Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.C[O:20][C:21](=O)/[CH:22]=[C:23](\[NH:25][C:26](=O)[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)/[CH3:24]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:21](=[O:20])[CH:22]=[C:23]([CH3:24])[N:25]=[C:26]2[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)CCc1cccc(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(CCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (1.10 g, 5.61 mmol) in DCM (20 mL) was added trimethylaluminium (5.7 mL, 11.4 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(3-(3-fluorophenyl)propanamido)but-2-enoate (1.00 g, 3.77 mmol) in DCM (8 mL) was added slowly and the resulting mixture was stirred at rt for 24 h. The mixture was then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as an orange solid (1.10 g, 71%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C@:4]([CH2:7][CH2:8][C:9]#[N:10])([CH3:6])[NH2:5].C(N(CC)CC)C.C([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32]C(=O)C)[C:26](Cl)=[O:27])(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:11])[C@:4]([CH2:7][CH2:8][C:9]#[N:10])([CH3:6])[NH:5][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([OH:32])=[C:23]([OH:22])[CH:24]=1
Reactant: COC(=O)[C@](C)(N)CCC#N
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@](C)(CCC#N)NC(=O)c1ccc(O)c(O)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
1.56 g of 2-(2-cyanoethyl)alanine methyl ester and 1.4 ml of triethylamine were added to a solution of crude 3,4-diacetoxybenzoyl chloride (prepared from 1.96 g of 3,4-diacetoxybenzoic acid and 2.08 g of phosphorus pentachloride) in 30 ml of dichloromethane, at 5° C. The reaction mixture was stirred at 0°-5° C. for one hour and then washed with 30 ml of water. The organic layer was separated off and dried over magnesium sulphate, and the solvent was distilled off. The resulting residue was dissolved in 10 ml of methanol, 8.3 ml of 28% aqueous ammonia solution were added, and the solution was stirred at room temperature for 23 hours. The mixture was then cooled to 5° C., adjusted to pH 2.0 with concentrated hydrochloric acid, diluted with 50 ml of water, and extracted with two 50 ml portions of dichloromethane. The organic extract was dried over magnesium sulphate, the solvent was distilled off, and the resulting residue was purified by silica gel chromatography (eluent: 2:1 mixture of cyclohexane and ethyl acetate), to give 1.60 g of the desired product as a colourless glass.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([O-:16])=O.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH2:19]([NH:26][C:14](=[O:16])/[C:13](/[O:17][CH3:18])=[CH:12]/[CH:11]=[CH:10]/[C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CO/C(=C\C=C\c1cc2ccccc2[nH]1)C(=O)[O-]
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CO/C(=C\C=C\c1cc2ccccc2[nH]1)C(=O)NCc1ccccc1
Yield: 32.4 %

Procedure:
This compound was prepared following the same procedure of Example 9 and starting from (2Z,4E)-5-(2-indolyl)-2-methoxy-2,4 pentadienoate (0.1 g, 0.39 mmol), benzylamine (0.043 ml, 0.39 mmol) and a solution of 2M trimethylaluminium in toluene (0.4 ml, 0.8 mmol). After crystallisation from isopropanol, 42 mg (32.4%) of the title compound were obtained, m.p.=204-205° C. 1H-NMR (acetone-d6): 10.55 (br s, 1H); 7.94 (br t, 1H); 7.51 (d, 1H); 7.38-7.21 (m, 6H); 7.18 (dd, 1H); 7.11 (ddd, 1H); 6.99 (ddd, 1H); 6.91 (d, 1H); 6.85 (d, 1H); 6.61 (s, 1H); 4.50 (d, 2H); 3.79 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[CH2:14][CH2:13][C:6]2=[C:7]([C:10]([OH:12])=[O:11])[S:8][CH:9]=[C:5]2[CH2:4]1)[CH3:2].[Li][CH2:18]CCC.CI>CC#N>[CH2:15]([C:3]1([CH2:1][CH3:2])[CH2:14][CH2:13][C:6]2=[C:7]([C:10]([OH:12])=[O:11])[S:8][C:9]([CH3:18])=[C:5]2[CH2:4]1)[CH3:16]
Reactant: [Li]CCCC
Reactant: CCC1(CC)CCc2c(csc2C(=O)O)C1
Solvent: CI
Solvent: CC#N
Product: CCC1(CC)CCc2c(C(=O)O)sc(C)c2C1

Procedure:
5,5-Diethyl-3-methyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid is prepared from 5,5-diethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid by treatment with tert.-BuLi followed by methyliodide in analogy to Example C; LC-MS: tR=1.03 min, [M+1+CH3CN]=294.27.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([CH2:17][NH2:18])[OH:16]>>[OH:16][CH2:15][CH2:17][NH:18][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NCCO
Reactant: Clc1nc2ccccc2n2ccnc12
Product: OCCNc1nc2ccccc2n2ccnc12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with ethanolamine according to a procedure that is similar to that followed in example 3 there is obtained 4-(2-hydroxyethylamino)imidazo[1,2-a]quinoxaline. m.p. (DSC)=150.8° C. (onset); IR (KBr): 3312, 1598, 1564 cm-1 ; 1H-NMR (CDCl3 /CD3OD): δ8.2 (1H,s), 8.1÷7.55 (2H,m), 7.55 (1H,s), 7.4÷7.2 (2H,m), 3.8 (4H,s); UV (EtOH): λmax =227, 285, 297, 317, 330 nm. Elementary analysis for C12H12N4 (m.w. 228.25): calcd. C 63.14, H 5.30, N 24.55%; found C 63.16, H 5.40, N 24.99%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:15][CH3:16].Cl>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1)[CH3:16]
Reactant: CCBr
Reactant: OB1OCc2ccc(O)cc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 65.4 %

Procedure:
H181 (110 mg, 0.73 mmol) was dissolved in DMF (6.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 117 mg, 2.93 mmol) and bromoethane (0.22 mL, 2.93 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (85 mg, 65% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.13 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.1 & 2.4 Hz, 1H), 4.91 (s, 2H), 4.02 (q, J=7.0 Hz, 2H) and 1.33 (t, J=7.2 Hz, 3H) ppm; Mp: 80-82° C.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[NH+]1C=CC=CC=1.[F:17][C:18]([F:23])([F:22])[C:19]([CH3:21])=O.O>C1(C)C=CC=CC=1>[CH3:21][C:19]1([C:18]([F:23])([F:22])[F:17])[NH:1][CH:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][O:4]1
Reactant: CC(=O)C(F)(F)F
Reactant: NC(CO)c1ccccc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C(F)(F)F)NC(c2ccccc2)CO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
45 g (328.0 mmol) of rac-2-amino-2-phenylethanol and 8.24 g (32.8 mmol) of pyridinium p-toluolsulphonate were added to 55.13 g (492.0 mmol) of 1,1,1-trifluoroacetone in toluene (1.35 l). The reaction mixture was boiled under reflux on a water separator for 16 h. The mixture was cooled to 0° C. and the solid formed was filtered off and dried under high vacuum. This gave 68.6 g (77% of theory, purity 85%) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:42]1([CH2:48][S:49](Cl)(=[O:51])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([S:49]([CH2:48][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)(=[O:51])=[O:50])[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(S(=O)(=O)Cc4ccccc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.5 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in tetrahydrofuran (1.5 ml) were added pyridine (0.02 ml), 4-dimethylaminopyridine (12 mg) and α-toluenesulfonyl chloride (43 mg), and the mixture was stirred at room temperature for 12 hours and then at 50° C. for 6 hours. After completion of the reaction, the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:acetone=3:1) and dried under reduced pressure to give the title compound (48 mg).
Reaction SMILES: [Mg].II.[CH2:4]([CH:6]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[CH3:5].[N:20]1[C:27](Cl)=[N:26][C:24](Cl)=[N:23][C:21]=1[Cl:22]>O1CCCC1>[Cl:22][C:21]1[N:23]=[C:24]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:6]([CH2:4][CH3:5])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:11]=2)[N:26]=[C:27]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH:6]([CH2:4][CH3:5])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][CH:11]=2)[N:20]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCCCC(CC)COc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC(CC)COc1ccc(-c2nc(Cl)nc(-c3ccc(OCC(CC)CCCC)cc3)n2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A 100 ml sulfonating flask equipped with stirrer, condenser, drying tube, dropping funnel and internal thermometer is charged under inert gas (dry nitrogen) with 3.65 g (0.15 mol) of magnesium turnings, and a few crystals of iodine are added as catalyst. 150 ml of anhydrous tetrahydrofuran are added, and a solution of 42.8 g (0.15 mol) of 4-(2-ethylhexyloxy)bromobenzene in 30 ml of tetrahydrofuran is added dropwise over a period of 45 minutes (room temperature). After slight heating on a water bath (40° C.), the Grignard reaction starts (cloudiness, exothermic reaction). The reaction mixture is stirred at 40° C. for one hour and then under reflux (66° C.) until the magnesium is almost completely dissolved (about 30 minutes). After cooling to room temperature, the Grignard solution is added dropwise at 0°-20° C. to a solution of 9.2 g (0.05 mol) of cyanuric chloride in 40 ml of tetrahydrofuran over a period of 60 minutes (350 ml sulfonating flask, stirrer, condenser, drying tube, dropping funnel, internal thermometer, inert gas). The mixture is stirred overnight under reflux (66° C.) and then evaporated to dryness. The residue is stirred in 100 ml of ice 2N hydrochloric acid and then extracted with 200 ml of toluene. The organic phase is shaken twice with 10% brine, dried over sodium sulfate and evaporated. The crude product (40.3 g, red oil) is still very impure (thin-layer chromatogram). For purification it is dissolved in 80 ml of 1:1 toluene/hexane and chromatographed over silica gel (5 cm×45 cm). 18.2 g (69.5%) of 2-chloro-4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazine are isolated as a yellow resin.
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([OH:24])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12])[CH3:6].Cl[C:27]1[N:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[F:25][CH:2]([F:1])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:23]=[C:22]([CH:21]=[C:10]([C:11](=[O:12])[NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH:9]=1)[O:24][C:27]1[N:28]=[CH:29][C:30]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[N:31][CH:32]=1)[CH3:6]
Reactant: CN(C)C(=O)c1cnc(Cl)cn1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)COC(F)F)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)cn3)cc(O[C@@H](C)COC(F)F)c2)cn1
Temperature: 140 °C
Reaction time: 5 h
Yield: 55.3 %

Procedure:
A mixture of 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-hydroxy-N-(5-methylpyrazin-2-yl)benzamide (0.19 g, 0.54 mmol), 5-chloro-N,N-dimethyl-pyrazine-2-carboxamide (100 mg, 0.54 mmol) and potassium carbonate (149 mg, 1.08 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours and the mixture reduced in vacuo. Ethyl acetate (50 mL) was added and the mixture washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude residue was chromatographed on silica, eluting with 0-5% methanol in DCM, to give the desired compound (150 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11])([CH3:3])[CH3:2].[H-].[Na+].[P:14]([Cl:18])(Cl)(Cl)=[S:15]>>[P:14]([Cl:18])([O:11][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])([O:11][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[S:15]
Reactant: S=P(Cl)(Cl)Cl
Reactant: Cc1ccc(C(C)C)c(O)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C(C)C)c(OP(=S)(Cl)Oc2cc(C)ccc2C(C)C)c1
Yield: 63 %

Procedure:
2-isopropyl-5-methylphenol was reacted with sodium hydride and thiophosphoryl chloride using the procedure of Example 21 to form bis(2-isopropyl-5-methylphenyl) chlorothiophosphate (31PNMR, singlet, 57 ppm). This compound was reacted with diphenylphosphonothioic amide by the General Method C(ii) (THF) yielding the compound of Formula I in which R1 =R2 =phenyl and R3 =R4 =2-isopropyl-5-methylphenoxy. Yield 63%; titration purity, 90%, MW593; 31PNMR, quartet 53 ppm. Test 2 (Table 2) showed that the product is a very strong extractant for zinc; however on long standing it crystallized from ESCAID solution.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=4)=[CH:22][C:21]=3[Cl:36])[C:15]2=[O:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:39][C:40]([F:48])([F:47])[CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]3[C:25]([Cl:26])=[CH:24][C:23]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([N:44]5[CH2:45][CH2:46][CH:41]([C:40]([F:48])([F:47])[F:39])[CH2:42][CH2:43]5)=[O:34])=[CH:31][CH:32]=4)=[CH:22][C:21]=3[Cl:36])[C:15]2=[O:37])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1
Reactant: FC(F)(F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1
Yield: 81.4 %

Procedure:
Stir a solution of 4-[(R)-3-(4′-Carboxy-3,5-dichloro-biphenyl-4-ylmethyl)-2-oxo-pyrrolidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Preparation 25) (0.1 g, 0.18 mmol), 4-(Trifluoromethyl)piperidine Hydrochloride (42 mg, 0.22 mmol), N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (42 mg, 0.22 mmol), 1-Hydroxybenzotriazole (73 mg, 0.22 mmol) and 4-Methylmorpholine (0.08 mL, 0.73 mmol) in CH2Cl2 (3 mL) at room temperature for 6 hr. Quench the reaction with 1N HCl and extract with EtOAc. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 0.10 g (80%) of desired product. MS (m/e): 582 (M−BOC+).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([NH:24][C@@H:25]([CH3:30])[C:26]([O:28]C)=O)[CH:5]=1)(=[O:3])[NH2:2].CO.[NH3:33]>>[NH2:33][C:26](=[O:28])[C@@H:25]([NH:24][C:6]1[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=1)[CH3:30]
Reactant: COC(=O)[C@H](C)Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: N
Solvent: CO
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Yield: 66 %

Procedure:
A solution of (S)-methyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)propanoate (4.128 g, 10.05 mmol) in 7M ammonia in methanol (100 mL, 700 mmol) was heated in a sealed tube for 3 days at 50° C. After cooling, the reaction mixture was evaporated in vacuo. The residue was triturated with 150 mL methanol and filtered to obtain the first batch of product. The filtrate was evaporated and chromatographed over silica gel with 50-100% acetone in hexanes. The product fractions were isolated and evaporated in vacuo. This residue was triturated with 40 mL methanol and filtered to give the second batch of product. The first and second batches of product were combined and triturated once more with 10 mL methanol, filtered and dried under vacuum at 50° C. to give (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamide (Example 1) as a pale tan-gray powder (2.620 g, 6.63 mmol, 66% yield). LC/MS: m/z=396.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6): 8.54 (2H, d, J=8.8 Hz), 8.27 (1H, s), 7.95 (1H, d, J=6.4 Hz), 7.74 (1H, s), 7.53 (1H, s), 7.31-7.24 (2H, m), 7.19-7.13 (2H, m), 7.08 (1H, s), 7.04-6.97 (3H, m), 4.60-4.51 (1H, m), 1.36 (3H, d, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O.Cl>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH3:9])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: COC(C)CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(C)CCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a solution of 1.06 g (8.0 mmol) of 5-methoxyhexanol dissolved in 5 ml of pyridine, 1.83 g (9.6 mmol) of p-toluenesulfonyl chloride dissolved in 5 ml of pyridine was dropped at below 5° C. on an ice-water bath. The mixture was stirred for 6 hours at room temperature and then poured into 100 ml of cold water. The mixture was then acidified by 6N-hydrochloric acid and extracted with isopropyl ether. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling off the solvent to obtain 5-methoxyhexyl p-toluenesulfonate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 0 °C

Procedure:
3-Hydroxy-4-nitro-benzoic acid 1a (3.17 g, 17.32 mmol) was dissolved in 40 mL of anhydrous methanol. The reaction solution was cooled down to 0° C. and added dropwise with thionyl chloride (3.09 g, 25.98 mmol) with stirring. Upon the completion of the addition, the resulting solution was heated to reflux for 2 hours. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate (200 mL). The combined organic phase was washed with saturated sodium bicarbonate solution (100 mL×3), saturated sodium chloride solution (100 mL×3) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound methyl 3-hydroxy-4-nitro-benzoate 1b (3.30 g as a yellow solid) yield: 96.7%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=[O:7].C1CCN2C(=NCCC2)CC1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[C:24]([S:29][CH3:30])[N:23]=1.Cl>CN(C=O)C>[Cl:21][C:22]1[CH:27]=[C:26]([NH:9][NH:8][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[N:25]=[C:24]([S:29][CH3:30])[N:23]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: NNC(=O)c1ccco1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nc(Cl)cc(NNC(=O)c2ccco2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
Into 150 mL of DMF, 65 g (515 mmol) of 2-furoic hydrazide and 70 mL (510 mmol) of DBU were dissolved, and a DMF solution of 4,6-dichloro-2-methylthiopyrimidine (50.0 g (256 mmol)/100 mL) was slowly added dropwise thereto at room temperature (inner temperature was controlled at 45° C. or lower). After stirring at room temperature for about 2 hours, the reaction solution was poured into ice-water and the pH was adjusted to 6 to 7 with a 2 mol/L hydrochloric acid solution, followed by collecting the resulting solid through filtration. The collected solid was dissolved into an organic solvent (chloroform/methanol=10/1) and, after washing with water, the solution was dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was triturated twice with chloroform to obtain 56.9 g of Compound A as white flocculent crystals (yield: 78%). The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane/ethyl acetate=6/4) to additionally recover Compound A in about 10% yield.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC.O>C1(C)C=CC=CC=1.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>[F:15][C:14]([F:17])([F:16])[CH:13]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:12]=[CH:11]/[C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([CH:27]=[CH2:28])[CH:10]=1
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1C(=O)O
Yield: 55.1 %

Procedure:
To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (600 mg, 1.23 mmol) in dry toluene (10 mL) was added tributyl(vinyl)stannane (470 mg, 1.48 mmol) and the mixture was degassed with argon for 15 min Pd(PPh3)4 (72 mg, 0.06 mmol) was added and the reaction mixture was refluxed for 2 h. The reaction mixture was brought to ambient temperature, water was added and the mixture extracted with EtOAc. The organic layer was washed with 2N HCl and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography on silica eluting with 30% EtOAc in petroleum ether to afford the title compound as brown solid (295 mg, 55%): 1H NMR (300 MHz, DMSO-d6) δ 13.05 (bs, 1H), 7.91 (s, 2H), 7.81-7.75 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.48 (dd, J=17.4, 10.8 Hz, 1H), 7.03 (dd, J=15.9, 8.7 Hz, 1H), 6.84 (d, J=15.6 Hz, 1H), 5.88 (d, J=16.5 Hz, 1H), 5.39 (d, J=12.3 Hz, 1H), 4.89-4.82 (m, 1H); ESIMS m/z 432.18 ([M−H]−); IR (thinfilm) 3418, 1689, 1114, 747 cm−1.