Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[P+](O[P+](O)=O)=O.C=O.[C:20](=O)([O-])[O-].[K+].[K+]>>[CH2:20]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][C:8](=[O:9])[NH:10]1
Reactant: NC(=O)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: O=[P+](O)O[P+](=O)O
Agent: [K+]
Product: O=C1Cc2ccccc2CN1
Temperature: 155 °C
Yield: 21 %

Procedure:
A mixture of phenylacetamide (5 g, 37 mmol), pyrophosphonic acid (80 g, 449.5 mmol) and paraformaldehyde (1.22 g, 40.7 mmol) is heated at 155° C. for 1 h to give a viscous black solution. It is poured into ice water and treated with potassium carbonate to pH 7. The solution is extracted with ethyl acetate, and the organic solution is washed with saturated potassium carbonate, dried over magnesium sulfate, and evaporated to dryness to give 1.145 g (21%) of the product as a yellow solid; MS (ESI) m/z 148.0 (M+1). [Ref: Heterocycles 26(9), 2385 (1987)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)C=Cc1ccc(N)cc1
Temperature: 75 °C

Procedure:
A mixture of 3-(4-nitro-phenyl)-acrylic acid methyl ester (2) (39.54 g, 0.191 mol) and SnCl2.2H2O (220 g, 0.98 mol) in anhydrous ethanol (300 ml) was heated at 50° C. for 1 hour and at 75° C. for 1 hour. The reaction mixture was allowed to cool to 10° C., treated with 20% NaOH solution to pH 8-9, and extracted with ethyl acetate (3×200 ml). The organic extract was washed with saturated NaCl (3×150 ml), dried (MgSO4), and evaporated under reduced pressure. Recrystallization from isopropanol (180 ml) afforded pure title compound in a form of yellowish crystals (17.938 g, 53%). 1H NMR (DMSO-d6, HMDSO), δ: 3.64 (3H, s); 5.73 (2H, s); 6.22 (1H, d, J=16.0 Hz); 6.57 (2H, d, J=8.0 Hz); 7.38 (2H, d, J=8.0 Hz); 7.50 (1H, d, J=16.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:4][C:5]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)=[N:6][C:7]=1[NH2:8].C1N=CN([C:36](N2C=NC=C2)=[O:37])C=1.C(N(CC)CC)C>CN(C)C=O.O.C(OCC)(=O)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:17]2[C:9]([C:5]2[N:6]=[C:7]3[C:2]([NH:1][C:36](=[O:37])[NH:8]3)=[C:3]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:4]=2)=[N:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=O)[nH]c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
225 mg (0.55 mmol) of the compound from example 63A were initially charged in dimethylformamide (2.5 ml), then 448 mg (2.76 mmol) of N,N-carbonyldiimidazole and 0.96 ml (6.90 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. The reaction mixture was subsequently diluted with water and ethyl acetate, and filtered. The solids were washed with water and, after drying under high vacuum, gave 112 mg (46% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:15]([C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH:18]=1)#[N:16].C1CCN2C(=NCCC2)CC1>C(#N)C>[O:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]([CH:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[CH:17]1[C:15]#[N:16])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(=O)Cc1ccccc1
Reactant: COc1ccc2c(c1)CCC=C2C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)C(C(=O)Cc1ccccc1)C1CCc2cc(OC)ccc2C1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
Methyl 3-oxo-4-phenylbutyrate (29.33 g, 153 mmol) and 1-cyano-6-methoxy-3,4-dihydronaphthalene (25.7, 139 mmol), the product of Step 2 of Example 1, were dissolved in 25 mL of acetonitrile. DBU (1.5 mL) was added and the reaction mixture was stirred for 2 h at ambient temperature. A second aliquot of DBU (1.5 mL) was then added and stirring continued overnight. The reaction mixture was partitioned between diethyl ether and 1N aqueous hydrochloric acid solution (4:1) and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with 1N aqueous hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluted with hexane/ethyl acetate (6:1) to give 33.9 g (65% yield) of the title compound; MS DCl--NH3M/Z: 395 (M+NH4)+.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][CH:7]([NH2:8])[CH:3]([CH2:4]2)[CH2:2]1.[CH3:9][CH:10]1[S:14](=[O:16])(=[O:15])[O:13][CH2:12][CH2:11]1>O1CCCC1>[CH:3]12[CH2:4][CH:5]([CH2:1][CH2:2]1)[CH2:6][CH:7]2[NH:8][CH2:12][CH2:11][CH:10]([S:14]([OH:16])(=[O:15])=[O:13])[CH3:9]
Reactant: NC1CC2CCC1C2
Reactant: CC1CCOS1(=O)=O
Solvent: C1CCOC1
Product: CC(CCNC1CC2CCC1C2)S(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of exo-2-aminonorbornane (1.0 g, 9.0 mmol) in tetrahydrofuran (THF, 10 mL) was added 2,4-butane sultone (1.28 g, 9.3 mmol). The solution was stirred at reflux for 3 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with THF (2×20 mL) and dried in vacuo. 1H NMR (DMSO, 500 MHz) δ ppm 8.43 (s (broad), 1H), 2.96 (m, 3H), 2.62 (m, 1H), 2.38 (m, 1H), 2.28, (m, 1H), 1.91 (m, 1H), 1.82 (m, 1H), 1.61 (m, 1H), 1.54 (m, 2H), 1.42 (m, 2H), 1.12 (m, 6H). 13C (DMSO, 125 MHz) δ ppm 60.92, 60.79, 53.61, 53.21, 44.55, 44.36, 39.80, 39.55, 36.27, 36.15, 36.11, 35.98, 35.19, 35.13, 29.62, 29.43, 28.07, 26.88, 17.56, 14.11. ES-MS 248 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:18]([C:19](O)=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:10]2)=[CH:4][CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:9]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[C:23]([CH:24]4[CH2:26][CH2:25]4)=[CH:22][C:18]([C:19]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:20])=[C:17]([F:27])[CH:16]=3)[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccc(Cl)cc3)C2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.4 %

Procedure:
A mixture of 4-((1-((4-chlorophenyl)(phenyl)methyl)azetidin-3-yl)-methoxy)-5-cyclopropyl-2-fluorobenzoic acid (50 mg, 0.11 mmol), methanesulfonamide (15 mg, 0.16 mmol), EDCI (31 mg, 0.16 mmol) and DMAP (20 mg, 0.16 mmol) in DCM (20 mL) was stirred at 25° C. for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with HCl (2.0 M, 20 mL) and brine (50×2 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase Combiflash (35%-38% MeCN in 0.5% NH4HCO3) to give the target product (11.0 mg, 19%) as an off-white solid. LCMS (ESI) Method A: RT=5.83 min, m/z: 543.5 [M+H]+. 1H-NMR (500 MHz, MeOH-d4): δ 7.31-7.29 (m, 4H), 7.23-7.19 (m, 5H), 7.14-7.11 (m, 1H), 6.69-6.66 (m, 1H), 4.51 (s, 1H), 4.08 (d, J=6.5 Hz, 2H), 3.39-3.34 (m, 2H), 3.32-3.13 (m, 5H), 2.94-2.90 (m, 1H), 1.99-1.96 (m, 1H), 0.84-0.80 (m, 2H), 0.58-0.54 (m, 2H).
Reaction SMILES: [C:1]12(C(O)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>C(#N)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Solvent: CC#N
Product: C1C2CC3CC1CC(C2)C3
Yield: 58 %

Procedure:
as shown in the mass spectrum of the reaction gases. In aqueous solutions the rates of decarboxylation were similar for the acids investigated. Adamantane-1-carboxylic acid, dissolved in ACN at a much lower concentration (~0.12 M), was found to decarboxylate at a significantly lower rate than the other acids with a decrease in rate as the photolysis proceeded (initial rate, 65 μmol/h; final rate, after 62% conversion, 28 μmol/h). However, the corresponding alkane, adamantane, was again formed in 58% yield by decarboxylation of this bridgehead carboxylic acid. A noise decoupled C NMR spectrum showed only two nonequivalent carbon atoms, yielding definite proof of the product, owing to its high symmetry. The usual electrochemical Kolbe reaction for these acids produces predominantly dimer with smaller amounts of the alkene. For the adamantane-1-carboxylic acid the Kolbe reaction, carried out in an alcoholic medium at a metal electrode, produces 1-alkoxyadamantane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[CH:27]=[CH:26][C:25]2[O:20][CH2:21][CH2:22][O:23][C:24]=2[CH:29]=1)=[O:31]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)OCCO2

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid. MS: 422.4 (M+H).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].O[C:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:18]2[O:19][C:20]3[C:25]([C:26](=[O:27])[CH:17]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=c1c(O)c(-c2ccccc2)oc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Oc2cccc(-c3cc(=O)c4ccccc4o3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 9.89 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 10.1 g of 3-hydroxyflavon and 8.66 g of dicyclohexylcarbodiimide was added to 100 ml of dry pyridine, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered to remove any insoluble materials which were washed with pyridine. The filtrate and the washing were combined and evaporated. 0.1N hydrochloric acid was added to the residue, and the mixture was washed with ethyl acetate. The aqueous layer was concentrated to 30 ml and allowed to stand overnight in a refrigerator to obtain 1 g of 3'-flavonyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride as colorless needles having a melting point of 201°-203° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[CH2:17][CH2:18][NH2:19].CCN(C(C)C)C(C)C>CC#N>[Cl:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[CH:15]=2)[N:10]=1
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: NCCc1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)c1cc(F)c(Cl)nc1NCCc1cccc(F)c1
Yield: 49 %

Procedure:
A mixture of 2,6-dichloro-5-fluoronicotinic acid (1.26 g, 6.0 mmol), 3-fluorophenethyl amine (1.25 mL, 9.0 mmol), DIEA (3.14 mL, 18 mmol) and MeCN (6 mL) was refluxed for 48 hrs and concentrated. The residue was dissolved in EtOAc (120 mL) and washed with saturated citric acid, water, brine, dried and concentrated. The organic layers were combined, dried (MgSO4) and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 6-chloro-5-fluoro-2-(3-fluorophenethylamino)nicotinic acid as a solid (920 mg, 49%). LRMS (M+H+) m/z 313.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:25])[F:24])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:7]=1.[N:26]1[N:30]2[CH:31]=[CH:32][CH:33]=[N:34][C:29]2=[C:28]([C:35](Cl)=[O:36])[CH:27]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH:23]([F:24])[F:25])=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[N:11]=[CH:10][C:9]=2[NH:21][C:35]([C:28]2[CH:27]=[N:26][N:30]3[CH:31]=[CH:32][CH:33]=[N:34][C:29]=23)=[O:36])[CH:7]=1
Reactant: O=C(Cl)c1cnn2cccnc12
Reactant: C[Si](C)(C)CCOCn1ncc(N)c1-c1cc(Cl)ccc1OC(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc(NC(=O)c2cnn3cccnc23)c1-c1cc(Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of 5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-ylamine (60.0 g, 154 mmol) in THF (100 mL) was added dropwise over 30 minutes to an ice/water cooled mixture of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (27.8 g, 153 mmol), and DIPEA (49.5 g, 383 mmol) in THF (300 mL). On complete addition the mixture was left to stir at room temperature for 1 hour. The solvent was evaporated and the residue diluted with 0.5 N aqueous HCl and extracted with ethyl acetate. The combined organic extract was passed through Celite® to remove the residual solid and the filtrate washed with 1M aqueous K2CO3, water and brine, dried (Na2SO4) and evaporated to give a red solid. The solid was triturated with 10% diethyl ether in cyclohexane. The solid was collected by filtration, washed with 1:1 diethyl ether in cyclohexane and left to air dry to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(5-chloro-2-difluoromethoxyphenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazol-4-yl]amide as an off-white solid (59.2 g, 73%). 1H NMR (300 MHz, CDCl3): δ (ppm) 9.61 (s, 1H), 8.77-8.78 (m, 1H), 8.51 (dd, 1H), 8.36 (s, 1H), 7.65 (d, 1H), 7.52 (dd, 1H), 7.36 (d, 1H), 7.29 (s, 1H), 7.01 (dd, 1H), 6.42 (t, 1H), 5.39-5.41 (m, 2H), 3.60-3.64 (m, 2H), 0.87-0.89 (m, 2H), 0.09 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[CH:17][N:18]([CH3:20])C)[C:6](=[O:16])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15])[CH3:2].[C:22]([NH:25][CH2:26][C@@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37]C(N)=[C:35]([F:40])[CH:34]=2)[CH2:28]1)(=[O:24])[CH3:23]>CCO>[C:22]([NH:25][CH2:26][CH:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][C:20]([NH:18]/[CH:17]=[C:5](/[C:6]([C:7]3[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=3[F:15])=[O:16])\[C:4]([O:3][CH2:1][CH3:2])=[O:21])=[C:35]([F:40])[CH:34]=2)[CH2:28]1)(=[O:24])[CH3:23]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)cc1F
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N)c(F)c2)C(=O)O1
Solvent: CCO
Product: CCOC(=O)/C(=C\Nc1ccc(N2CC(CNC(C)=O)OC2=O)cc1F)C(=O)c1cc(F)c(F)cc1F

Procedure:
Triethylamine (2.09 mL, 15 mmol) was added with stirring to a solution of 2,4,5-trifluorobenzoyl chloride (1.95 g, 10 mmol) and ethyl 3-dimethylaminoacrylate 20 (1.43 g, 10 mmol) in 1,4-dioxane (20 mL). The mixture was stirred at r.t. overnight, and solvent was removed under vacuum. The residue was dissolved in ethyl ether (100 mL) and hexanes (20 mL), and the resulting mixture was washed with water (2×100 mL), 2% aq. citric acid (2×100 mL), brine (100 mL), 2.5% aq. NaHCO3 (2×100 mL), and brine (100 mL). The organic layer was dried (MgSO4), and the solvents removed under vacuum to provide ethyl-2-(dimethylamino)methylene-2-(2,4,5-trifluorobenzoyl)acetate 21 as a light orange oil (Yield 2.55 g (85%). MS (m/z): 302 [M+H]+. Rt 4.9 min.). A solution of Compound 21 (0.301 g, 1.0 mmol) and 5-(S)-acetamidomethyl-3-(4-amino-3-fluorophenyl)-oxazolidine-2-one (0.267 g, 1.0 mmol) in EtOH (9 mL) was agitated at 40° C. for 16 h. The solvent was removed under vacuum, and the resulting residue dissolved in ethyl ether (75 mL). The ether solution was washed with 3% aq. citric acid (2×40 mL), brine (40 mL), and dried (MgSO4). The solvent was removed under vacuum to afford Compound 22 as a thick light-orange oil. Yield 0.50 g (90%). MS (m/z): 524 [M+H]+. Rt 5.5 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15]>O1CCCC1>[Cl:15][C:14]1[N:13]=[C:20]([Cl:21])[N:19]=[C:17]([N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[CH3:1])[N:16]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
2-Methylbenzimidazole (5.0 g) was dissolved in tetrahydrofuran (50 ml), and sodium hydride (60% purity, oily) (1.6 g) was added thereto at room temperature. After stirring for 1 hour, cyanuric chloride (7.0 g) was added at room temperature, followed by stirring for 3 hours. Ice water was added, followed by extraction with ethyl acetate, washing with a saturated sodium chloride aqueous solution and drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 2.6 g of the desired product as a white powder (m.p. at least 300° C.).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:15])([F:14])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[BH4-].[Na+].Cl>CCO.O>[F:14][C:5]([F:15])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(F)(F)CCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCC(F)(F)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
2,2-Difluoro-4-phenyl-butyric acid ethyl ester (0.23 g, 1 mmol) was dissolved in EtOH (4 ml) and treated with NaBH4 (39.4 mg, 1 mmol). After 30 minutes stirring at room temperature, the reaction mixture was cooled to 0° C., acidified to pH 1 with 1N HCl (2 ml), diluted with H2O (10 ml). The aqueous phase was extracted with ether (3 times). The combined organic phases were dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was chromatographed over silica gel (hexane-ethylacetate 99:1) to provide 2,2-difluoro-4-phenyl-butan-1-ol (0.11 g, 58%) as light yellow oil, MS: m/e=186.1 (M+).
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.[C:7]1(O)[CH:12]=[CH:11]C=[CH:9][CH:8]=1>[F-].[K+]>[O:2]([CH2:3][CH2:4][OH:5])[C:1]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccccc1
Reactant: O=C1OCCO1
Agent: [F-]
Agent: [K+]
Product: OCCOc1ccccc1
Yield: 99.2 %

Procedure:
Ethylene carbonate (89.9 g, 1.02 mole), phenol (94.1 g, 1.0 mole) and potassium fluoride (1 g, 0.5 percent of total reactant weight) were placed in a 500 ml round-bottomed flask equipped with a condenser and gas bubbler. A magnetic stirrer provided agitation. The mixture was heated to 160° C.±2° C. in an oil bath. After 2.5 hours the reaction vessel was removed from the oil bath, cooled and the contents removed. Purification of the product by distillation gave 137 g of 2-phenoxyethanol (99 percent conversion based on phenol limiting reagent).
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>C1C=CC=CC=1>[CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][C:4]([Cl:16])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)CCC[C@@H](C)CC(=O)O
Solvent: c1ccccc1
Product: CC(C)CCC[C@@H](C)CC(=O)Cl
Yield: 95.4 %

Procedure:
A solution of 11.37 g (66.1 mmoles) of (R)-(+)-3,7dimethyloctanoic acid in 50 ml of benzene was stirred while 10 ml (114.6 mmoles) of oxalyl chloride was added. The solution was stirred and refluxed overnight then concentrated in vacuo giving 12.03 g (95.6 %) of (R)-(+) -3,7-dimethyloctanoyl chloride as an oil. An 8.2 g (43.0 mmoles) sample of this material in 10 ml of dichloromethane was added to a stirred solution of 6.2 (43.0 mmoles) of Meldrum's Acid and 8.68 ml of pyridine in 40 ml of dichloromethane, at 0° C. The resulting solution was stirred overnight then treated with cold 3N agueous HCl. The organic phase was separated and the agueous phase was extracted with dichloromethane. The dichloromethane extracts were combined dried (Na2SO4), and concentrated in vacuo giving 12.1 g of crude product. This material was dissolved in 100 ml of methanol and the solution was refluxed for 4 hr then cooled and concentrated in vacuo. The residue was chromatographed on silica gel giving (R)-5,9-dimethyl-3-oxodecanoic acid methyl ester as an oil, eluted with pet. ether - ether mixtures.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([N:13]([CH3:45])[C:14]([N:16]([CH3:44])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:43])[O:39][CH2:40][CH2:41]Cl)[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+]>CN(C=O)C.O>[F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([N:13]([CH3:45])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:41][CH2:40][O:39][C:38]4=[O:43])[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)[CH3:44])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](NC(=O)OCCCl)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](N3CCOC3=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of the compound (0.19 g) obtained in step 1 in DMF (5.0 mL) was added sodium hydride (0.022 g) at 0° C., and the mixture was stirred at room temperature for 4 days. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 10→100% ethyl acetate/hexane) to give the title compound (0.12 g, 65%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[NH:6]2.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C1C=CN=CC=1)C>[C:17]([O:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[NH:6]2)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc2c(O)c(OC)ccc2[nH]1
Agent: CN(C)c1ccncc1
Product: COC(=O)c1cc2c(OC(C)=O)c(OC)ccc2[nH]1
Yield: 75 %

Procedure:
A stirred solution of methyl 4-hydroxy-5-methoxyindole-2-carboxylate (0.51 g) and DMAP (10 mg) in acetic anhydride (5 ml) was heated at 80° C. for 4 hours. The reaction was concentrated in vacuo and the residue dissolved in dichloromethane and washed with hydrochloric acid (2.0 M), saturated aqueous sodium hydrogen carbonate solution, water, aqueous saturated sodium chloride solution and dried (MgSO4). The solution was concentrated in vacuo and the residue was purified by column chromatography using 50% diethyl ether:iso-hexane as eluent to give the product as a white solid (0.58 g, 75%), NMR d CD3SOCD3) 2.34 (s, 3H), 3.75 (s, 3H), 3.85 (s, 3H), 6.99 (d, 1H), 7.19 (d, 1H), 7.29 (d, 1H), 11.93 (brs, 1H); M/z (+) 264 (MH+).