Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([O:14]C)=[C:10]([CH3:13])[CH:11]=2)[C:6]([CH3:18])([CH3:17])[CH2:5]1)(=[O:3])[CH3:2].C(N1C2C(=C(C)C(O)=C(C)C=2)C(C)C1)(=O)C>>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:16])[C:9]([OH:14])=[C:10]([CH3:13])[CH:11]=2)[C:6]([CH3:18])([CH3:17])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1c(C)cc2c(c1C)C(C)(C)CN2C(C)=O
Agent: CC(=O)N1CC(C)c2c1cc(C)c(O)c2C
Product: CC(=O)N1CC(C)(C)c2c1cc(C)c(O)c2C
Yield: 74.9 %

Procedure:
Treatment of 15 (741 mg, 3 mmol) according to a procedure similar that used for making 11a afforded 16 (524 mg, 75% yield) as a colorless solid, mp 173°-174° C. Spectral data: 13C NMR (CD3 SOCD3): δ 11.7, 17.3, 23.9, 27.0, 40.6, 63.7, 115.4, 121.1, 122.8, 135.6, 149.2, 167.2; HRMS: calcd. for C14H19NO2 233.1415, fnd. 233.1416. Anal: calcd. for C14H19NO2C, 72.08, N, 6.00, H, 8.20, fnd. C, 71.88, N, 5.95, H, 8.22.
Reaction SMILES: CC[N:3](CC)CC.[Al+3].[Cl-].[Cl-].[Cl-].[CH:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.[C:22]1(=[O:28])[O:27][CH2:26][CH2:25][CH2:24][CH2:23]1>ClCCCl.ClC(Cl)C>[C:12]12([NH:3][C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: CCN(CC)CC
Reactant: O=C1CCCCO1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: O=C(CCCCO)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.6 mL (25 mmol) of Et3N in 6.7 mL of 1,2-dichloroethane was added drop by drop under ice cooling to a suspension of 2.47 g (18.3 mmol) AlCl3 in 13.3 mL of dichloroethane. At room temperature a solution of 2.77 g (18.3 mmol) adamantane and 1.55 mL (16.7 mmol) delta-valerolactone in 10 mL of 1,2-dichloroethane was added to the mixture. After one hour of stirring at room temperature the mixture was quenched with ice water and stirred for another 30 minutes. The suspension was filtered by Celite. After addition of dichloromethane, separation of the organic layer, washing it with water, drying it with Na2SO4 and the solvent was evaporated. The product can be taken for further reactions.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.F[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:37]1[CH:46]=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:47][CH3:48])[CH:43]=2)[C:38]=1[CH:49]=[O:50]>O1CCCC1.ClCCl.[Cl-].[NH4+]>[C:1]([O:5][C:6](=[O:23])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([CH:49]2[O:50][C:30]3[C:31](=[CH:32][CH:33]=[C:34]([F:36])[CH:35]=3)[C:37]3[C:38]2=[C:39]2[C:44](=[CH:45][CH:46]=3)[CH:43]=[C:42]([O:47][CH3:48])[CH:41]=[CH:40]2)=[CH:18][CH:17]=1)[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCN1CCCCC1)c1ccc(Br)cc1
Reactant: COc1ccc2c(C=O)c(-c3ccc(F)cc3F)ccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc2c3c(ccc2c1)-c1ccc(F)cc1OC3c1ccc(N(CCN2CCCCC2)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Dissolve (4-bromo-phenyl)-(2-piperidin-1-yl-ethyl)-carbamic acid tert-butyl ester in dry tetrahydrofuran (20 mL). Cool to −78° C. and add 1.6 M n-butyl lithium in hexanes (0.79 mL). After 30 minutes, add 2-(2,4-difluoro-phenyl)-6-methoxy-naphthalene-1-carbaldehyde (0.25 g, 0.839 mmol) and stir 45 minutes cold. Warm to room temperature over 1 hour. Reflux 2 hrs. Cool to room temperature and dilute with dichloromethane (20 mL) and saturated aqueous ammonium chloride (20 mL). Separate the organic layer and wash the aqueous layer twice with dichloromethane. Combine the organics and dry over magnesium sulfate. Filter and concentrate in vacuo. Purify the residue by column chromatography using a silica gel column eluting with a linear gradient beginning with dichloromethane and ending with 4:1 dichloromethane methanol to give 0.45 g (92%) of the title compound: mass spectrum (ion spray) m/z=583.3 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH:26]([C:29]1[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=1)([CH3:28])[CH3:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:35]([C:31]1[S:30][C:29]([CH:26]([CH3:27])[CH3:28])=[N:33][C:32]=1[CH3:34])=[O:36]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: Cc1nc(C(C)C)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1nc(C(C)C)sc1C(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), 2-isopropyl-4-methyl-thiazole-5-carboxylic acid (9.0 mg, 0.048 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (13 mg, 0.066 mmol), 1-hydroxybenzotriazole (9.0 mg, 0.066 mmol) and dichloromethane (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in minimum amount of dichloromethane and purified on silica gel column, which was eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (13 mg, 59% yield). 1H NMR (CDCl3): δ 0.96 (s, 3 H) 1.00-1.35 (m, 6 H) 1.38 (d, J=6.78 Hz, 6 H) 1.55-2.35 (m, 21 H) 2.39 (s, 3 H) 2.59 (m, 2 H) 2.95 (s, 3 H) 3.26 (m, 2 H) 5.37 (m, 1 H); MS: (M+H)+=510.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][N:6]1[C:10]2[C:11]([C:15]([O:17]C)=O)=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:19].O1CC[CH2:22][CH2:21]1>>[CH2:21]([C:15]([C:11]1[C:10]2[N:6]([CH3:5])[C:7](=[O:19])[NH:8][C:9]=2[CH:14]=[CH:13][CH:12]=1)([OH:17])[CH2:1][CH3:2])[CH3:22]
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1cccc2[nH]c(=O)n(C)c12
Product: CCC(O)(CC)c1cccc2[nH]c(=O)n(C)c12
Temperature: 40 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A solution of ethylmagnesium bromide (3M solution in diethyl ether; 32 mL, 96 mmol) was added dropwise to a suspension of methyl 3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-carboxylate (5.00 g, 24.2 mmol) in tetrahydrofuran (50 mL) at 0° C. The mixture was stirred at 40° C. overnight. The reaction was quenched with water and 1N HCl, extracted with ethyl acetate, washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from ethanol/diethylether to afford the title compound as colorless crystals (3.39 g, 70%). mp 199-201° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7]C(=O)OCC)[CH:2]=1.[CH3:13][O:14][CH2:15][CH:16]1[CH2:20][O:19][C:18](=O)[O:17]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[CH3:13][O:14][CH2:15][CH:16]1[O:17][C:18](=[O:19])[N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:20]1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(=O)Nc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COCC1CN(c2cccnc2)C(=O)O1
Yield: 83.6 %

Procedure:
A mixture of 16.8 g of ethyl pyridin-3-yl-carbamate, 20 g of 4-methoxymethyl-1,3-dioxolan-2-one and 2.8 g of potassium carbonate was heated to 160° for 3 h. The mixture was cooled and treated with ethyl acetate and water. The phases were separated, the aqueous phase was extracted with ethyl acetate and the organic phase was washed with saturated sodium chloride solution. The organic phases were combined, dried with magnesium sulfate and concentrated. Chromatography of the residue (21 g) on silica gel with ethyl acetate/methanol mixtures (1:0-20:1) yielded 17.6 g of (RS)-5-methoxymethyl-3-pyridin-3-yl-oxazolidin-2-one which was recrystallized from diethyl ether. M.p.: 65°-66°.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH:5]([CH3:25])[C:6]([C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:11]=[C:10]([CH2:21][CH3:22])[C:9]=1[C:23]#[N:24])=O.CN.Cl.O>CO.C(Cl)Cl>[CH2:21]([C:10]1[C:9]([C:23]#[N:24])=[C:8]([C:6]2[O:2][CH:3]=[CH:4][C:5]=2[CH3:25])[N:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:11]=1)[CH3:22]
Reactant: CCc1nn(-c2ccc(OC)cc2)c(C(=O)C(C)CC(OC)OC)c1C#N
Agent: CN
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCc1nn(-c2ccc(OC)cc2)c(-c2occc2C)c1C#N
Temperature: 25 °C
Reaction time: 14 h
Yield: 40 %

Procedure:
To a stirred solution of 5-(4,4-dimethoxy-2-methylbutanoyl)-3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonitrile (20 mg, 0.05 mmol) in MeOH (1.5 mL) were added methylamine (2.0 M solution in methanol, 0.20 mL, 0.4 mmol) and conc. HCl (0.1 mL) at ambient temperature in a closed microwave tube. The reaction mixture was stirred at ambient temperature for 14 h then additional methylamine (2.0 M solution in methanol, 2.70 mL, 5.4 mmol) and conc. HCl (0.3 mL) were added and the reaction was heated to 8° C. for 14 hours. Water and CH2Cl2 was added, the phases separated and the organic phase was concentrated under reduced pressure. Purification using a silica plug (heptane/CH2Cl2/Et2O-1:0:0-1:1:0-0:1:0-0:1:1) yielded 3-ethyl-1-(4-methoxyphenyl)-5-(3-methylfuran-2-yl)-1H-pyrazole-4-carbonitrile (5 mg, 0.02 mmol, 30%).
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1.Cl>C1COCC1>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[O:3][C:4]3[C:5]([C:11](=[O:13])[CH:12]=2)=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=3)=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)c3ccc(O)cc3o2)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (38.7 mmol, 3 equivalents) is added in one portion to a well-stirred solution of 2′,4′-dihydroxyacetophenone (12.9 mmol) in dry THF (15 ml) at −78° C. under an argon atmosphere. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After re-cooling it −78° C., a solution of 4-methoxybenzoyl chloride (14.2 mmol) in THF (20 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied onto a mixture of ice (300 g) and concentrated HCl (10 ml) and extracted with dichloromethane (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (100 ml) and sulfuric acid (0.5 ml) are added to the residue, and the mixture is heated at 95–100° C. under an argon atmosphere for from 30 minutes to one hour. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised from methanol to give 4′-methoxy-7-hydroxyflavone. 1H NMR (250 MHz, d6-DMSO): δ 10.90 (br s, OH), 8.01–7.11 (dm, 4H), 7.87 (d, 1H), 7.00 (d, 1H), 6.93 (d, 1H), 6.81 (s, 1H), 3.86 (s, 3H); 13C NMR (62.90 MHz, d6-DMSO): δ176.24 (s), 162.58 (s), 162.00 (s), 161.87 (s), 157.39 (s), 127.93 (s), 126.41 (s), 123.42 (s), 116.07 (s), 114.83 (s), 114.48 (s), 105.07 (s), 102.48 (s), 55.46 (s); EI-MS (70 eV) m/e (rel. abund.)=268.07356 (100). The product is beige and exhibits the UV absorption maximum at λ=323 nm with ε=26450 (in 2-propanol) (cf. FIG. 2).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].NCCCCS([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:41])[CH:25]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)=O.C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][S:5]([NH:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:41])[CH:25]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCBr
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCCC1CNS(=O)(=O)CCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCCC1CNS(=O)(=O)CCCBr
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
A solution of Part A 3-bromopropyl sulfonyl chloride (1.06 g, 4.8 mmol) in dichloromethane (5 mL) was added dropwise to a cooled (-10° C.) stirred solution of Example 6a, Part B amine (1.05 g, 3.02 mmol) and triethyl amine (1.44 mL, 9.6 mmol) in dichloromethane (15 mL). After a few minutes, a precipitate formed. The suspension was stirred at -10° C. for 2.5 hours, diluted with dichloromethane (35 mL) and washed with 1N HCl solution (2×15 mL). The dichloromethane solution was dried (MgSO4), filtered and the solvent was removed in vacuo. The crude oil was purified on silica gel (Merck, 150 mL) eluting with 50% ethyl acetate in hexane to give title compound as a white foam (1.160 g, 72%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[N:11]=[C:10]([C:25]2[CH:26]=[N:27][C:28]([C:31]([C@H:33]3[CH2:38][CH2:37][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:35][CH2:34]3)=O)=[CH:29][CH:30]=2)[CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C(OCC)(=O)C.O>[CH3:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][N:16]=2)[N:11]=[C:10]([C:25]2[CH:26]=[N:27][C:28]([C:31]([C@H:33]3[CH2:34][CH2:35][C@H:36]([C:39]([O:41][CH3:42])=[O:40])[CH2:37][CH2:38]3)=[CH2:1])=[CH:29][CH:30]=2)[CH:9]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)c2ccc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)cn2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=C(c1ccc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)cn1)[C@H]1CC[C@H](C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a flask was added methyltriphenylphosphonium bromide (444 mg, 1.24 mmol) and THF (3.1 mL). The mixture was cooled to 0° C., and potassium tert-butoxide (1.0 M in THF, 1.39 mL, 1.39 mmol) was added. The mixture was stirred at 0° C. for 30 minutes. A solution of methyl trans-4-[(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)carbonyl]cyclohexanecarboxylate (310 mg, 0.622 mmol) in THF (2 mL) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The reaction was diluted with ethyl acetate and water, and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (0-60%) to afford methyl trans-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)ethenyl]cyclohexanecarboxylate as a white solid. MS ESI calcd. for C27H28F3N4O2 [M+H]+ 497. found 497.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[N:38]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[N:38]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Cc1nccc(Br)n1
Product: Cc1nccc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)n1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2-methylpyrimidine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.159, m/z=450; 1H NMR (CDCl3) 1.33 (m, 3H), 1.52 (m, 3H), 1.63 (m, 3H), 1.80-1.95 (m, 2H), 2.15-2.30 (m, 3H), 2.75 (s, 3H), 2.90 (m, 1H), 3.51 (m, 2H), 5.68 (m, 1H), 6.99 (m, 4H), 7.20 (m, 2H), 7.41 (m, 1H), 7.79 (d, 2H), 8.60 (m, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[C:4]=1[CH3:12].B(Br)(Br)Br>ClCCCl>[CH3:12][C:4]1[C:5]2[C:6](=[N:7][O:8][N:9]=2)[CH:10]=[CH:11][C:3]=1[OH:2]
Reactant: COc1ccc2nonc2c1C
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: Cc1c(O)ccc2nonc12

Procedure:
To a solution of 5-methoxy-4-methyl-2,1,3-benzoxadiazole (3.00 g, 18.2 mmol) in 120 mL of DCE was added 17.6 mL of BBr3 at one portion and the mixture was stirred at reflux for 12 hours under Ar, then the solvent was removed under reduced pressure and the residue was purified by silica gel column to give 4-methyl-2,1,3-benzoxadiazol-5-ol.
Reaction SMILES: [C:1]([NH:4][C:5]([C:7]1[C:12]([NH2:13])=[N:11][C:10]([NH2:14])=[C:9]([Cl:15])[N:8]=1)=[O:6])(=[NH:3])N.[CH2:16]([N:19]=[C:20]=[O:21])[CH2:17][CH3:18].C[N:23](C)C=O>>[NH2:13][C:12]1[C:7]([C:5]([N:4]=[CH:1][NH:3][NH:23][C:20]([NH:19][CH2:16][CH2:17][CH3:18])=[O:21])=[O:6])=[N:8][C:9]([Cl:15])=[C:10]([NH2:14])[N:11]=1
Reactant: N=C(N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CN(C)C=O
Reactant: CCCN=C=O
Product: CCCNC(=O)NNC=NC(=O)c1nc(Cl)c(N)nc1N
Temperature: 90 °C

Procedure:
N-amidino-3,5-diamino-6-chloro-2-pyrazinecarboxamide (4.58 g., 0.02 mole) dissolved in N,N-dimethylformamide (120 ml.) is treated dropwise with propylisocyanate (1.87 g., 0.022 mole) over a 10 min. period at 90° C. The solution is heated at 90° C. for 1 hour, filtered and poured into water (150 ml.) to precipitate 3,5-diamino-6-chloro-N-{[ (propylaminocarbonyl)amino]aminomethyl-}-2-pyrazinecarboxamide which on recrystallization from n-propanol gives 3.14 g. melting at 220°-221° C.
Reaction SMILES: [C:1](#N)C.[F:4][C:5]([F:11])([F:10])[S:6]([O-:9])(=[O:8])=[O:7].[Na+].FF.[F-:15].[Na+].C[C:18]1[C:19]([CH3:24])=[N:20][CH:21]=[CH:22][CH:23]=1>>[F:4][C:5]([F:11])([F:10])[S:6]([O-:9])(=[O:8])=[O:7].[F:15][N+:20]1[C:19]([CH3:24])=[CH:18][CH:23]=[CH:22][C:21]=1[CH3:1]
Reactant: [F-]
Reactant: CC#N
Reactant: Cc1cccnc1C
Agent: FF
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Product: Cc1cccc(C)[n+]1F

Procedure:
In 20 ml of anhydrous acetonitrile 0.50 g (4.67 mmoles) of 2.6- dimethylpyridine and 0.803 g (4.67 mmoles) of sodium trifluoromethanesulfonate as the XM reactant were dissolved, and to the resultant solution a mixed gas of fluorine and nitrogen (1:9) was added at a rate of 30 ml/min. at -40° C. under vigorous stirring. The amount of the fluorine gas introduced amounted to 8.93 mmoles. After the completion of the reaction, sodium fluoride was filtered and the solvent was distilled off. The resultant residue was recrystallized from THF to give 0.88 g (yield: 73%) of N-fluoro-2,6-dimethyl-pyridinium trifluoromethanesulfonate. The resultant product was further recrystallized with THF/acetonitrile to obtain 0.82 g (yield: 69%), the physical properties of which are shown in Table 6.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:19]1[N:20]=[CH:21][N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=1)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7]2)[CH3:2]>C(O)(=O)C.[C].[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14]([C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)([OH:18])[CH:15]([CH3:17])[CH3:16])[CH:8]=[CH:7]2)[CH3:2]
Reactant: CCOc1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
1-(6-Ethoxynaphthalen-2-yl)-1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanol (0.60 g) was dissolved in acetic acid (10 ml). To the solution was added 10% palladium carbon (0.2 g), and the mixture was stirred under hydrogen atmosphere at 50° C. for 2 h then at 60° C. for 3 h. The catalyst was filtered off, filtrate was concentrated to dryness. Recrystallization from THF-ethyl acetate gave the titled compound (0.21 g) as a colorless powder.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCN(C(C)C)C(C)C.[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23](Cl)=[O:24])=[N+:19]=[N-:20]>ClCCCl>[N:18]([C:21]([CH3:27])([CH3:26])[CH2:22][C:23]([N:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[O:24])=[N+:19]=[N-:20]
Reactant: CCCCCCNC
Reactant: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCCCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a stirred ice cold solution of N-methylhexan-1-amine (4.69 mL, 1.0 equiv, 30.9 mmol) and DIEA (7.0 mL, 1.3 equiv, 40.2 mmol) in anhydrous DCE (150 mL) was added 3-azido-3-methylbutanoyl chloride (5.0 g, 30.9 mmol) in small portions over 5 min. The reaction was removed from the ice bath and stirred at room temperature for 1 h. The reaction mixture was poured into a separatory funnel and washed with 1 M HCl (3×100 mL) and saturated sodium hydrogen carbonate (2×100 mL). The organic layer was separate and dried over anhydrous MgSO4, filtered, concentrated and dried under high vacuum to give a yellow oil (5.14 g, 72.0%). This material was used without further purification. 1H NMR (CDCl3, 400 MHz): δ 0.88-0.94 (m, 3H), 1.2-1.35 (m, 6H), 1.47 (d, 6H), 1.47-1.66 (m, 2H), 2.51 (s, 2H), 2.94-3.04 (d, J=40 Hz, 3 H), 3.30-3.40 (m, 2H). LRMS (ESI+) for C12H24N4O (240.2); Found: 241 (MH+).
Reaction SMILES: CI.[CH3:3][O:4][CH:5]([O:10][CH3:11])[CH2:6][C:7](=O)[CH3:8].C[CH2:13][O:14]CC>>[CH3:3][O:4][CH:5]([O:10][CH3:11])[CH2:6][CH:7]([CH2:13][OH:14])[CH3:8]
Reactant: CCOCC
Reactant: COC(CC(C)=O)OC
Solvent: CI
Product: COC(CC(C)CO)OC
Temperature: 25 °C
Yield: 54 %

Procedure:
CH3I (18.5 mL, 297 mmol) in 50 mL of ether was added slowly, to maintain reflux, to a suspension of Mg (6.0 g, 250 mmol) in 50 mL of ether. The solution was vigorously stirred during the addition. After the magnesium was consumed, the solution was chilled with an ice bath to ≅5° C. Acetylacetaldehyde dimethyl acetal (16.5 mL, 124 mmol) in 50 mL of ether was added very slowly, over a period of 2 h. After the addition was complete, the reaction was stirred for an additional hour while warming to room temperature. The reaction was quenched with 1 mL of saturated (NH4)2SO4 (aq) and filtered. The residue was washed with ether (2×50 mL). The combined filtrates were dried over Na2SO4, and the solvent was removed under water aspirator vacuum (67 mmol, 54% yield). Distillation of the residue yielded 9.9 g of 3-hydroxymethylbutanal dimethyl acetal, bp4.2 53°-56° C. bp10 60°-65° C., bp14 72°-79° C. in agreement with Malik, O. P.; Kapil, R. S., Anand, N., Ind. J. Chem. 14B (1976) 449); 1H--NMR (200 MHz, CDCl3) δ 1.24 (s, 6H, CH3), 1.80 (d, J=5.9 Hz, 2 H, CH2), 3.36 (s, 6 H, CH3O), 3.41 (s, 1 H, OH), 4.66 (t, J=5.9 Hz, 1 H, CH), 13C--NMR (50 MHz, CDCl3) δ 29.46 (CH3), 43.85 (CH2), 52.61 (CH3O), 68.63 (COH), 102.51 (CH).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH3:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH3:17])[CH:10]=2)[CH2:27][CH2:26]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
53 mg (98%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-ethyl-1H-pyrazol-5-yl)propanal (31 mg, 0.138 mmol), 1-(2-fluorophenyl)piperazine (28 mg, 0.154 mmol), DIPEA (0.036 mL, 0.206 mmol) and NaBH(OAc)3 (89 mg, 0.418 mmol).