Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([CH:14]3[CH2:17][C:16](=[O:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:17][C@H:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C([C@H]1C[C@@H](O)C1)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]cyclobutanone (50 mg, 0.2 mmol) in MeOH (2.5 ml) at 0° C. was added NaBH4 (3.7 mg, 0.1 mmol). After 10 mins the reaction mixture was warmed to RT and stirred for a further 1 h. The solvent was evaporated in vacuuo and the crude solid was partitioned between DCM and 0.5 M NaOH. The organic phase was separated, dried (Na2SO4), filtered and concentrated at reduced pressure. The resulting yellow oil was purified by silica gel FCC (eluant DCM.MeOH/NH3 90:10:1) to provide the title compound as off white solid (35 mg, 70%).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:7]Cl.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCC.[I-].[K+].C1(C)C=CC=CC=1.O1CCCC1>[CH3:15][C:14]([CH3:16])([CH2:7][C:6]1[CH:5]=[C:4]([CH3:3])[CH:11]=[C:10]([CH3:12])[CH:9]=1)[CH:13]=[O:17]
Reactant: Cc1cc(C)cc(CCl)c1
Reactant: CC(C)C=O
Agent: CCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(CC(C)(C)C=O)c1
Temperature: 75 °C
Yield: 55.6 %

Procedure:
A pre-mix of 125 g of 30% by weight sodium hydroxide solution, 5 g of potassium iodide, 10 g of tetradecyltrimethylammonium bromide, 200 ml of tetrahydrofuran and 200 ml of toluene was heated to 75° C. A mixture of 155 g of 3,5-dimethylbenzyl chloride, 110 g of isobutyraldehyde, 50 ml of tetrahydrofuran and 50 ml of toluene was added dropwise to this pre-mix while stirring vigorously. The entire mixture was then boiled under reflux for 6 hours. The phases were then separated and the organic phase was first washed with warm water and then filtered with the addition of activated carbon. Finally, distillation was carried out using a packed column with wire spirals. The distillation, carried out in a temperature range of from 72° C. to 74° C. at 0.25 mbar, yielded 106 g of 92% 2,2-dimethyl-3-(3,5-dimethylphenyl)-propionaldehyde.
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([C:55]([O:57][CH2:58][C:59]1C=CC=[CH:61][CH:60]=1)=[O:56])[C@H](C(N[C@H](C(C(OCC)=O)=O)CC1C=CC=CC=1)=O)CC(C)C.C(OCCCC)CCC.[Na].C(Cl)(Cl)Cl>C(O)CCC.CO>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:2]([C:7]([NH:9][C@H:10]([C:18]([C:55]([O:57][CH2:58][CH2:59][CH2:60][CH3:61])=[O:56])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Na]
Solvent: CCCCO
Solvent: CCCCOCCCC
Solvent: CO
Product: CCCCOC(=O)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Yield: 43 %

Procedure:
This compound was prepared from Z-Leu-Phe-OH and butyl oxalyl chloride in 43% yield by the procedure described for the synthesis of Z-Leu-Phe-CO2Et, except that butyl oxalyl chloride was used in place of ethyl oxalyl chloride and sodium butyloxide in butanol was used for enol ester hydrolysis. Single spot on TLC, Rf =0.54 (CHCl3 :CH3OH=50:1) MS(FAB) m/e=497 (m+1), 1H NMR (CDCl3) ok.
Reaction SMILES: CN1C(=O)CCC1.[CH3:8][C:9]([O-:12])(C)[CH3:10].[Na+].CC(O)C.Br[C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Br:25])[CH:24]=1>C1(C)C=CC=CC=1>[Br:25][C:23]1[CH:22]=[N:21][CH:20]=[C:19]([O:12][CH:9]([CH3:10])[CH3:8])[CH:24]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CC(C)O
Product: CC(C)Oc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To NMP (15 eq, 313 mmol, 30.4 ml), NaOtBu (1.5 eq, 31.3 mmol, 3.01 g) is added portion-wise. The mixture is stirred for 1 h at r.t., then 2-propanol (15 eq, 313 mmol, 24 ml) is added over a period of 15 min, followed by the addition of 3,5-dibromopyridine (Sigma-Aldrich, St. Louis, USA) (1 eq, 20.9 mmol, 5.0 g). The resulting mixture is heated at 75° C. for 2 h. After cooling down to r.t., toluene (30 ml) is added and the mixture is washed with water, dried over MgSO4, filtered, and concentrated. Purification of the crude product using column chromatography (hexane/EtOAc) yields the title compound; [M+H]+=217.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]([C:14]([OH:16])=[O:15])[CH2:3][CH2:2]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: ClCc1ccccc1
Reactant: O=C(O)C1CCCc2[nH]c3ccccc3c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCCc2[nH]c3ccccc3c21

Procedure:
A stirred mixture of 13 g. 1,2,3,4-tetrahydrocarbazole-4-carboxylic acid, 7.8 g. benzyl chloride and 6.5 g. sodium carbonate in dry dimethylformamide was heated on a steam bath for one hour and filtered. The dimethylformamide was evaporated under reduced pressure and the resulting oil was taken up in ether. The ether solution was washed with water, dried and evaporated to give, after recrystallization, 15.5 g. of the title compound, m.p. 108°-112°C. (heptane).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[O:49]=[C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:56](=[O:67])[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=2[C:63]([F:66])([F:65])[F:64])[CH2:54][CH2:55]1)[CH2:47][NH:46][C:21]([C:19]1[CH:18]=[N:17][N:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:20]=1)=[O:23]
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnn(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 24.8 %

Procedure:
DIPEA (223 mg, 0.3 mL, 1.72 mmol) was added to a stirred solution of 1-phenyl-1H-pyrazole-4-carboxylic acid (65 mg, 0.34 mmol) in DMF (5 mL). HOBT (51 mg, 0.38 mmol) and EDCI (165 mg, 0.86 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (133 mg, 0.38 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 41 mg (24.55% yield) of 1-phenyl-1H-pyrazole-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.62%. 1H NMR (DMSO-d6): δ 9.0 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.9-7.74 (m, 4H), 7.7 (t, 1H), 7.6 (t, 3H), 7.4 (t, 1H), 4.24 (d, 2H), 3.8 (s, 1H), 3.66 (s, 3H), δ 3.5 (s, 2H), 3.2 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[C@H:17]1[CH2:32][N:20]2[CH2:21][CH2:22][N:23]([C:25]3[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:24][C@@H:19]2[CH2:18]1)(=O)=O>CN(C=O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C@@H:17]2[CH2:32][N:20]3[CH2:21][CH2:22][N:23]([C:25]4[N:26]=[CH:27][C:28]([F:31])=[CH:29][N:30]=4)[CH2:24][C@@H:19]3[CH2:18]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reactant: OCc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(CO[C@H]2C[C@H]3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
A solution of 1.15 mL (10.2 mmol) of 4-fluorobenzyl alcohol in 35 mL of dry DMF was treated with 0.48 g (12 mmol) of sodium hydride (60% oil dispersion), and the mixture was stirred at 50° C. for 30 minutes. A solution of 1.15 g (3.64 mmol) of (7R,8aS)-7-methanesulfonyloxy-2-(5-fluoropyrimidin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 7) in 35 mL of dry DMF was added and the solution stirred at 100° C. for 18 hours. The solution was cooled, diluted with water, and extracted with diethyl ether (2×). The combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with ethyl acetate gave 0.25 g (20%) of the title compound. Mp (.D-(−)-tartrate) 76-81° C. 13C NMR (base, CDCl3): δ 36.3, 43.6, 48.8, 51.3, 60.2, 61.9, 70.4, 76.6, 115.0, 115.3, 129.43, 129.53, 134.0, 144.9, 145.2, 149.9, 153.2, 158.9, 160.6, 163.9. HRMS calc'd for C18H20F2N4O (MH+): 347.1683, found: 347.1706.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[C:13]([CH2:24]O)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:33])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[C:13]([CH2:24][Cl:33])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1c(CO)n(CC2CC2)c(=O)c2ccc(OCc3ccccc3)cc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCOc1c(CCl)n(CC2CC2)c(=O)c2ccc(OCc3ccccc3)cc12
Yield: 96.6 %

Procedure:
To a suspension of 6-benzyloxy-4-butoxy-2-cyclopropylmethyl-3-hydroxymethyl-1(2H)-isoquinolinone (6.11 g, 15 mmol) in toluene (50 mL) was added thionyl chloride (2.2. mL, 30 mmol). The obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-benzyloxy-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone (6.17 g, 96.7%) as crystals.
Reaction SMILES: CS[C:3]1[N:8]=[N:7][C:6](SC)=[C:5]2[CH:11]=[N:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:4]=12.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[O:24]1[CH2:25][CH2:26][N:21]([C:3]2[N:8]=[N:7][C:6]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:5]3[CH:11]=[N:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:14][C:4]=23)[CH2:22][CH2:23]1
Reactant: CSc1nnc(SC)c2cc(-c3ccccc3)ncc12
Reactant: C1COCCN1
Product: c1ccc(-c2cc3c(N4CCOCC4)nnc(N4CCOCC4)c3cn2)cc1
Temperature: 180 °C

Procedure:
1 part by weight of 1,4-dimethylmercapto-7-phenylpyrido(3,4-d)pyridazine and 10 parts by volume of morpholine are placed in a glass tube, and the glass tube is sealed. The reaction system is heated at 180° C for 8 hours. The excess amount of morpholine is removed by evaporating under reduced pressure, and water is added to the residue. Thus precipitated crude crystals are collected by filtration. The crude crystals are adsorbed on a column packed with silica-gel, followed by eluting with a mixture of acetone and benzene (1:4). The eluate is concentrated under reduced pressure and recrystallized from methanol to obtain 1,4-dimorpholino-7-phenylpyrido(3,4-d)pyridazine as pale yellow needles melting at 186° to 188° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:12]=2[I:21])=[C:7]([I:22])[CH:6]=1)=[O:4].[OH-].[K+].O>C1COCC1>[I:21][C:12]1[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=1[I:22]
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2I)c(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(C(=O)O)cc2I)c(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
2,2′-Diiodo-biphenyl-4,4′-dicarboxylic acid dimethyl ester (3.24 g, 6.21 mmol) was dissolved in 20 mL THF and KOH (1.02 g, 2.5 eq.) was added, followed by 5 mL water. The reaction was stirred at room temperature overnight. The reaction was heated to 50° C. for 7 hours. The reaction was cooled to room temperature. Organic solvent was removed by rotovap. The aqueous layer was acidified with concentrated HCl to give pale white solid. The solid was filtered and dried on vacuum overnight to give the product 2,2′-Diiodo-biphenyl-4,4′-dicarboxylic acid (2.74 g, yield 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:11][CH:12]=[CH2:13])[C:8]([OH:10])=[O:9])=[O:5].S(Cl)(Cl)=O.O.[C:24](=O)([O-])O.[Na+]>CO>[CH3:24][O:9][C:8](=[O:10])[C@@H:7]([NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:18])[CH2:11][CH:12]=[CH2:13]
Reactant: C=CC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: C=CC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a mixed solvent of 2N aqueous sodium hydroxide solution (27.4 ml) and THF (55 ml), L-allylglycine (5.22 g) was dissolved, and 2,6-dichlorobenzoyl chloride (7.79 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 1 hour. After concentrating the reaction solution to remove methanol, water (100 ml) was added thereto and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 3N hydrochloric acid in small portions thereto, and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid (11.65 g). NMR (H1, CDCl3): δ 2.66-2.73 (1H, m), 2.80-2.86 (1H, m), 4.99 (1H, td, J=7.6, 5.6 Hz), 5.18-5.25 (2H, m), 5.76-5.86 (1H, m), 6.39 (1H, brd, J=7.6 Hz), 7.25-7.34 (3H, m) (2) Under an argon atmosphere, a solution of (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid (11.46 g) in methanol (120 ml) was cooled to 0° C. Thionyl chloride (5.22 ml) was added dropwise to the solution while keeping the reaction temperature not higher than 10° C., and thereafter the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and sodium hydrogen carbonate was added thereto in small portions to neutralize it. After concentrating the reaction solution to remove methanol, aqueous layer was extracted twice with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was recrystallized from hexane/ethyl acetate mixed solvent to obtain (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (11.68 g). NMR (H1, CDCl3): δ 2.62-2.69 (1H, m), 2.76-2.83 (1H, m), 3.79 (3H, s), 4.96 (1H, td, J=7.8, 5.4 Hz), 5.14-5.21 (2H, m), 5.72-5.82 (1H, m), 6.42 (1H, brd, J=6.8 Hz), 7.25-7.34 (3H, m)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[CH:16]1([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2I)[CH2:18][CH2:17]1.O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)(Cl)Cl.[Cu](I)I.CO>[CH:16]1([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=3)[C:10]2=[O:13])[CH2:18][CH2:17]1
Reactant: O=C1NCCc2ccc(C(F)(F)F)cc21
Reactant: Ic1cnccc1C1CC1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1c2cc(C(F)(F)F)ccc2CCN1c1cnccc1C1CC1
Temperature: 120 °C
Reaction time: 24 h
Yield: 12.9 %

Procedure:
7-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one (I-4-d: 100 mg, 0.465 mmol) was reacted with 4-cyclopropyl-3-iodopyridine (I-73c: 125.3 mg, 0.51 mmol), 1,4-dioxane (5 mL), copper iodide (8.8 mg, 0.0465 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (6.6 mg, 0.0465 mmol) and potassium phosphate (246 mg, 1.16 mmol). The resulting mixture was stirred for 24 hours at 120° C. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was concentrated to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3), followed by preparative HPLC afforded 20 mg of the product (12.9% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14].N1C=CC=CC=1.[C:22]1([CH3:34])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[C:22]1([CH3:34])[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[S:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:10](=[O:15])[CH2:11][CH2:12][C:13]=1[CH3:14])(=[O:31])=[O:32]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC1=C(c2cc(C)ccc2N)C(=O)CC1
Solvent: c1ccncc1
Product: CC1=C(c2cc(C)ccc2NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)CC1

Procedure:
0.700 g (3.25 mmol) of 2-(2-amino-5-methylphenyl)-3-methyl-2-cyclopenten-1-one, 0.283 g (3.58 mmol) of pyridine, 0.782 g (3.58 mmol) of 2-mesitylenesulfonyl chloride, and 3 mL of M.C were loaded to a 20 mL vial, and then reacted for 12 hours. The work-up was the same as in Example 7 (1.29 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[O:27])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[O:27]=[C:19]1[N:18]([C:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:28])[CH2:13][CH:14]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20]1
Reactant: O=c1[nH]c2ccccc2n1C1=CCN(CCCC(O)c2ccc(F)cc2)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CC=C(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2.0 g of 1-(p-fluoro-phenyl)-4-[4-(2-oxo-1-benzimidazolinyl)-1,2,3,6-tetrahydro-1-pyridyl]-1-butanol in 60 ml of chloroform at room temperature, was added portionwise 3.2 g of a fine powder of manganese dioxide. After completion of addition, the mixture was stirred for another 2 hours at room temperature, and the precipitate was filtered off. The filtrate was concentrated to dryness under reduced pressure, and the residue was recrystallized from dioxane containing water, to obtain γ-[4-(2-oxo-1-benzimidazolinyl)-1,2,3,6-tetrahydro-1-pyridyl]-p-fluorobutyrophenone, melting at 146° - 147 5°C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[F:8][C:9]([F:15])([F:14])[C:10](OC)=[O:11]>CO>[F:8][C:9]([F:15])([F:14])[C:10]([NH:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])=[O:11]
Reactant: COC(=O)C(F)(F)F
Reactant: NC1CCNC1=O
Solvent: CO
Product: O=C1NCCC1NC(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
A suspension of Intermediate 2 (181 g), methyl trifluoroacetate (218 ml) and methanol (2.6 l) was stirred for 2 h. The solvent was then removed in vacuo to afford the title compound as a cream solid (355 g). Mass spec. MNH4+ (found) 214 MNH4+ (calculated) 214
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH2:23][CH2:24][O:25][CH3:28])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CI
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CCCO)nc3N21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A solution of 160.0 mg (0.46 mmol) (4R,9aR)-6-(3-hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 4 ml tetrahydrofuran was cooled to 0 deg C. and treated with 24.0 mg (0.51 mmol, 60% dispersion in mineral oil) sodium hydride. After 30 min 32 μl (0.51 mmol) methyl iodide was added and the cooling bath was removed. After 6 h another 0.64 μl (1.02 mmol) methyl iodide was added and the reaction was stirred overnight. The reaction mixture was poured into water and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:4) as eluant to afford the desired compound as a colorless oil (73.9%).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:11](N)=[C:10]([CH3:13])[CH:9]=[CH:8][N:7]=1.N([O-])=[O:15].[Na+]>OS(O)(=O)=O.O>[OH:15][C:11]1[C:6]([CH:2]=[O:1])=[N:7][CH:8]=[CH:9][C:10]=1[CH3:13]
Reactant: O=N[O-]
Reactant: Cc1ccnc(C2OCCO2)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccnc(C=O)c1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(1,3-dioxolanyl)-4-methyl-3-aminopyridine (0.60 g, 3.3 mmol) in 15 mL of 10% H2SO4 at 0° C. (ice bath) with stirring was added dropwise a solution of NaNO2 (0.38 g, 5.5 mmol) in 3 mL of water. The mixture was stirred at 0° C. for 15 min and then heated in a steam-bath for 30 min. The resulting solution was evaporated at room temperature under reduced pressure to yield 3-hydroxy-4-methyl-2-formylpyridine as a syrup, which was dissolved in 15 mL of water, decolorized with charcoal and filtered. To the filtrate was added a solution of thiosemicarbazide (0.31 g, 3.3 mmol) in 5 mL of 5% HCl. The mixture was refluxed for 30 min, cooled and the yellow precipitate was filtered, washed with water, and recrystallized from aqueous ethanol solution (1:1, v/v) containing 5% conc. HCl to afford 0.21 g (30%) of product: the mp and all spectroscopic data were identical with those obtained in Example XLIII.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.Cl.[O:12]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]1.C(N(CC)CC)C>CCO.O>[I:8][C:7]1[C:2]([NH:17][C@@H:14]2[CH2:15][CH2:16][O:12][CH2:13]2)=[N:3][C:4]([NH2:10])=[N:5][C:6]=1[CH3:9]
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: N[C@@H]1CCOC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N)nc(N[C@@H]2CCOC2)c1I
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A mixture of 4-chloro-5-iodo-6-methylpyrimidin-2-amine (7.03 g, 26.08 mmol), (R)-tetrahydrofuran-3-amine hydrochloride (Milestone PharmTech, 3.90 g, 31.3 mmol) and triethylamine (9.236 g, 91.3 mmol) in EtOH (150 mL) and water (50 mL) was refluxed for 2-3 days. The reaction was monitored by LC/MS. After completion, the reaction mixture was cooled to ambient temperature and partitioned between 150 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted by ethyl acetate 3 times. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate afforded (R)-5-iodo-6-methyl-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (4.53 g, 54% yield). MS (EI) for C9H13IN4O: 321.0 (MH+).