Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:21]([OH:24])(=[O:23])=[O:22])[C:5]([CH:8]=[CH:9][C:10]2[C:11]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1.[C:25](=[O:28])([O-:27])[O-].[Na+].[Na+].Cl[C:32]([O:34][CH2:35][CH:36]1[C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33]>O.O1CCOCC1>[CH:8](/[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:32]([O:34][CH2:35][CH:36]2[C:48]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:42]3[C:37]2=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:33])=[CH:3][C:4]=1[S:21]([OH:24])(=[O:23])=[O:22])=[CH:9]\[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:25]([O:27][CH2:35][CH:36]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=3[C:43]3[C:48]2=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:28])=[CH:12][C:11]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(C=Cc2ccc(N)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(/C=C/c2ccc(NC(=O)OCC3c4ccccc4-c4ccccc43)cc2S(=O)(=O)O)c(S(=O)(=O)O)c1)OCC1c2ccccc2-c2ccccc21
Yield: 72 %

Procedure:
To a solution of commercially available 4,4′-diaminostilbene-2,2′-disulfonic acid (10 g, 27.0 mmol) in a mixture of 270 mL water and 30 mL dioxane was added 14.3 g (135 mmol) of sodium carbonate and the solution stirred until homogeneous. At this time 9-fluorenylmethyl chloroformate was added and the mixture allowed to stir overnight. The solution was filtered and the solids washed with water (200 mL). The collected solids were then suspended in 600 mL of water and 50 mL conc hydrochloric acid added. After 30 minutes the solution was filtered and the solids dried in a vacuum oven overnight at 50° C. to provide the title compound 21.8 g (72%) as a orange-brown solid. MS (ES-NEG): [M−H] 813.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([NH:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH3:3].Cl.Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH:2]([C:4]3[CH:9]=[CH:8][C:7]([C:10]4([NH:13][C:14](=[O:16])[CH3:15])[CH2:12][CH2:11]4)=[CH:6][CH:5]=3)[CH3:3])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(=O)NC1(c2ccc(C(C)Cl)cc2)CC1
Agent: Cl
Product: CC(=O)NC1(c2ccc(C(C)N3CCN(c4ccc(F)cc4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-(1-chloroethyl)phenyl)cyclopropyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=149-150° C.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].[CH2:28](Br)[CH:29]=[CH2:30]>>[CH2:30]([O:26][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH:29]=[CH2:28]
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: C=CCBr
Product: C=CCOc1cc(-c2nc(CNC(=O)c3ncccc3C)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 97 and allyl bromide, white solid N-[2-(3-allyloxy-4-difluoromethoxy phenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained following the procedure of Example 3.
Reaction SMILES: [F:1][C:2]([F:46])([CH2:44][OH:45])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[N:21][C:22]([O:28]CC4C=CC(OC)=CC=4)=[C:23]([O:25][CH2:26][CH3:27])[CH:24]=3)=[CH:15][C:14]=2[F:38])=[CH:6][C:5]=1[C:40]([F:43])([F:42])[F:41].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:46][C:2]([F:1])([CH2:44][OH:45])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([O:25][CH2:26][CH3:27])[C:22](=[O:28])[NH:21][CH:20]=3)=[CH:15][C:14]=2[F:38])=[CH:6][C:5]=1[C:40]([F:41])([F:42])[F:43]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(F)(F)CO)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CC(F)(F)CO)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A mixture of N-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide (50 mg, 0.077 mmol) in DCM (5 mL) was added TFA (0.012 mL, 0.154 mmol). The mixture was stirred at 20° C. for 1 h. LCMS showed the reaction was finished. The mixture was concentrated to give crude product, which was purified by preparative HPLC (Column: ASB C18 150*25 mm; Mobile phase A: Water+0.1% HCl; Mobile phaseB: MeCN; Flowrate: 25 mLl/min; Gradient Profile Description: 26-56 (B %)) to give N-(4-(2,2-difluoro-3-hydroxypropyl)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide (16.72 mg, 0.032 mmol, 41.0% yield): 1H NMR (400 MHz, CD3OD-d4) δ 8.01 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.36-7.26 (m, 3H), 7.23 (s, 1H), 4.12 (d, J=7.1 Hz, 2H), 3.80 (s, 2H), 3.68 (t, J=12.8 Hz, 2H), 3.41 (t, J=17.1 Hz, 2H), 1.45 (t, J=6.9 Hz, 3H). ES-LCMS m/z 529 (M+H).
Reaction SMILES: CO[CH:3]=[C:4]([C:9]([O:11]C)=O)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][CH:15]([O:26][CH3:27])[CH2:16][NH:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[NH:19].CO>C(OCC)C>[CH3:27][O:26][CH:15]([O:14][CH3:13])[CH2:16][N:17]1[C:9](=[O:11])[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][N:19]=[C:18]1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: COC(CNC(=N)c1cccnc1)OC
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cnc(-c2cccnc2)n(CC(OC)OC)c1=O

Procedure:
Dimethyl methoxymethylenemalonate and N-(2,2-dimethoxy-ethyl) -3-pyridinecarboxamidine were subjected to a procedure similar to that described in Example 1.b. Chromatography, with methanol:diethyl ether (gradient, 0:100, 10:90) as the eluent, gave methyl 1-(2,2-dimethoxy-ethyl)-2-(3-pyridyl)pyrimidin-6(1H)-one-5-carboxylate as an oil; MS: m/z=320(M+1); TLC: Rf =0.4, methanol:diethyl ether (5:95).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: Sc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSc1ccccc1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and benzenthiol.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[O:18][C:17](=[O:19])[C:16]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:15]=1>CN1CCOCC1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:15][C:16]1([C:17]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18]
Reactant: O=C1OC(c2ccco2)=NC12CCCCC2
Reactant: CC(C)[C@H](N)C(=O)O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)C1(NC(=O)c2ccco2)CCCCC1)C(=O)O
Yield: 12.5 %

Procedure:
10 ml of N-methylmorpholine was added to 1.0 g (9.1 mmol) of L-valine and 2.0 g (9.1 mmol) of 2-(2-furanyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and heated under reflux overnight. The reaction solution was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with a 10% aqueous potassium hydrogensulfate solution and then saturated brine, followed by drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and it was purified by silica gel chromatography to obtain 384 mg (12.5%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]1
Reactant: Brc1cccc2cc[nH]c12
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Brc1cccc2c(C3CCNCC3)c[nH]c12

Procedure:
This compound was prepared following the procedure described in Example 1 (parts A and B) starting with 0.95 g (4.8 mmol) of 7-bromoindol and 1.89 g (12.3 mmol) of 4-piperidone monohydrate hydrochloride. After the usual work-up 1.1 g (89% of yield) of the desired product were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([O:1][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: O=C1CCc2c(O)cccc21
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCC3=O)nc1
Yield: 30.3 %

Procedure:
Using a method similar to Intermediate 1, using 4-hydroxy-1-indanone (2.44 g, 16.5 mmol), 6-chloronicotinamide (234 g, 15.0 mmol) and K2CO3 (3.11 g, 22.5 mmol) gives the title compound (1.22 g) as a yellow solid. Mass spectrum (ion spray): m/z=269 (M+1); 1HNMR (DMSO-d6): 8.57 (s, 1H), 8.29 (d, 1H), 8.03 (s, 1H), 7.55-7.46 (M, 4H), 7.19 (d, 1H), 2.81 (t, 2H), 2.61 (t, 2H).
Reaction SMILES: [CH3:1][Ge:2]([CH3:17])([CH3:16])[C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([Ge:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1.[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)=O.[OH-].[K+].Cl>C(O)(C)C.O1CCCC1>[CH3:11][Ge:9]([CH3:10])([CH3:12])[C:7]1[CH:6]=[C:5]([C:13](=[O:15])[CH:14]=[CH:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:4]=[C:3]([Ge:2]([CH3:16])([CH3:1])[CH3:17])[CH:8]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1cc([Ge](C)(C)C)cc([Ge](C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[Ge](C)(C)c1cc(C(=O)C=Cc2ccc(C(=O)O)cc2)cc([Ge](C)(C)C)c1
Yield: 53.7 %

Procedure:
3',5'-Bis(trimethylgermyl)acetophenone 163 mg (0.46 mmol) and 96 mg (0.58 mmol) of methyl 4-formylbenzoate was dissolved in 4 ml of a mixture of isopropanol and tetrahydrofuran (1:1). To the mixture was added 2.5 ml of 0.75N aqueous potassium hydroxide solution with stirring and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted to pH3.8 with 0.2N hydrochloric acid and extracted with AcOEt. The extract was evaporated. The residue was purified by column chromatography on silicagel [eluent: methylene chloride-MeOH (10:1)] and recrystallized from a mixture of methylene chloride, MeOH and n-hexane to give 120 mg of yellow prisms, m.p. 194°-195.5° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5]([Cl:13])=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([C:21]([F:20])([F:30])[F:31])[CH:23]=3)=[CH:9][CH:10]=2)[C:5]([Cl:13])=[N:4][N:3]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Nc1ccc2c(Cl)nnc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(CNc2ccc3c(Cl)nnc(Cl)c3c2)c1
Temperature: 85 °C
Yield: 26.2 %

Procedure:
A mixture of 1,4-dichloro-6-amino-phthalazine (33 mg, 0.154 mmol), K2CO3 (79 mg, 0.57 mmol), DMF (5 mL) and 3-(trifluoromethyl)benzyl bromide (2.0 mL, 0.17 mmol) were heated to 85° C. for 18 h. The reaction was cooled, poured onto water and extracted with EtOAc. The combined organic layers were washed with H2O, brine, dried (Na2SO4) and concentrated. Column chromatography (Hexanes/EtOAc) afforded the desired product (15 mg, 26.3%) as a yellow solid. m/z 372.08 (M+1).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C2CCCNC2)C=CC=CC=1.[CH:25]([C:27]1[CH:42]=[CH:41][C:30]([O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][N:33]=2)=[CH:29][CH:28]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:61]CCCl>>[ClH:61].[CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:25][C:27]3[CH:42]=[CH:41][C:30]([O:31][C:32]4[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][N:33]=4)=[CH:29][CH:28]=3)[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Reactant: C1CCC(C2CCCNC2)CC1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(C2CCCNC2)cc1
Solvent: CC(=O)O
Product: Cl
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCC(C4CCCCC4)C3)cc2)nc1
Yield: 37 %

Procedure:
Using a method similar to Example 345, a mixture of 3-cyclohexyl-piperidine and 3-phenyl piperidine (from step 1 above) (3:1, 0.118 g), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.183 g, 0.755 mmol), sodium triacetoxyborohydride (0.247 g, 1.16 mmol), and acetic acid (0.067 mL, 1.17 mmol) in 1,2-dichloroethane (10.0 mL) provides, after reverse-phase HPLC, 0.155 g (37%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C24H32N3O2 394.2495, found 394.2478; 1H NMR (methanol-d4): 8.68 (d, 1H, J=2.4 Hz), 8.38 (dd, 1H, J=2.4, 8.3 Hz), 7.69-7.63 (m, 2H), 7.37-7.32 (m, 2H), 7.18 (d, 1H, J=8.8 Hz), 4.42 (d, 1H, J=13.2 Hz), 4.34 (d, 1H, J=13.2 Hz), 3.62-3.55 (m, 1H), 3.54-3.47 (m, 1H), 2.92 (dt, 1H, J=3.4, 13.2 Hz), 2.84 (t, 1H, J=12.2), 2.08-2.00 (m, 1H), 2.00-1.92 (m, 1H), 1.87-1.66 (m, 7H), 1.39-1.02 (m, 7H).
Reaction SMILES: [H-].[Na+].C[O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].O[C:15]1(C)[CH2:24][CH2:23][C:22]2[C:17](=[C:18]([CH2:36][CH2:37][CH3:38])[C:19]([C:32]([CH3:35])([CH3:34])[CH3:33])=[C:20](CC([O-])=O)[C:21]=2[CH:25]([CH3:27])[CH3:26])[O:16]1.[O:40]1CCCC1>>[OH:40][C:20]1[C:21]([CH:25]([CH3:26])[CH3:27])=[C:22]2[C:17](=[C:18]([CH2:36][CH2:37][CH3:38])[C:19]=1[C:32]([CH3:34])([CH3:35])[CH3:33])[O:16][CH:15]([CH2:7][C:5]([OH:4])=[O:6])[CH2:24][CH2:23]2
Reactant: C1CCOC1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CCCc1c2c(c(C(C)C)c(CC(=O)[O-])c1C(C)(C)C)CCC(C)(O)O2
Agent: [H-]
Agent: [Na+]
Product: CCCc1c2c(c(C(C)C)c(O)c1C(C)(C)C)CCC(CC(=O)O)O2
Reaction time: 0.42 h

Procedure:
Suspend sodium hydride (47.2 g of 56% in mineral oil, 1.10 mol) in anhydrous tetrahydrofuran (1 L). Place under a nitrogen atmosphere and add, by dropwise addition, trimethyl phosphonoacetate (209.4 g, 1.15 mol). Stir the 25 minutes and add a solution of 2-hydroxy-2-methyl-7-t-butyl-5-isopropyl-8-propyl-chroman-6-yl-acetate (0.5 mol) in tetrahydrofuran (1 L). Stir at room temperature for 18 hour then heat at reflux for 4 hours. Cool, evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: O.[C:2]1([P:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][CH2:22][I:23]>C1C=CC=CC=1>[I-:23].[F:21][CH2:22][P+:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: FCI
Solvent: c1ccccc1
Solvent: O
Product: FC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [I-]

Procedure:
An alternate synthesis of the vinylic fluorinated variant of 3,4-cyclopropyl-heptadecanoic acid can be achieved from the ketone compound described above (FIG. 12). A modified version of the mechanism is from Burton and Greenlimb 1975. J. Org. Chem. 40: 2796-2801; and in Schlosser and Zimmermann 1969. Synthesis 1: 75-76. Fluoromethyltriphenylphosphonium iodide was synthesized in a round-bottomed flask fitted with a water-cooled reflux condenser. The flask was charged with triphenylphosphine and fluoroiodomethane in dry benzene. The resulting solution was refluxed for 64 hr with moderate stirring. Upon completion of the reaction, the white insoluble phosphonium salt was collected on a glass funnel, washed with hot benzene, and dried in a vacuum dessicator for 12 hr.
Reaction SMILES: [CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[CH2:9][CH:8]([C:20]([OH:22])=O)[CH2:7]1)=[O:5])[CH3:2].O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH2:27]>>[CH2:1]([N:3]([CH3:23])[C:4]([N:6]1[CH2:7][CH:8]([C:20]2[O:22][N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]=2)[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=2)[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N(C)CC)C2)cc1
Reactant: NC(=NO)c1ccccc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4)no3)CN(C(=O)N(C)CC)C2)cc1

Procedure:
64 mg (0.20 mmol) of 1-[ethyl(methyl)carbamoyl]-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 45A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 12 mg (14% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([F:22])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.C(Cl)Cl.[C:26]1(B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30][CH2:29][CH2:28]C=1.C(OCC)(=[O:43])C>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:3]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([F:22])[CH:10]=2)=[N:4][C:5]([C:30]2[CH2:31][CH2:26][O:43][CH2:28][CH:29]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Reactant: CCOC(C)=O
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CCOCC3)cnc2N)cc1F
Temperature: 110 °C
Yield: 85 %

Procedure:
To a solution of tert-butyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (21 g, 57.0 mmol) in DME (127 mL) was added PdCl2(dppf).CH2Cl2 adduct (2.329 g, 2.85 mmol), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.18 g, 62.7 mmol), and 2 M Na2CO3aqueous solution (63.4 mL). The reaction was heated at 110° C. for 16 h. To the reaction mixture was added 200 mL of ethyl acetate, washed with water (2×100 mL), brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 0-100% of EtOAc/DCM to provide tert-butyl 4-(3-amino-6-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoate (18 g, 48.5 mmol, 85%). LCMS (m/z): 372.3 (MH+), 0.95 min.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][CH2:10][O:11][C:12]([CH2:14][C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)=[O:13]>C1(C)C=CC=CC=1>[CH2:10]([O:11][C:12](=[O:13])[CH:14]=[C:15]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:9]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(CC(=O)OCC)NCc1ccccc1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
Benzylamine (89.1 g, 0.83 moles) is added over 10 minutes to a suspension of 5A powdered molecular sieves (270 g) and diethyl 1,3-acetonedicarboxylate (160 g) (0.79 moles) in 350 ml toluene (external cooling applied to control exotherm). The suspension is stirred at room temperature for 14-17 hours and then filtered to provide 2. The filter cake is washed with three portions of toluene. The combined filtrates may be used as is in the subsequent ketene reaction.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.[O:33]1[CH2:37][CH2:36][O:35][CH:34]1[CH2:38][CH:39]([C:41]1([OH:45])[CH2:44][NH:43][CH2:42]1)[OH:40].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:43]2[CH2:42][C:41]([CH:39]([OH:40])[CH2:38][CH:34]3[O:33][CH2:37][CH2:36][O:35]3)([OH:45])[CH2:44]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: OC(CC1OCCO1)C1(O)CNC1
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)(C(O)CC2OCCO2)C1
Reaction time: 0.17 h
Yield: 35.9 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (287 mg, 0.730 mmol), prepared using procedures similar to those described in U.S. Pat. No. 7,019,033, 4-(dimethylamino)pyridine (178 mg, 1.46 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg, 0.88 mmol) were dissolved in DMF (3 mL). The mixture was stirred at ambient for 10 minutes and then 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (0.729 mmol) in DMF (2 mL) was added and the mixture was stirred for 15 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, gradient 90% ethyl acetate in hexanes to 100% ethyl acetate) gave 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (148 mg, 0.262 mmol, 36% yield): MS (EI) for C21H20F3IN2O5: 565 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[C:4]([CH3:23])[CH:3]=1.C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=1[N:42]=[C:43]=[O:44]>C(Cl)Cl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=1[NH:42][C:43]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[C:4]([CH3:23])[CH:3]=1)=[O:44]
Reactant: Cc1cc(N)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a mixture of 3-(4-amino-2-methylphenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (92 mg, 0.30 mmol) and triethylamine (0.125 mL, 0.90 mmol) in 2.5 mL CH2Cl2 at rt was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.065 mL, 0.45 mmol) and the reaction stirred at rt. After 2.5 hours the reaction was quenched with 0.3 mL MeOH, and then stored overnight in the refrigerator. The reaction mixture was filtered and rinsed with EtOAc to give the title compound as an off-white solid (130 mg, 84%). 1H NMR (DMSO-d6) δ: 10.69 (s, 1H), 9.09 (s, 1H), 8.87 (d, J=2.9 Hz, 1H), 8.63 (dd, J=7.5, 2.2 Hz, 1H), 7.99 (dd, J=7.9, 1.2 Hz, 1H), 7.33-7.53 (m, 4H), 7.24-7.29 (m, 1H), 7.13-7.17 (m, 1H), 7.00-7.10 (m, 2H), 4.15-4.23 (m, 1H), 3.64-3.73 (m, 1H), 3.46-3.56 (m, 2H), 3.07-3.15 (m, 1H), 2.33 (s, 3H)