Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([OH:17])([CH3:16])[CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl>>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]([OH:17])([CH3:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CC(O)(Cn1ccnc1)c1cc(F)ccc1O
Reactant: ClCc1ccc(Cl)cc1Cl
Product: CC(O)(Cn1ccnc1)c1cc(F)ccc1OCc1ccc(Cl)cc1Cl
Yield: 31.6 %

Procedure:
The general procedure of Example 6 was repeated using 4-fluoro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol [compound (2-4)] and 2,4-dichlorobenzyl chloride, to thereby yield 2-(2-((2,4-dichlorobenzyl)oxy)-5-fluorophenyl)-1-(1H-1-imidazolyl)-2-propanol as colorless crystals (yield: 31.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33]>CC(C)=O.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:33][CH:32]=[CH2:31])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1
Reactant: Cc1c(CCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)c(C)c(CCC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Using 845 mg of the product of Example 23 as starting material, diluted in 23 ml of dimethyl ketone, 476 mg of potassium carbonate and 225 μl of allyl bromine was added. The reaction was refluxed overnight. The reaction was then diluted with water and the acetone removed in vacuo. Then the reaction was extracted with CH3CO2Et and the organic phase was dried and concentrated to yield after flash chromatography (hexane 8, ethyl acetate 2) 790 mg of the compound, which was then hydrolyzed following the procedure of Example 2.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:29])([F:28])[F:27])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16]C(=O)C3C=CC(Cl)=CN=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1.[Cl:30][C:31]1[C:32]([C:39]([OH:41])=O)=[N:33][CH:34]=[C:35]([C:37]#[N:38])[CH:36]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:27])([F:29])[F:28])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:39](=[O:41])[C:32]3[C:31]([Cl:30])=[CH:36][C:35]([C:37]#[N:38])=[CH:34][N:33]=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1
Reactant: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@]1(c2cc(NC(=O)c3ncc(C#N)cc3Cl)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 22.2 %

Procedure:
A flask was charged with (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (6a, 0.075 g, 0.257 mmol) and 3-chloro-5-cyanopicolinic acid (Bionet Research, 0.047 g, 0.257 mmol). The solids were dissolved in a mixture of THF (2 mL)/MeOH (1 mL) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (Aldrich, 0.129 g, 0.436 mmol) was added. The reaction was stirred at RT for 25 min. Additional 0.5 equiv. chloro-5-cyanopicolinic acid and 1 equiv. 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride were added. After 1 hour, the reaction was quenched with aqueous saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. The filtrate was concentrated and purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 80% over 20 min. The product containing fractions were combined and neutralized with aqueous sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (0.026 g, 0.057 mmol, 22.18% yield) as white solid. MS m/z=457 [M+H]+. Calculated for C18H13ClF4N6O2: 456.8
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[N:3]1[C:9]1[S:10][C:11]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Br)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][N:6]2[CH2:5][CH:4]([CH3:8])[N:3]([C:9]3[S:10][C:11]4[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:12]=4[N:13]=3)[CH:2]([CH3:1])[CH2:7]2)[CH:27]=1
Reactant: COC(=O)Cc1cccc(CBr)c1
Reactant: CC1CNCC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(CN2CC(C)N(c3nc4ccc(C(F)(F)F)cc4s3)C(C)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
A mixture of 2-(2,6-dimethyl piperazine-1-yl)-6-trifluoromethyl benzothiazole (163 mg), (3-bromomethylphenyl)acetic acid methyl ester (126 mg), potassium carbonate (75 mg) and dimethylformamide (4 mL) was stirred at room temperature for 18 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (171 mg). Yield: 65%.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1>CN(C)C=O>[CH2:23]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:10]1=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1N(Cc1ccccc1)Cc1ccccc1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(F)c(F)cc2n(CC2CC2)c(=O)n1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A solution of 3-dibenzylamino-6,7-difluoro-1H-quinazoline-2,4-dione (Example 16) (0.43 g, 1.1 mmol) in 10 mL of N,N-dimethylformamide is added to a suspension of sodium hydride (0.05 g, 1.3 mmol) in 10 mL of N,N-dimethylformamide and stirred for 30 minutes. Bromomethylcyclopropane (0.16 mL, 1.6 mmol) is added, and the mixture is stirred at 25° C. for 18 hours. The reaction is quenched with 1 mL of water and concentrated in vacuo. The residue is dissolved in chloroform, washed with water, brine, and dried over magnesium sulfate. The solution is concentrated and purified via chromatography (SiO2, CHCl3) to give 0.33 g of the title compound as a solid. MS CI: m/z 448 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]#[N:8].[C:9]([N:17]=[C:18]=[O:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[C:7]([C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[NH:1][C:18]([NH:17][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:19])#[N:8]
Reactant: N#CC1=C(N)CCC1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: C1COCCO1
Product: N#CC1=C(NC(=O)NC(=O)c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of 2-aminocyclopent-1-enecarbonitrile (400 mg, 3.7 mmol) in 1,4-dioxane (20 mL) was added benzoyl isocyanate (545 g, 3.7 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitate was collected by filtration, washed with 1,4-dioxane, and dried to give N-(2-cyanocyclopent-1-enylcarbamoyl)benzamide (720 mg, 76%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 11.33 (s, 1H), 11.22 (brs, 1H), 7.99-7.97 (m, 2H), 7.67-7.63 (m, 1H), 7.54-7.51 (m, 2H), 3.04-3.0 (m, 2H), 2.51-2.47 (m, 2H) 1.95-1.90 (m, 2H). MS 256 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([N+:23]([O-])=O)=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:8]([F:13])=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:2]=[CH2:3].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([F:13])=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:6]=1[NH2:23])[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(OC)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(OC)c(F)c(Nc2ccc(I)cc2F)c1N
Temperature: 70 °C
Yield: 96.3 %

Procedure:
To a solution of (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (Intermediate 7, 1.0 g, 2.22 mmol) in THF (8 mL) was drop wise added NaOMe solution [prepared by dissolving Na metal (51 mg, 2.2 mmol) in methanol (5 mL)] at −78° C. After complete addition, the reaction mixture was warmed to room temperature and stirred for 16 h. The progress of reaction was monitored by TLC. After completion, reaction mixture was concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (20 mL×3). The combined organic layer was washed with water (20 mL×2), dried over anhydrous sodium sulfate and concentrated to yield 3-allyloxy-6-fluoro-5-methoxy-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (820 mg). A suspension of (3-allyloxy-6-fluoro-5-methoxy-2-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (800 mg, 1.73 mmol) in ethanol (10 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution, a freshly prepared solution of Na2S2O4 (900 mg, 5.2 mmol) in water (1.8 mL) was added drop wise and stirred the reaction mixture at 90° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and brine. The combined organic layer was dried over anhydrous sodium sulfate and concentrated to yield 6-allyloxy-3-fluoro-N2-(2-fluoro-4-iodo-phenyl)-4-methoxy-benzene-1,2-diamine (720 mg). 1H-NMR (400 MHz, CDCl3): δ3.74 (2H, bs), 3.83 (3H, s), 4.56 (2H, d, J=5.6), 5.32 (1H, d, J=10.8), 5.40-5.45 (2H, m), 6.04-6.09 (1H, m), 6.24 (1H, t), 6.52 (1H, d, J=7.6), 7.21 (1H, d, J=8.4), 7.36 (1H, d, J=10.4).
Reaction SMILES: [CH2:1](I)I.[CH3:4][C:5]([CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][CH2:7][CH3:8]>C(OC)(C)(C)C>[CH2:7]([CH:6]1[CH2:4][C:5]1([CH3:1])[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[OH:15])[CH3:8]
Reactant: ICI
Reactant: CCC=C(C)C(O)CCCCC
Solvent: COC(C)(C)C
Product: CCCCCC(O)C1(C)CC1CC
Reaction time: 0.08 h

Procedure:
To a dry 2 liter multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 8 g of a ZnCu and 75 ml of Methyl Tertiary Butyl Ether (MTBE) was added. The resulting mixture was stirred for 5 minutes. After the temperature of the mixture was stabilized, 24 g of CH2I2 was added over 10 minutes while stirring. After the temperature of the mixture was stabilized, the mixture was heated to reflux. As the temperature of the mixture reached 44° C., 17 g of 4-methyl-3-decene-5-ol was added over 30 minutes. After the addition of 4-methyl-3-decene-5-ol, a first sample was taken. Additional samples were taken every hour for three hours. Then the sample was quenched with saturated NH4Cl, aqueous layer separated and the organic layer filtered through celite.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13](CCl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1.[CH2:28]([SH:31])[CH2:29][CH3:30].[OH-].[Na+]>>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([S:31][CH2:28][CH2:29][CH3:30])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:7]=2[CH:25]=1
Reactant: CCCS
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: [Na+]
Agent: [OH-]
Product: CCCSc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 14, a solution of 8-trifluoromethyl-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine was heated with propanethiol and sodium hydroxide to give 8-trifluoromethyl-1-(propylthio)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCCCCCCCCCCN3CCOCC3)cccc21
Solvent: CO
Product: NCCCCCCCCCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 12-morpholinyldodecylphthalimide (320 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[NH:5][C:6](=[O:12])[NH:7]2.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[C:4](=[O:13])[NH:5][C:6](=[O:12])[NH:7]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: O=c1[nH]c(=O)c2c(Br)cccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=c1[nH]c(=O)c2c(-c3ccccc3)cccc2[nH]1

Procedure:
See J. Med. Chem., 50(7):1675 (2007), 76759-011. To a mixture of 5-bromoquinazoline-2,4(1H,3H)-dione (900 mg, 3.73 mmol) and Pd(Ph3P)4 (216 mg, 0.187 mmol) in DME (90 mL) was added phenylboronic acid (683 mg, 5.60 mmol) followed by a solution of sodium bicarbonate (941 mg, 11.2 mmol) in water (30 mL) and the reaction heated at reflux for 40 h. At the conclusion of this period, the organic solvent was removed under reduced pressure. The resulting mixture was filtered and the solid washed with water. The solid was concentrated under reduced pressure from MeOH/DCM to remove the water to yield 5-phenylquinazoline-2,4(1H,3H)-dione as an off-white solid. The 5-phenylquinazoline-2,4(1H,3H)-dione (9.64 g, 40.4 mmol) was added to POCl3 (75 mL, 810 mmol) followed by PhN(CH3)2 (10.3 mL, 81.0 mmol). Upon completion of addition, the reaction mixture was heated to reflux (105° C.) where it was stirred for 2 hours. After this time, the reaction mixture was allowed to cool to ambient temperature. Once at the prescribed temperature, the reaction mixture was concentrated under reduced pressure, diluted with DCM and then quenched by the addition of cold 1M K3PO4 solution. The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by ISCO chromatography (330 g column) using hexanes/EtOAc (0-25% over 20 min, flow rate 100 mL/min) to give 2,4-dichloro-5-phenylquinazoline (7.11 g, 63.9% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) ppm 8.04 (1H, m) 7.96 (1H, m) 7.59 (1H, dd, J=7.28, 1.25 Hz) 7.45 (3H, dd, J=5.02, 1.76 Hz) 7.32 (2H, m).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:45]([CH3:46])[N:44]=[CH:43][N:42]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:41]2[N:45]([CH3:46])[N:44]=[CH:43][N:42]=2)=[O:40])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1ncnn1C
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3ncnn3C)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N, 1-dimethyl-1H-1,2,4-triazole-5-carboxamide (Intermediate 49).
Reaction SMILES: [NH:1]1[CH:5]=[C:4](CCCCN)[N:3]=[CH:2]1.[Cl:11][C:12]1[CH:13]=[C:14]2[NH:20][C:19](=O)[O:18][C:16](=O)[C:15]2=[CH:22][CH:23]=1>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]2[C:15]([C:16](=[O:18])[N:20]([CH2:14][CH2:13][CH2:12][CH2:23][N:3]3[CH:4]=[CH:5][N:1]=[CH:2]3)[CH:19]=[N:20]2)=[CH:22][CH:23]=1
Reactant: NCCCCc1c[nH]cn1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Solvent: CCO
Product: O=c1c2ccc(Cl)cc2ncn1CCCCn1ccnc1
Reaction time: 20 h

Procedure:
A mixture of 1.39 g of imidazole-4-butanamine, 1.98 g of 4-chloroisatoic anhydride and 25 ml of ethanol was left at room temperature for 20 hours and concentrated. The residue and 5 ml of triethyl orthoformate were heated in an oil bath at 100°-125° C. for 3 hours and concentrated. The mixture was treated with ether to obtain the desired product, mp 123°-125° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](/[P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])\[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])(/[C:9](=[CH:8]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:16])[CH3:19]
Reactant: CCOC(=O)/C(=C\c1ccccc1Br)P(=O)(OCC)OCC
Reactant: C#CCCCCCCCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccccc1/C=C(\C(=O)OCC)P(=O)(OCC)OCC
Reaction time: 42 h
Yield: 25.3 %

Procedure:
Ethyl 3-(2-bromophenyl)-2-E-(diethoxyphosphinyl)-propenoate (7.84 g, 20.0 mmol) prepared according to Example 4 was placed in a three neck round bottom flask equipped with a condenser, stir bar, internal thermometer, and argon inlet. 1-Tridecyne (6.30 g, 34.9 mmol) and triphenylphosphine (0.161 g, 0.614 mmol) were added along with triethylamine (110 ml) and the system was degassed by repeated vacuum-argon cycles. Under an argon atmosphere, palladium acetate (0.048, 0.214 mmol) was added, and heating in an oil bath (100°-105° C.) was started. The internal temperature stayed in the range of 89°-92° C. during the reaction. Within a few hours a light precipitate started forming. After about 42 hours, additional tridecyne (1.0 g, 5.5 mmol) was added. The reaction was stopped after 53 hours. After cooling the reaction mixture was filtered and the precipitate was washed with triethylamine. The filtrate was stripped down to a reddish oil. Multiple chromatographies on silica eluting with ethyl acetate in hexane (32% ethyl acetate was best) yielded a yellow liquid, 2.43 g, 5.08 mmol, 25.3% yield; 1H NMR (CDCl3) ∂0.88 (m, 3H), 1.17 (t, J=7.2 Hz, 3H), 1.21 to 1.48 (several m, 22H), 1.64 (quintet, J=7.5 Hz, 2H), 2.43 (t, J=7.2 Hz, 2H), 4.22 (m, 4H), 7.19 to 7.48 (several m, 4H), 8.06 (d, J=23.7 Hz, 1H); CI mass spectrum m/z 491 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=2)[N:3]=[CH:2]1.[C:16]1([C:22](Cl)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[C:22]([N:1]1[CH:5]=[C:4]([C:6]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=2)[N:3]=[CH:2]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc(-c2c[nH]cn2)n[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.3 %

Procedure:
Ethyl 3-(1H-imidazol-4-yl)-1H-pyrazole-5-carboxylate (6.79 mmol, 1.4 g) was suspended in DCM (20 ml) under nitrogen atmosphere. Triphenylmethyl chloride (8.15 mmol, 2.271 g) was added and stirred for 10 min at RT. Triethylamine (8.15 mmol, 1.136 ml) was added and the resulting mixture was stirred for 20 h at RT after which DCM (10 ml) and triphenylmethyl chloride (1 g) was added. The stirring was continued for another 4.5 days. More triphenylmethyl chloride (1.14 g) and triethylamine (0.6 ml) was added and the mixture was stirred for another day. The mixture was diluted with DCM and washed with NaHCO3. The organic phase was dried, filtered and evaporated. The residue was purified by trituration from ACN. 1.837 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.28 (t, 3H), 4.25 (q, 2H), 6.89 (s, 1H), 7.09-7.18 (m, 6H), 7.18-7.33 (m, 6H), 7.36-7.47 (m, 3H), 7.50 (s, 1H), 7.55 (s, 1H), 13.63 (bs, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.CCCCCC.[CH3:35][O:36][N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1>C1COCC1>[CH3:35][O:36][N:37]1[CH2:42][CH2:41][C:40](=[CH:2][O:3][CH3:4])[CH2:39][CH2:38]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CON1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=C1CCN(OC)CC1
Temperature: -60 °C
Reaction time: 0.33 h

Procedure:
A mixture of (methoxymethyl)triphenylphosphonium chloride (35.8 g, 104 mmol) in THF (160 mL) was cooled to −60° C. and treated with a 2.5M solution of n-BuLi in hexane (42 mL, 105 mmol). After 20 min, a solution of 1-methoxy-piperidin-4-one [prepared according to Journal of Organic Chemistry (1961), 26, 1867-74] (9 g, 70 mmol) in THF (80 mL) was added, and the reaction mixture was allowed to warm to 10° C. over 2 h. The reaction was quenched with saturated ammonium chloride, and the solvent was removed under reduced pressure. The residue was partitioned between water and chloroform and the organic layer dried with sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel. Yield: 9.2 g of 1-methoxy-4-methoxymethylene-piperidine as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: OCCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(CCO)cc2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (2.94 g) and 1-fluoro-4-nitrobenzene (3.0 g) in dimethylformamide (21 mL) was added potassium carbonate (4.41 g) and the solution was stirred at 120° C. for 4 hours. After cooling to room temperature, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the title compound having the following physical data.