophenyl)-5-methylpyrimidine 78 (250 mg, 1.008 mmol), palladium acetate (50 mg), cesium carbonate (400 mg, 1.23 mmol), (S)-2-methyl piperazine (200 mg, 2 mmol) and 2-Di-t-butylphosphino)-biphenyl (50 mg, 0.167 mmol) was stirred in dioxane:water (10 ml, v/v 5:1) at reflux temperature for 4 hours. The reaction was cooled, diluted with MeCl2 (100 ml) and H2O (50 ml). The organic layer was separated, dried (MgSO4), filtered and solvent evaporated. The residue was purified by chromatography eluting with 100% EtOAc then with 10% v/v MeOH/EtOAc/NH4OH yielding product 79 as a white solid. (220 mg. 81%) ESMS (MH, 269).
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].C(N(CC)CC)C.[C:18](OC)(=[O:23])[CH2:19][C:20]([CH3:22])=O>C1(C)C=CC=CC=1>[CH2:7]([N:9]1[C:18]([OH:23])=[CH:19][C:20]([CH3:22])=[N:10]1)[CH3:8]
Reactant: CCNN
Reactant: COC(=O)CC(C)=O
Agent: O=C(O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCn1nc(C)cc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 23 g of ethyl hydrazine oxalate and 22 ml of triethylamine in 500 ml of toluene was stirred at room temperature for 15 minutes. 17 ml of methyl acetoacetate was added and the mixture was azeotroped for 1.5 hours. The mixture was evaporated and the residue was purified by flash chromatography on silica gel using dichloromethane/methanol (97:3) for the elution to give 19 g of 2-ethyl-5-methyl-2H-pyrazol-3-ol as an orange solid.