Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([N:23]([CH3:25])[CH3:24])=[C:17]([O:26][CH3:27])[CH:16]=1>C(O)(=O)C.O>[CH3:25][N:23]([CH3:24])[C:18]1[C:17]([O:26][CH3:27])=[CH:16][C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: COC(=O)c1cc(OC)c(N(C)C)c(OC)c1
Reactant: CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1N(C)C
Temperature: 30 °C
Reaction time: 4 h

Procedure:
A suspension of 21.6 g. of dimethylsulfone and 7.7 g. of sodium hydride (50% dispersion in oil) in 80 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 3 hours under an atmosphere of nitrogen and the exclusion of moisture. The mixture was cooled to 30° C. and 15.6 g. of 4-(dimethylamino)-3,5-dimethoxybenzoic acid methyl ester were added. After stirring at room temperature for 4 hours, 500 ml. of water were added and the solution was made neutral with glacial acetic acid. The precipitate was removed by filtration with suction, washed with water, dried, recrystallized from ethyl acetate/cyclohexane, whereby there was obtained 4'-(dimethylamino)-3',5'-dimethoxy-2-(methylsulfonyl)-acetophenone having a melting point of 111°-112° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:26])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[OH-].[Li+]>O1CCCC1.CO>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=3[CH3:26])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(COc2ccc(-c3ccc(OC)cn3)cc2)c(C)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-[4-(5-methoxy-pyridin-2-yl)-phenoxymethyl]-5-methyl-furan-2-carboxylic acid methyl ester (52) (70 mg) and 1M aqueous lithium hydroxide (1 mL) in tetrahydrofuran/methanol (2:1 by volume) (12 mL) was stirred at room temperature for 16 hours. The reaction mixture was acidified to between pH6 and pH7, and partitioned between ethyl acetate and water. The organic phase was separated, washed with brine and dried (MgSO4). After removal of the solvent, the residue was purified by HPLC. Compound 53 was obtained as a solid (2.5 mg). LC/MS System A: Rt=2.90 mins, m/z (ES+)=340 ((M+H) for C19H17NO5).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=1)=[O:39]>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:20][CH:21]=3)[N:10]([CH2:37][C:38](=[O:39])[NH:40][C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][N:42]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: COC(=O)c1cccc2[nH]c(C(=O)Nc3ccc(N4CCOCC4=O)cc3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1nc(C(=O)Nc1ccc(N3CCOCC3=O)cc1)n2CC(=O)Nc1ccc(Cl)cn1
Reaction time: 4 h

Procedure:
72.0 mg (0.183 mmol) 2-[4-(3-Oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 7 mL DMF. Sequentially 37.8 mg (0.274 mmol) K2CO3 and 54.6 mg (0.219 mmol) 2-bromo-N-(5-Chloro-pyridin-2-yl-)-acetamide were added and the resulting mixture was stirred for 4 h at 80°. The mixture was diluted with 200 mL toluene and washed with 50 mL of a saturated NaHCO3-solution. The product was not completely soluble in toluene, so ethyl acetate had to be added. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) to give 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester as a light brown amorphous solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[NH:10][CH2:11][C:12](=[O:39])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH2:26][O:27]C(=O)C)=[O:23])=[CH:17][C:16]=1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=[O:46])C>CO>[CH2:1]([O:8][C:9](=[O:40])[NH:10][CH2:11][C:12](=[O:39])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH2:26][OH:27])=[O:23])=[CH:17][C:16]=1[C:31](=[O:46])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: CC(=O)OCCNC(=O)Nc1ccc(CNC(=O)CNC(=O)OCc2ccccc2)c(Cc2ccccc2F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CNC(=O)OCc1ccccc1)NCc1ccc(NC(=O)NCCO)cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of benzyl{[[2-(o-fluorobenzyl)-4-[3-(2-acetoxyethyl)ureido]phenyl]methylcarbamoyl]methyl}carbamate dissolved in 10 ml of absolute methanol are treated with 50 mg of sodium methylate, stirred at room temperature for 1 hour and buffered with a small amount of acetic acid. The mixture is poured on to ice/10% sodium bicarbonate and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. After crystallisation from ether/ethanol, there is obtained benzyl{[[2-(o-fluorobenzoyl)-4-[3-(2-hydroxyethyl)ureido]phenyl]methylcarbamoyl]methyl}carbamate which melts at 117°-120° C.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.O.C(OCC)(=O)C.[OH-].[Na+]>FC(F)(F)C(O)=O>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[N:33][CH:34]=[C:35]([F:38])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCO3)CC1
Yield: 24.8 %

Procedure:
A solution of 3.03 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 45 mL of trifluoroacetic acid was stirred for 1 hour and 30 minutes at room temperature. The reaction mixture was cooled with ice, added with 30 mL of water and 30 mL of ethyl acetate, and adjusted to pH 10 with a 2 mol/L sodium hydroxide aqueous solution. The organic layer was separated and the aqueous layer was extracted 7 times with ethyl acetate. The organic layer was combined therewith and the solvent was concentrated to 10 mL under reduced pressure, whereby insoluble matter was filtered out. The solvent was evaporated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography [eluate; chloroform:methanol=92:8], recrystallized from 3 mL of ethyl acetate to give 0.611 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one (anhydrate) as a light yellow solid.
Reaction SMILES: [N:1]([C@@:4]1([OH:19])[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3].C(OC(=O)C)(=O)C.[Br:27]Br>C(O)(=O)C>[N:1]([C@@:4]1([OH:19])[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([Br:27])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@]1(O)C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: [N-]=[N+]=N[C@]1(O)C[C@H](n2cc(Br)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3'-Azido-5-bromo-2'-doxyuridine was prepared from the known 3'-azido-2'-deoxyuridine (T. A. Krenitsky, et al., J. Med. Chem., 26, 891, (1983)) (0.827 g, 3.3 mMol) by first acetylating the 5'-hydroxyl with acetic anhydride (15 mL) then by brominating the 5 position by the addition of acetic acid (0.5 mL) and bromine (0.566 g). The red-brown solution was stirred at room temperature for two hours. The reaction was taken to an oil in vacuo and triturated with ethyl ether. The oil was dissolved in methanol ammonia to remove the acetyl group. The desired product was isolated by chromatography on silica gel by elution with CHCl3 :MeOH (95:5 v/v). The yield as 32%.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2].[CH3:17][Mg]Br>C1COCC1>[OH:2][CH:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C=O)COC1(C)C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of (R)-tert-butyl 4-formyl-2,2-dimethyloxazolidine-3-carboxylate (Intermediate 182, 10.18 g, 44.40 mmol) in THF (188 mL) at −78° C. was added methyl magnesium bromide (16.28 mL, 48.84 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stir overnight under nitrogen atmosphere. Re-cooled reaction mixture to −78° C. and added dropwise additional 13 mL (0.9 eq, to bring total to 2 eq) of methyl magnesium bromide. Allowed reaction mixture to stir at −78° C. for 3 hours and warm to room temperature. The reaction mixture was quenched with water and diluted with ethyl acetate saturated sodium chloride (brine). The resulting emulsion was filtered thru celite and the layers separated. The organic layers were dried over magnesium sulfate, filtered, concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound as a colorless oily solid (8.42 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:11](=[O:18])[C:10]3[CH:19]=[CH:20][CH:21]=[N:22][C:9]2=3)[CH:5]=[CH:6][CH:7]=1>[Pd].C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]3[CH:19]=[CH:20][CH:21]=[N:22][C:9]2=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c2c(n(-c3cccc(Cl)c3)c3ncccc13)CCNC2
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: O=c1c2cnccc2n(-c2cccc(Cl)c2)c2ncccc12
Reaction time: 15 h

Procedure:
Oxidize 10-(3-chlorophenyl)-6,7,8,9-tetrahydropyrido[2,3-b] [1,6]naphthyridin-5(10H)-one (1.6 mmol) in a refluxing solution of xylene (15 ml), using air as the oxidant and 5% Pd on C (15 mg) as the catalyst. Follow the procedure of Tetrahedron Letters26, 1259-1260 (1985); pass air through the hot solution for 15 hours. Evaporate the xylene and elute the residue from silica gel with chloroform to provide 10-(3-chlorophenyl)pyrido[2,3-b] [1,6]naphthyridin-5(10H)-one, m.p. 222°-224° C. after crystallization from CH3Cl/pet. ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12].B.CO.Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C(=O)Nc1ccc(F)cc1Cl
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CNc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A suspension of the above propanamide (19.9 g, 92 mmol) in THF (200 ml) was cooled on an icebath. A 1M solution of borane in THF (100 ml, 100 mmol) was added and the mixture stirred at room temperature for 16 h. Methanol (50 ml) was carefully added followed by 1N hydrochloric acid (50 ml). The volume was concentrated in vacuo to 50 ml, water (200 ml) was added and pH in the aqueous phase was adjusted to 10 with 2N sodium hydroxide. The mixture was extracted with dichloromethane (3×100 ml) and the combined organic phases were extracted with 4N hydrochloric acid. The phases were separated, pH in the aqueous phase was adjusted to 10 with 6N sodium hydroxide and extracted with dichloromethane (2×100 ml). The organic phase was washed with water (50 ml) and dried (MgSO4). The solvent was evaporated in vacuo to give 15.0 g of N-(2-chloro-4-fluorophenyl)-N-(2-methyl-1-propyl)amine.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][NH:18][CH3:19].C([O-])(O)=O.[Na+]>Cl.CC(O)C>[Cl:1][C:2]1[N:11]=[C:10]([N:18]([CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH3:13])[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNCc1ccccc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccccc1CN(C)c1nc(Cl)nc2ccccc12
Yield: 39.2 %

Procedure:
A mixture of 2,4-dichloro-quinazoline (88 wt %, 525 mg, 2.3 mmol), (2-methoxy-benzyl)-methyl-amine (300 μL, 2.01 mmol) and 1 drop of concd HCl in i-PrOH (8 mL) was reacted for 5 days then concd in vacuo. Satd NaHCO3 (5 mL) was added then the product extracted into CHCl3 (2×4 mL). The organic portion was washed with water (1×3 mL) then dried (MgSO4), filtered through a plug of silica with an EtOAc wash then purified by MPLC (SiO2/0-20% i-PrOH in CHCl3) yielding the title compound as a white solid (247 mg; 39%). 1H NMR (CDCl3) δ 7.83-7.77 (m, 2H), 7.67 (m, 1H), 7.40-7.32 (m, 2H), 7.26 (m, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 4.96 (s, 2H), 3.81 (s, 3H), 3.31 (s, 3H); LC-MS (ESI+; 314 ([M+H]+)).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O.ClCCl>[O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere sulfur trioxide pyridine complex (6.34 g, 39.8 mmol) was added portionwise to a chilled (0° C.) solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (2.30 g) and triethylamine (5.55 mL, 39.8 mmol) in dimethyl sulfoxide (11.5 mL) and dichloromethane (23 mL). The solution was stirred at 0° C. for another hour, poured into 70 mL of saturated aqueous ammonium chloride and then extracted with diethyl ether (3×100 mL). The combined organics were washed with water (2×30 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 3-oxoazetidine-1-carboxylate as a clear oil.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:32][CH3:33])=[C:7]([CH:21]=[C:22]([N:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:23]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13](NS(C)(=O)=O)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:34]C1C=CC(CP(=O)(OCC)OCC)=CC=1>>[C:1]([C:5]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[CH:21]=[C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([F:34])=[CH:12][CH:11]=2)[C:6]=1[O:32][CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2)cc(N2CCC(=O)NC2=O)cc1C(C)(C)C
Reactant: CCOP(=O)(Cc1ccc(F)cc1)OCC
Product: COc1c(/C=C/c2ccc(F)cc2)cc(N2CCC(=O)NC2=O)cc1C(C)(C)C

Procedure:
The title compound was prepared according the procedures described in Example 1, Part H and Example 1, Part I using the product obtained in Example 1, Part G (50 mg, 0.164 mmol) and diethyl 4-fluorobenzylphosphonate (40.5 mg, 0.164 mmol). The title compound was obtained as a solid (30 mg, 46%). 1H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.72 (t, J=6.6 Hz, 2H), 3.76 (s, 3H), 3.79 (t, =6.6 Hz, 2H), 7.21 (m, 4H), 7.30 (d, J=16.3 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H), 7.73 (m, 2H), 10.35 (s, 1H).
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22](=O)[CH3:23]>C(#N)C>[CH3:23][C:22]1[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[S:1][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CC(=O)c1cnccc1Cl
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1sc2ccncc2c1C
Temperature: 25 °C
Yield: 17.2 %

Procedure:
To a solution of ethyl 2-mercaptoacetate (5.52 g, 0.046 mol) and triethylamine (5.52 g, 0.055 mol) in acetonitrile (100 mL) at room temperature was added 1-(4-chloropyridin-3-yl)ethanone (6.5 g, 0.042 mol). The reaction mixture was heated at reflux for 18 hours. Upon cooling to room temperature, the solvent was evaporated and the residue obtained partitioned between ethyl acetate and water. The organic layer was dried over anhydrous NaHSO4, filtered and concentrated. The oily residue was passed through a pad of silica (ethyl acetate/hexane: 5/1) to afford ethyl 3-methylthieno[3,2-c]pyridine-2-carboxylate (1.6 g, 22%). LCMS (FA) ES+ 222; 1H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.50 (d, J=5.6 Hz, 1H), 7.98 (d, J=17.6 Hz, 1H), 4.37 (d, J=7.2 Hz, 2H), 3.58 (t, J=5.9 Hz, 2H), 1.38 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([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.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCCCC>[CH:1]([C@H:14]1[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][CH2:20]1)([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: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCC
Product: O[C@@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.3 g, 1.13 mmol) in dry pentane (10 ml) was added to a suspension of LiAlH4 (0.21 g, 5.64 mmol) in dry pentane (20 ml). The resulting reaction mixture was stirred under N2 for 20 hr at room temperature, and then quenched with 10% NaOH, diluted with ethyl acetate (30 ml), and the precipitate removed by filtration. The organic phase was washed with brine and dried over anhydrous Na2SO4. Removal of solvent followed by flash chromatography of the crude product produced pure (3R,6S)-6-benzhydryl-tetrahydro-pyran-3-ol, 33a, 0.23 g (75%, [α]D=(+61.6, c=1, MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[C:25]12([CH2:35][NH2:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:25]12([CH2:35][NH:36][C:7]([C:6]3[C:2]([NH2:1])=[N:3][N:4]([C:10]4[N:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[CH:5]=3)=[O:9])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: Nc1nn(-c2ncccn2)cc1C(=O)O
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nn(-c2ncccn2)cc1C(=O)NCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-amino-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (50 mg, 0.24 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.08 mL, 0.48 mmol), 1-adamantan-1-ylmethan-amine (40 mg, 0.24 mmol), and BOP (128 mg, 0.29 mmol). The resulting mixture is stirred at RT for 18 h. Water (3 mL) is added, and the mixture is filtered. The solid is washed well with water and dried in vacuo to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ9.22 (1H, s), 8.75 (2H, s), 8.07 (1H, s), 7.33 (1H, s), 5.85 (2H, s), 2.90 (2H, d, J 5.2), 1.91 (3H, s), 1.61 (6H, m), 1.46 (6H, s). MS (M+1)=353.23; RT=1.31 min *IC50.
Reaction SMILES: [K].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[N+:12]([C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=1[CH3:23])([O-:14])=[O:13].Cl>C(OCC)C.O.C(OCC)(=O)C.CCO>[O:5]=[C:3]([CH2:23][C:16]1[CH:17]=[C:18]([Cl:22])[C:19]([Cl:21])=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])[C:2]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 61984.1 %

Procedure:
To a suspension of potassium (49.2 g, 1.26 mol) in anhydrous diethyl ether (500 ml), a solution of absolute EtOH (319 ml) and anhydrous diethyl ether (260 ml) was added dropwise under nitrogen during a period of four hours. The resulting solution was diluted with anhydrous diethyl ether (1200 mL) and then diethyl oxalate (171 ml, 1.26 mol) was added dropwise in about 30 minutes. To the resulting yellow mixture, a solution of 2-nitro-4,5-dichlorotoluene (260 g, 1.26 mmol), prepared as described by Cohen and Dakin in J. Chem. Soc., 79, 1133, in anhydrous diethyl ether (450 ml) was added dropwise in one hour at RT. Stirring was continued for additional three hours and the dark-brown mixture was settled at RT for two days. The potassium salt was collected by suction and dried to give a dark-brown powder. This was suspended in a mixture of water (400 ml) and ethyl acetate (400 ml), then acidified with 10% HCl. The organic phase was washed with brine, aqueous sat. NaHCO3 and again brine, then it was dried with MgSO4. Evaporation produced 239 g of title compound (781 mmol, yield 62.0%) as a light brown solid that was used as such for the next step, m.p.=92-94° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:29])=[CH:4][C:5]([F:28])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:23])=[C:15](F)[C:16]=3[O:18][CH:19]([CH3:21])[CH3:20])[C:11](=[O:24])[C:10]([C:25]([OH:27])=[O:26])=[CH:9]2)[CH:7]=1.[CH3:30][NH2:31]>>[NH2:1][C:2]1[C:3]([F:29])=[CH:4][C:5]([F:28])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:23])=[C:15]([NH:31][CH3:30])[C:16]=3[O:18][CH:19]([CH3:21])[CH3:20])[C:11](=[O:24])[C:10]([C:25]([OH:27])=[O:26])=[CH:9]2)[CH:7]=1
Reactant: CN
Reactant: CC(C)Oc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1OC(C)C
Reaction time: 24 h

Procedure:
1-(5-Amino-2,4-difluorophenyl)-6,7-difluoro-8-isopropyloxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) was added to a 40% aqueous solution (2.1 g) of methylamine, and the mixture was left to stand for 24 hours at about 55° C. The reaction mixture was concentrated under reduced pressure. Diisopropyl ether (0.5 ml) was added to the residue, and deposits were separated by filtration. The filtrate was concentrated under reduced pressure. Ethanol (about 0.1 ml) was added to the resultant residue, and the mixture was left to stand. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (60 mg) as a pale brown powder.