Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH2:9])=[C:5]([NH2:10])[N:4]([CH3:11])[C:3]1=[O:12].[CH3:13][O:14][C:15]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:16]=1[C:17](O)=O>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[NH:9][C:17]([C:16]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:23][C:15]=3[O:14][CH3:13])=[N:10][C:5]=2[N:4]([CH3:11])[C:3]1=[O:12]
Reactant: COc1cc(OCc2ccccc2)ccc1C(=O)O
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Product: COc1cc(OCc2ccccc2)ccc1-c1nc2c([nH]1)c(=O)n(C)c(=O)n2C

Procedure:
Prepared analogously to Example 14 from 1,3-dimethyl-4,5-diamino-1H,3H-pyrimidin-2,6-dione and 2-methoxy-4-benzyloxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([O:17]C)=O)[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[CH3:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH:27][CH3:26])=[O:17])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1
Reactant: CN
Reactant: COC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Product: CNC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
This compound was prepared from 1.48 g. (4.2 mmol) of the end product of Example 9 and mono-methylamine according to the procedure described above in Example 11. Recrystallization from acetone/ether/hexane gave the desired product, mp 170°-172°. An analytical sample was prepared by recrystallization from the same solvent system and isolated as colorless needles: mp 170°-172°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[S:5][CH:6]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[S:5][C:6]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1csc(CC(=O)O)c1
Reactant: O=C(Cl)c1ccccc1
Product: Cc1cc(CC(=O)O)sc1C(=O)c1ccccc1
Yield: 44.1 %

Procedure:
Using the procedure of Example 15, 6.65 gm of 4-methyl-thiophene-2-acetic acid and 5.96 gm of benzoyl chloride were reacted to obtain 4.87 gm of 4-methyl-5-benzoyl-thiophene-2-acetic acid melting at 86° C. The product occurred as a colorless solid soluble in benzene, ether, ethanol, chloroform and acetone and insoluble in water.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:13](Cl)(=[O:15])[CH3:14].[Sn](Cl)(Cl)(Cl)Cl.O>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]([CH3:12])=[C:5]([C:13](=[O:15])[CH3:14])[C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1cc(C)sc1C
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1c(C)sc(C)c1C(C)=O
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A solution of methyl 2,5-dimethyl-3-thiophene acetate (33.2 g, 0.18 mol) in CH2Cl2 (150 ml) was added to a solution of acetylchloride (15.5 ml, 0.216 mol) and tin (IV) chloride (23.2 ml, 0.198 mol) in CH2Cl2 (200 ml) at 0°-5° C. over a 15 minute period. The solution became a deep red color and was stirred at 0°-5° C. for two hours. H2O (200 ml) was added to the mixture, and the organic layer was separated, washed with saturated aqueous NaHCO3 (1×100 ml), dried over MgSO4, and treated with activated charcoal. The solvent was removed in vacuo to give the product (40.2 g, 97% yield) as an oil with crystallized slowly on standing; mp 68°-71° C.; IR (KBr) 1745 and 1650 cm-1 ; mass spectrum m/z 226 (M+); 1H NMR (CDCl3) δ 2.30 (s, 3H, thiophene-CH3), 2.47 (s, 3H, COCH3), 2.60 (s, 3H, thiophene-CH3), 3.67 (s, 5H, CH2CO2CH3).
Reaction SMILES: C1(COC([NH:11][C:12]2[O:13][C:14](=[O:30])[C:15]3[NH:20][CH2:19][N:18]([C@@H:21]4[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]4[OH:23])[C:16]=3[N:17]=2)=O)C=CC=CC=1>[Pd].CN(C=O)C>[CH:19]1[N:18]([C@@H:21]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:24]([OH:25])[C@H:22]2[OH:23])[C:16]2[N:17]=[C:12]([NH2:11])[O:13][C:14](=[O:30])[C:15]=2[N:20]=1
Reactant: O=C(Nc1nc2c(c(=O)o1)NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)o1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10% Palladium on charcoal (172 mg) was added to a solution of 5-[[(phenylmethoxy)carbonyl]amino]-3-(β-D-ribofuranosyl)imidazo[4,5-d][1,3]oxazin-7(1H)-one (172 mg, 0.41 mmol) in DMF (7 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 h. The mixture was filtered through prewashed Celite and was concentrated under high vacuum. The residue was dissolved in water and filtered through a Millipore Millex-HV filter (0.45 μm). The filtrate was lyophilized to give oxanosine as a white powder: 115 mg, (100%). Crystallization from warm water gave oxanosine (75%) as colorless needles: mp 191°-192° C.; [α]25D -38.7° (c 1, H2O); IR (KBr) 3440-3200, 1802, 1772, and 1550 cm-1 ; MS [(+) FAB]m/z 285 (M+H+); NMR (D2O) δ3.80-3.91 (m, 2), 4.21-4.23 (m, 1), 4.40 (t, 1, J=4.6 Hz), 4.69 (t, 1, J=5.5 Hz), 5.80-5.85 (d, 1, J=5.5 Hz), 7.98 (s, 1); UV max (H2O) 245 nm (ε11760), 287 (8450).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[N:4]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH3:11])[N:4]=[C:3]([N:2]([CH3:1])[C:21]([NH:20][S:17]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)(=[O:18])=[O:19])=[O:22])[N:8]=1
Reactant: CNc1nc(C)cc(OC)n1
Reactant: O=C=NS(=O)(=O)c1cccs1
Solvent: CC#N
Product: COc1cc(C)nc(N(C)C(=O)NS(=O)(=O)c2cccs2)n1

Procedure:
To a mixture, 1.5 g of 2-methylamino-4-methoxy-6-methylpyrimidine in 50 ml of acetonitrile is added 1.9 g of 2-thiophenesulfonyl isocyanate. Filtration affords N-[N-(4-methoxy-6-methylpyrimidin-2-yl)-N-methylaminocarbonyl]-2-thiophene sulfonamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:21]=[CH:20][C:7]2[N:8]([CH2:17][O:18][CH3:19])[C:9](=[O:16])[C:10]3[CH:11]=[CH:12][CH:13]=[N:14][C:15]=3[C:6]=2[CH:5]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:19][O:18][CH2:17][N:8]1[C:7]2[CH:20]=[CH:21][C:4]([CH2:3][CH:2]=[O:1])=[CH:5][C:6]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]1=[O:16]
Reactant: COCn1c(=O)c2cccnc2c2cc(CCO)ccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCn1c(=O)c2cccnc2c2cc(CC=O)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.2 %

Procedure:
The compound (50 mg, 0.18 mmol) prepared in step 4 was dissolved in dichloromethane (10 ml), added with Dess-Martin periodinane (112 mg, 0.26 mmol) at 0° C. The resulting mixture was stirred for 90 minutes at room temperature and poured into saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was then purified by flash column chromatography (ethylacetate:hexane=1:1) to obtain the title compound (25 mg, yield: 50%, white solid).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH:17]1[N:21]2[C:22]3[C:28]([CH:29]=O)=[CH:27][NH:26][C:23]=3[N:24]=[CH:25][C:20]2=[N:19][N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].O>O.CN(C=O)C.C1COCC1>[C:12]([O:11][C:10](=[O:16])[NH:9][CH2:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][CH2:29][C:28]2[C:22]3[N:21]4[CH:17]=[N:18][N:19]=[C:20]4[CH:25]=[N:24][C:23]=3[NH:26][CH:27]=2)[CH2:3][CH2:4]1)([CH3:13])([CH3:15])[CH3:14]
Reactant: O=Cc1c[nH]c2ncc3nncn3c12
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](NCc2c[nH]c3ncc4nncn4c23)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl trans-4-aminocyclohexylmethylcarbamate (0.059 g, 0.258 mmol, AMRI) was added to a mixture of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine-8-carbaldehyde (0.0403 g, 0.215 mmol, Preparation #38) and THF (1.0 mL). The mixture was stirred at ambient temperature for about 90 min. Sodium triacetoxyborohydride (0.068 g, 0.32 mmol) was added. After about 3 h, DMF (0.500 mL) was added. After about 15 h, Na(OAc)3BH (0.091 g, 0.43 mmol) was added. After about 24 h, Na(OAc)3BH (0.091 g, 0.43 mmol) was added. The mixture was warmed to about 40° C. After about 22 h, the mixture was allowed to cool to ambient temperature. Saturated aqueous NaHCO3/water (1:1, 2 mL) was added. After vigorously stirring for about 1 h, the solution was diluted with water (3 mL) and then extracted with EtOAc (6×10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified silica gel chromatography eluting with a gradient of 10-100% [(1% 7 N NH3 in MeOH) in 10% MeOH/DCM]/DCM to give tert-butyl(trans-4-((6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-8-yl)methylamino)cyclohexyl)methylcarbamate (0.0476 g, 53%): LC/MS (Table 1, Method a) Rt=1.24 min; MS m/z 400 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[CH:4]=[N:5][OH:6].[CH2:13]1C(=O)N(Cl)[C:15](=[O:16])[CH2:14]1.C(O)C#C.CCN(CC)CC>CN(C=O)C.O.N1C=CC=CC=1>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]([F:12])[C:3]=1[C:4]1[CH:13]=[C:14]([CH2:15][OH:16])[O:6][N:5]=1
Reactant: ON=Cc1c(F)ccc(F)c1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: C#CCO
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: OCc1cc(-c2c(F)ccc(F)c2Cl)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A sol. of 2-chloro-3,6-difluoro-benzaldehyde oxime (21.3 g, 111 mmol) in DMF (66.7 mL) was added dropwise to a sol. of NCS (14.9 g, 111 mmol) and pyridine (1.78 mL) in DMF (222 mL). The mixture was stirred for 1 h at rt, and a sol. of propargyl alcohol (4.99 g, 89.1 mmol) in DMF (71 mL) was dropwise added. The reaction mixture was heated to 85° C., and a sol. of Et3N (15.5 mL, 111 mmol) in DMF (89.3 mL) was slowly added. The reaction mixture was stirred at 85° C. for 60 min, and was allowed to cool to rt. The mixture was diluted with water (533 mL), and was extracted with EtOAc (2×). The combined org. extracts were washed with water and brine, were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 40:60) yielded the title compound (17.0 g, 78%). LC-MS: tR=0.84 min; ES+: 287.12.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:29](C(C)C)CC)(C)C.CS(Cl)(=O)=O>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24][NH2:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CO)C1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CN)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
To a 0° C. solution of 1.30 g of 1-(benzyloxycarbonyl)-2-hydroxymethyl-4-(tert-butyloxycarbonyl)-piperazine in 20 mL of CH2Cl2 was added 720 mg of diisopropylethylamine, then 510 mg of methanesulfonyl chloride. The mixture was allowed to warm to room temperature over 2 h, then diluted with 50 mL of EtOAc and washed with 25 mL of saturated NaHCO3, 2×25 mL of 1N HCl, 25 mL of saturated NaHCO3, and 25 mL of brine. The organic phase was dried over MgSO4 and concentrated to a yellow oil. This oil was dissolved in 10 mL of DMF and 360 mg of sodium azide was added. The mixture was heated to 100° C. and stirred overnight at this temperature, then cooled, diluted with 25 mL of EtOAc, and washed with 3×10 mL of water and 10 ml of brine. The organic phase was dried over MgSO4 and concentrated to an oily yellow solid. Of this solid, 475 mg was dissolved in 5 mL of 9:1 THF-water and 398 mg of triphenylphosphine was added. The mixture was heated to 50° C. and stirred at this temperature for 16 h, then cooled, poured into 30 mL of 1N HCl, and extracted with 2×10 mL of EtOAc. The aqueous phase was made very basic (pH>12) by addition of 5N NaOH, then extracted with 5×20 mL of EtOAc. The combined organic extracts were dried over MgSO4, and concentrated to yield 48 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ7.28-7.40 (m, 5H), 5.15 (ABq, J=12.4 Hz, 2H), 3.82-4.22 (m, 4H), 2.66-3.30 (m, 5H), 1.45 (br s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3ccccc3Cl)cc2)no1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 40 mg, 0.142 mmol) in CH3CN (2 mL) were added 2-chlorophenol (22 μL, 0.22 mmol) and K2CO3 (40 mg, 0.29 mmol). The mixture was heated at 90° C. for 4 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-chloro-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (37 mg, 79%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.94 (d, J=8.1 Hz, 2H), 7.61 (d, J=9.5 Hz, 3H), 7.44 (dd, J=8.1, 1.5 Hz, 1H), 7.19-7.35 (m, 2H), 6.92-7.01 (m, 1H), 5.29 (s, 2H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[F:49][C:50]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:51]=1[CH2:52][NH2:53]>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:53][CH2:52][C:51]2[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:50]=2[F:49])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: NCc1ccc(F)cc1F
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NCc1ccc(F)cc1F)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and 2,4-difluorobenzylamine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C22H15BrF2N4O3S, 532.0; m/z found, 533/535 [M+H]+, 555/557 [M+Na]+. HPLC (reverse phase): RT=9.64 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 11.31 (s, 1H), 8.92-8.86 (m, 2H), 8.62-8.53 (m, 1H), 8.35-8.29 (m, 1H), 7.96-7.90 (m, 1H), 7.90-7.83 (m, 1H), 7.41-7.32 (m, 1H), 7.15-7.10 (m, 1H), 7.09-7.03 (m, 1H), 6.94-6.82 (m, 2H), 6.31-6.24 (m, 1H), 4.53 (br s, 2H).
Reaction SMILES: Cl.[C:2]1([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH:16]=[N:17]O)[CH:13]=[N:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(Cl)(Cl)Cl.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>[Zn]>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[C:2]1([C:8]#[C:9][C:10]2[CH:11]=[C:12]([CH2:16][NH2:17])[CH:13]=[N:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=Cc1cncc(C#Cc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NCc1cncc(C#Cc2ccccc2)c1
Reaction time: 0.25 h
Yield: 11.9 %

Procedure:
Add zinc dust (0.39 g, 6.04 mmol) in small portions to a solution of 5-phenylethynyl-pyridine-3-carbaldehyde oxime hydrochloride, (prepared as described in EXAMPLE 6), (0.16 g, 0.60 mmol) in trifluoroacetic acid (1.4 mL) while keeping the internal reaction temperature between about 15-20° C. using a chilled water bath. After 15 min, add a 1:1 mixture of 2 N sodium hydroxide and chloroform, while stirring vigorously and cooling in an ice bath. Filter away the solids and wash the filtrate with water, an aqueous saturated solution of sodium chloride, dry (magnesium sulfate), filter and concentrate. Purify the residue by reverse phase HPLC, eluting with 5:95 to 100:0 acetonitrile:water with 0.02% trifluoroacetic acid, to give the title compound as pale yellow solid (0.015 g, 11.9%).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:35](Cl)(=[O:57])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:35](=[O:57])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)Oc1cc(C(=O)CNC(C)(C)C)ccc1Oc1ccc(C)cc1

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with docosanoyl chloride there is obtained 3-(docosanoyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with methanesulfonic acid to yield the methanesulfonate salt. When this methanesulfonate is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3-(docosanoyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate.
Reaction SMILES: ClC1C=C(N=C=O)C=CC=1.CN.NC(N)=O.C(CC(O)=O)#N.N([O-])=O.[Na+].NC1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=2)[C:32](=[O:41])[N:31](C)[C:30](=O)C=1.[H][H].ClC1C=C(N2C(N)=C(N)C(=O)N(C)C2=O)C=CC=1>>[CH3:30][NH:31][C:32]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)=[O:41]
Reactant: [H][H]
Reactant: Cn1c(=O)cc(N)n(-c2cccc(Cl)c2)c1=O
Agent: CN
Agent: Cn1c(=O)c(N)c(N)n(-c2cccc(Cl)c2)c1=O
Agent: N#CCC(=O)O
Product: CNC(=O)Nc1cccc(Cl)c1

Procedure:
N-Methyl-N'-(3-chlorophenyl)urea was prepared preliminarily from 3-chlorophenyl isocyanate and methylamine by the same procedure as in Reference Example 1. The urea compound as the starting material was reacted with cyanoacetic acid to form a uracil ring. Using sodium nitrite a nitroso group was introduced into the 5-position of the uracil ring in the obtained 6-amino-1-(3-chlorophenyl)-3-methyluracil and then reduced with hydrogen gas to prepare 1-(3-chlorophenyl)-5,6-diamino-3-methyluracil.
Reaction SMILES: COC(=O)[CH:4]([C:17]#[N:18])[C:5]1([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1.[Cl-].[Na+]>CS(C)=O.O>[F:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH2:4][C:17]#[N:18])[CH3:16]
Reactant: COC(=O)C(C#N)C1(C)CCOc2ccc(F)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(CC#N)CCOc2ccc(F)cc21
Reaction time: 4 h
Yield: 86.7 %

Procedure:
A mixture of 3.1 g (11.8 mmol) of cyano(6-fluoro-4-methylchroman-4-yl)acetic acid methyl ester and 2.47 g (42.4 mmol) of sodium chloride in 30 mL of wet DMSO was warmed to reflux. The reaction was monitored by TLC. After 4 hours, the reaction was cooled and diluted with water and extracted with diethyl ether. The combined organic layers were washed with four portions of water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2.1 g (87%) of (6-fluoro-4-methylchroman-4-yl)acetonitrile as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2].[CH3:16][Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCCC1.CI.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH:12]([CH3:16])[C:11](=[O:15])[C:8]=2[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)c1csc2c1CCCC2=O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1csc2c1CCC(C)C2=O
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (the compound of Preparation Example 3) (1.0 g) in tetrahydrofuran (9 mL) was added dropwise 1.0M lithium hexamethyldisilazide-tetrahydrofuran solution (4.9 mL). After stirring at −70° C. for 15 minutes, methyl iodide (0.34 mL) was added and the solution was warmed to room temperature and was stirred for 30 minutes. After an aqueous solution of saturated ammonium chloride was added and a further dilution with water, extraction was carried out with ethyl acetate. After the organic layer was washed with saturated sodium chloride water and dried with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (426 mg) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[NH:7]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8]1.CN(C=O)C.IC(C)C>CCOCC.O>[CH:2]([N:7]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8]1)([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1cc[nH]c1
Agent: [K+]
Solvent: CC(C)I
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccn(C(C)C)c1
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
Potassium t-butoxide (6.7 g, 60 mmol) was added to a stirred 0° C. solution of 1-(1H-pyrrol-3-yl)ethanone (5.0 g, 46 mmol) of DMF (150 mL). After stirring for 30 minutes, 2-iodopropane (10.1 g, 60 mmol) was added and the mixture was stirred overnight at approximately 25° C. The mixture was diluted with Et2O and H2O. The portions were separated, and the aqueous portion was extracted two more times. The organic portions were combined and washed with brine and then dried with Na2SO4. The mixture was filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography (30 percent ether/pentane over silica gel), affording 3.9 g of yellow oil.