Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C([O:13][C:14](=[O:19])[C:15]([OH:18])([CH3:17])[CH3:16])C.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1.Cl>O1CCCC1>[CH3:17][C:15]([O:18][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=1)([CH3:16])[C:14]([OH:13])=[O:19]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (0.91 M, 275 mL) at −70° C. under nitrogen and was added ethyl-2-hydroxyisobutyrate (36 mL, 34.7 g, 0.263 mol) over 12 min. After stirring for additional 10 min, 2-chloro-5-trifluormethylpyridine was added in one portion. The cooling bath was removed and the reaction was allowed to warm to room temperature overnight. Sodium hydroxide (105 mL, 5N) was added, and the reaction was refluxed overnight. The reaction mixture was partially concentrated on a rotary evaporator, diluted with water (150 mL), and extracted with hexane (2×150 L). The aqueous layer was separated and acidified with 2N HCl (350 mL, 0.7 mol), and the resulting suspension was cooled to 0° C. After aging for 20 min, the precipitate was collected by filtration, which was washed with water (4×150 mL) and air-dried to afford 38.0 g of a tan solid. (85.5%). Treatment with Darco KB and recrystallization in 3:1 heptane/isopropyl acetate provided the title compound as a white crystalline material. 1H NMR (500 MHz, CD3OD): δ 8.38 (br s, 1H), 7.93 (dd, 1H), 7.13 (d, 1H), 1.70 (s, 6H). LC-MS: m/e 250 (M+H)+ (2.6 min).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)[O:16][C:15](=O)[C:12]2([CH2:14][CH2:13]2)[C:11](=[O:18])[O:10]1>C(O)C>[CH:1]1([N:7]2[CH2:14][CH2:13][CH:12]([C:11]([OH:18])=[O:10])[C:15]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: NC1CCCCC1
Solvent: CCO
Product: O=C(O)C1CCN(C2CCCCC2)C1=O
Yield: 36.7 %

Procedure:
A mixture of cyclohexylamine (1.02 mL; 8.82 mmol) and 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.5 g; 2.94 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 30 to 100% ethyl acetate in heptane with 5% acetic acid) to afford 0.228 g (36%) of 1-cyclohexyl-2-oxopyrrolidine-3-carboxylic acid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O>CS(C)=O>[N:15]1([CH2:14][CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: NCCCN1CCOCC1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(NCCCN2CCOCC2)c1
Temperature: 100 °C
Reaction time: 60 h

Procedure:
28.2 g 3-fluoronitrobenzene and 158.4 g 4-(3-aminopropyl)morpholine were dissolved in 300 ml dimethyl sulfoxide, and the batch was stirred for 60 h at 100° C. After cooling, the batch was poured into 1 l water. The mixture was extracted several times with methyl tert-butyl ether, and the combined organic phases were reduced to dryness on a rotary evaporator. The product obtained was an orange-brown oil.
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN([CH:30]=[O:31])C>>[C:14]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH:30]=[O:31])=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C=O
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Triphenyl amine (98.32 g, 0.393 mol) is suspended in DMF (280 ml). Phosphorus oxychloride (66.24 g, 0.432 mol) is added dropwise to it over a 30-minutes period without external cooling. After stirring for one more hour, the reaction is heated to 80° C. (bath temperature) for 2 ½ hours. After cooling to room temperature, the reaction is slowly poured onto ice-cold water (8 liters) with vigorous stirring. After 30 minutes, aqueous sodium hydroxide (5 N, 250 ml) is added to the reaction, and stirring is continued for one hour. The obtained precipitate is filtered off, washed with water (2 liters), then with methanol (2 litres) and dried to give 4-diphenylaminobenzaldehyde as a beige solid (90.47 g, 0.331 mol, 84%), which is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[NH2:18].C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[Cl:8][C:6]1[N:7]=[C:2]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[C:15]([F:14])[CH:16]=2)[C:3]([C:11]([NH2:13])=[O:12])=[N:4][C:5]=1[CH2:9][CH3:10]
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCOCC3)c(F)c2)nc1Cl
Yield: 66.1 %

Procedure:
A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (600 mg), 3-fluoro-4-(morpholin-4-yl)aniline (500 mg), diisopropylethylamine (880 μL), and N-methylpyrrolidone (2.5 mL) was reacted in a microwave reaction device at 180° C. for 1 hour. After leaving to be cooled, to the reactant was added water, and the precipitated solid was collected by filtration and then washed with ethanol to obtain 5-chloro-6-ethyl-3-{[3-fluoro-4-(morpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide (640 mg) as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:37])[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:18])[N:6]([CH2:19][CH2:20][CH2:21][N:22]([CH3:35])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)[C:5]1=[O:36].Cl>O1CCOCC1.O>[OH:36][CH:5]1[C:4]([CH3:37])([CH3:3])[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:18])[N:6]1[CH2:19][CH2:20][CH2:21][N:22]([CH3:35])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1
Reactant: COc1ccc(CCN(C)CCCN2C(=O)c3cc(OC)c(OC)cc3C(C)(C)C2=O)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CCN(C)CCCN2C(=O)c3cc(OC)c(OC)cc3C(C)(C)C2O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
0.49 gm (13.0 millimols) of sodium borohydride were added at 0° C. to a solution of 4.0 gm (8.2 millimols) of 1-[4,4-dimethyl-6,7-dimethoxy-1,3-dioxo-(2H,4H)-isoquinolin-2-yl]-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane in a mixture of 100 ml of dioxane and 20 ml of water. The mixture was stirred at room temperature for 8 hours and subsequently admixed with 100 ml of 2 N hydrochloric acid. After extraction with chloroform, the organic extract was dried over sodium sulfate and evaporated in vacuo, leaving as a residue 3.25 gm (80% of theory) of 1-[3-hydroxy-4,4-dimethyl-6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl]-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([OH:6])[C:4]#[CH:5].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:6][CH:3]([C:2]([CH3:11])([CH3:1])[CH2:7][CH2:8][CH2:9][CH3:10])[C:4]#[CH:5]
Reactant: C1CCOCC1
Reactant: C#CC(O)C(C)(C)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C#CC(OC1CCCCO1)C(C)(C)CCCC
Reaction time: 16 h

Procedure:
To a solution of 58 parts of 4,4-dimethyl-1-octyn-3-ol in 116 parts by volume of dry benzene is added first 158 parts of tetrahydropyran then, with cooling, 0.29 part of p-toluenesulfonic acid. The reaction mixture is stored at room temperature for about 16 hours, then is diluted with benzene and washed successively with dilute aqueous sodium hydroxide and water. Drying over anhydrous sodium sulfate followed by removal of the solvent under reduced pressure affords 4,4-dimethyl-1-octyn-3-ol tetrahydropyran-2-yl ether.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[O:16][CH3:17])[CH:3]=1.[CH:18](OC)(OC)OC.Cl.[OH-].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C.O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][CH3:18])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[O:16][CH3:17])[CH:3]=1
Reactant: COC(OC)OC
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNc1nnc(Cl)cc1-c1ccc(F)cc1OC
Temperature: 0 °C

Procedure:
To a solution of 6-chloro-4-(4-fluoro-2-methoxy-phenyl)-pyridazin-3-ylamine (300 mg, 1.18 mmol) in trimethyl orthoformate (1.00 g, 1.04 mL, 9.46 mmol) were added 2-3 drops of trifluoroacetic acid. The reaction mixture was stirred at reflux for 2 hours and then concentrated under vacuum. The residue was dissolved in 5 mL toluene and concentrated again under vacuum. This was repeated for three times to completely remove all volatiles. The residue was dissolved in tetrahydrofuran (3 mL) and borane tetrahydrofuran complex (1M solution, 2.96 mL, 2.96 mmol) was added in portions at 0° C. The reaction mixture was stirred at 90° C. for 2 hours and the resulting brown solution was cooled down to 0° C. and 25% aqueous hydrochloric acid (1 mL) was added slowly. The mixture was stirred at 90° C. for 1 hour and then poured on 30 mL water and 30 mL ethyl acetate. Aqueous sodium hydroxide solution (25%, 2 mL) was added and the layers were separated. The aqueous layer was extracted a second time with 30 mL ethyl acetate. The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Light yellow solid (119 mg, 37.6%). MS (ESI+): m/z=268.065 ([M+H]+).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([CH3:19])[CH:21]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)C1(CC(C)C)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CC(C)C)CCCC1OC(=O)c1cccc(C)c1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-iso-butyl-cyclopentane carboxylate (5.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (2.85 ml) was slowly added, then 3-methyl-benzoyl chloride (4.68 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 7.77 g of yellow liquid. MS: m/e 333(M++1), 332(M+), 287(M+—OCH2CH3), 258, 213(M+−CH3C6H4CO), 197(M+—CH3C6H4CO2), 119(base), 91, 77.
Reaction SMILES: [CH:1](/[C:14]1[CH:25]=[CH:24][C:17]([CH:18]=[CH:19][C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=1)=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O.[OH-].[Li+].Cl>O1CCCC1>[CH:1](/[C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCC/C=C/c1ccc(C=CC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCC/C=C/c1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-[(E)-1-tridecenyl]cinnamate (342 mg, 1 mmole from Example 16 in 50% aqueous tetrahydrofuran (25 ml) was added lithium hydroxide monohydrate (420 mg, 10 equivalents) and the mixture was stirred at room temperature overnight. The cloudy mixture was acidified with dilute hydrochloric acid and extracted with ether. The extracts were washed with brine, dried (magnesium sulphate) and evaporated to a white crystalline solid. Yield 330 mg (100%). Recrystallisation from methanol afforded material of mp 107° C., νmax (mull) 2600 (broad), 1710, 1680, 1625, 1425, 1308, 1285 cm-1 ; δ(DMSO-d6) 0.82 (3H, distorted t, CH3), 1.25 (18H, m. alkylene chain), 2.18 (2H, m, allylic CH2), 6.37 (2H, distorted s), 6.48 (1H, d, J 15 Hz, C=CHCO2), 7.52 (4H, AB quartet, J 7.5 Hz, Δν 18 Hz, aromatics), 7.60 (1H, d, J 15 Hz, ArCH=C--CO2) λmax (MeOH) 307 (31,200), 226 (12,200) nm.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: OCCc1ccccc1
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCCc1ccccc1
Reaction time: 3 h

Procedure:
From 2-phenylethanol (5.0 g; 41 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 3 h. The yield was 1.43 g (88%).
Reaction SMILES: [OH:1][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][NH2:21])=[O:19]>CCOCCO>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][N:21]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([OH:1])[CH3:11])=[O:19]
Reactant: NNC(=O)c1ccccn1
Reactant: CC(O)C(=O)c1ccccc1
Solvent: CCOCCO
Product: CC(O)C(=NNC(=O)c1ccccn1)c1ccccc1
Reaction time: 2 h
Yield: 46.7 %

Procedure:
21.5 g of 2-hydroxypropiophenone and 20.6 g of picolinic acid hydrazide are stirred in 250 ml of ethyl cellosolve for 18 hours at 110° C. and then for 2 hours at room temperature. The light yellow solution is concentrated on a rotary evaporator to approx. 50% of its volume. The yellow crystals which have precipitated are isolated by filtration and washed with isopropanol and then with water. After the crystals have been dried under vacuum at 50° C., 18 g of 2-hydroxypropiophenone picolinoylhydrazone are obtained which gives the following microanalysis:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][CH:25]=1)=[O:21])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:20]([NH:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([I:30])=[CH:28][CH:29]=1)=[O:21])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC)C(=O)NCc1ccc(I)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC[C@H](NC(=O)[C@@H](N)CCC(=O)OC)C(=O)NCc1ccc(I)cc1

Procedure:
A solution of (S)-methyl 4-(tert-butoxycarbonylamino)-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate (0.448 g, 0.723 mmol) in DCM (10 mL) and TFA (4.0 mL) was stirred at room temperature overnight. After the solvent was evaporated, the reaction mixture was diluted with DCM, washed with sat. K2CO3 and concentrated in vacuo to afford (S)-methyl 4-amino-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate. A solution of the above product ((S)-methyl 4-amino-5-((S)-1-(4-iodobenzylamino)-5-methoxy-1,5-dioxopentan-2-ylamino)-5-oxopentanoate), 4-isothiocyanatobenzenesulfonamide (0.171 g, 0.80 mmol) in acetonitrile (10 mL) containing DIPEA (0.40 mL) was stirred at room temperature under nitrogen for 48 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by flash chromatography 5% MeOH in DCM as eluent to give (S)-methyl 5-(4-iodobenzylamino)-4-((S)-5-methoxy-5-oxo-2-(3-(4-sulfamoylphenyl)thioureido)pentanamido)-5-oxopentanoate (0.469 g) as a white solid. MS (ESI), 756 (M+Na)+, 377 (M/2+H)+.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH3:18][O:19][C:20]1[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25](/[CH:26]=[CH:27]/[O:28][CH3:29])[C:20]=3[O:19][CH3:18])[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Reactant: CO/C=C/c1cccc(B(O)O)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C/c1cccc(-c2nsc(-c3ccc(OC(C)C)c(Cl)c3)n2)c1OC
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
A mixture of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (200 mg, 0.599 mmol), {2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}boronic acid (D101) (187 mg, 0.899 mmol), tripotassium phosphate (318 mg, 1.499 mmol) and Pd(Ph3P)4 (69.3 mg, 0.060 mmol) in N,N-Dimethylformamide (DMF) (5 mL) and Water (2 mL) was stirred at 120° C. (Microwave) for 10 min. The reaction mixture was poured to water. Then the mixture was extracted with EA. The combined organic layers were washed with water and then dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography to give 5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-3-{2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazole (D102) (152 mg). MS (ES): C21H21ClN2O3S requires 416.1. found 417.1 (M+H+).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:23]=2)[N:6]=1)(=O)=O.[CH2:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][C:42]=1[OH:49])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][C:42]=1[O:49][C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:23]=2)[N:6]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)COc1nc(S(C)(=O)=O)nc(Oc2cccc(C(=O)N(C)C)c2)c1[N+](=O)[O-]
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Product: CCOC(=O)COc1nc(Oc2cc(C#N)ccc2OCc2ccccc2)nc(Oc2cccc(C(=O)N(C)C)c2)c1[N+](=O)[O-]

Procedure:
In a similar manner, 2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (R), was treated with 2-benzyloxy-5-cyanophenol to yield 2-(2-benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (S).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=2)[CH:16]=1)(C)(C)C.[C:37]1([OH:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[OH-].[K+]>>[NH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([CH2:26][C@H:8]([NH2:7])[CH2:9][O:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:20]=3)[CH:16]=2)=[CH:28]1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(C=Cc2ccnc(F)c2)c1)Cc1c[nH]c2ccccc12
Agent: [K+]
Agent: [OH-]
Product: N[C@H](COc1cncc(C=Cc2ccnc(Oc3ccccc3)c2)c1)Cc1c[nH]c2ccccc12
Yield: 9.3 %

Procedure:
A mixture of Example 216B (50 mg, 0.1 mmol), phenol (94 mg, 1.0 mmol) and KOH (11.2 mg, 0.2 mmol) was heated at 140 C in a sealed bottle for 2 hrs. The mixture was concentrated to dryness. The residue was then treated with TFA (1 mL) at rt for 10 min. Upon Removal of TFA, the crude product was purified on C18 HPLC to give rhe title compound (4.3 mg, 5.3%). MS (DCI/NH3) m/z 463 (M+1)+; 1HNMR (400 MHz, MeOD) δ ppm 3.30 (m, 1 H) 3.48 (dd, J=13.81, 7.06 Hz, 1 H) 4.00 (m, 1 H) 4.27 (dd, J=10.43, 5.83 Hz, 1 H) 4.40 (dd, J=10.43, 3.07 Hz, 1 H) 7.15-7.01 (m, 5H) 7.26-7.23 (m, 2H) 7.48-7.32 (m, 6H) 7.59 (d, J=7.98 Hz, 1 H) 7.87 (m, 1 H) 8.16 (d, J=5.52 Hz, 1 H) 8.35 (s, 1 H) 8.53 (s, 1 H).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2].[N:23]1[CH:28]=[C:27]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:26]=[N:25][CH:24]=1>>[C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][C:27]2[CH:26]=[N:25][CH:24]=[N:23][CH:28]=2)=[O:16])=[C:6]([CH2:19][CH2:20][CH3:21])[C:5]=1[OH:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cncnc1
Product: CCCc1c(OCCCCCC(=O)NCCCCc2cncnc2)ccc(C(C)=O)c1O

Procedure:
6-(4-Acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid was allowed to react with 5-pyrimidine butanamine according to procedure A and the product was purified by crystallization from carbon tetrachloride to give 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(5-pyrimidinyl)-butyl]hexanamide, the title compound mp 87°-89°, in 73% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]3[CH2:13][CH2:14][O:15][C:7]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.C[O-].[Na+].[CH3:27][O:28][CH2:29]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:27][O:28][CH3:29])[C:10](=[O:12])[CH2:9][N:8]3[CH2:13][CH2:14][O:15][C:7]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: O=C1CN2CCOC2(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: COCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)CN2CCOC2(c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 0.08 h

Procedure:
A solution of 2.8 g. of 10-chloro-11b-(2-chlorophenyl)-2,3, 5,11b-tetrahydrooxazolo[3,2-d] [1,4]benzodiazepin-6(7H)-one in 50 ml. of dimethylformamide was cooled to -10° and treated with 0.65 g. of sodium methoxide. After stirring for 5 minutes, the mixture was cooled to -40° and 1 ml. of chlorodimethyl ether was added. The cooling bath was removed and when the temperature had reached 0° the reaction mixture was poured into 300 ml. of ice-water. The precipitated material was collected by suction and dissolved in methylene chloride. The solution was dried over sodium sulfate, filtered and evaporated. The residue was crystallized from a mixture of ether and hexane to give, after recrystallization from ethanol, 10-chloro-11b-(2-chlorophenyl)-7-methoxymethyl-2,3,5,11b-tetrahydrooxazolo[3,2-d] [1,4]benzodiazepin-6(7H)-one as white prisms, m.p. 144°-147°.