Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=[N:11]O)[CH:4]=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[OH:9][C:6]1[C:5]([CH3:10])=[CH:4][C:3]([NH2:11])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: CC1=CC(=NO)C(C)=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(N)c(C)c(C)c1O
Reaction time: 2 h

Procedure:
The method of Smith and Schubert, J. Am. Chem. Soc. 1948, 70, 2656, was followed. 2,3,5-Trimethyl-1,4-benzoquinone-1-mono-oxime (50 g, 0.30 mol) was dissolved in aq. sodium hydroxide solution (49.5 g, 1.24 mol of NaOH in 720 mL of water). The resulting intense red solution was cooled in an ice bath and stirred while sodium dithionite (126.1 g, 0.73 mol) was added. The red color faded and a beige precipitate formed. The mixture was stirred for 2 hours and allowed to come to ambient temperature. It was then cooled in ice and filtered. The crude 25a was pressed dry, rapidly transferred to an evacuated atmosphere and dried further (50° C./0.3 torr, 24 hours), mp 130°-131° C. with dec. (lit.: Smith, L. I.; Schubert, W. M. J. Am. Chem. Soc. 1948, 70, 2656; 132°-134° C. dec.). Spectral data: 1H NMR (CD3 SOCD3): δ 1.90 (s, 3H), 2.05 (2s, 3H each), 4.10 (br s, 2H), 6.25 (s, 1H), 7.10 (br s, 1H); 13C NMR (CD3SOCD3): δ 12.88, 13.25, 16.78, 114.39, 118.43, 122.25, 123.95, 138.81, 144.11.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[C:5](/[NH:11][C:12](=[O:14])[CH3:13])=[C:6](/[N:8]([CH3:10])C)\[CH3:7])[CH3:2].[CH:16]1(N)C[CH2:17]1>C(O)(=O)C.O>[CH2:1]([O:3][C:4](=[O:15])/[C:5](/[NH:11][C:12](=[O:14])[CH3:13])=[C:6](/[NH:8][CH:10]1[CH2:17][CH2:16]1)\[CH3:7])[CH3:2]
Reactant: CCOC(=O)/C(NC(C)=O)=C(\C)N(C)C
Reactant: NC1CC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)/C(NC(C)=O)=C(\C)NC1CC1

Procedure:
(Z)-2-Acetylamino-3-dimethylamino-but-2-enoic acid ethyl ester (4.3 g, 20 mmol) and cyclopropylamine (1.14 g, 20 mmol) were stirred at room temperature in acetic acid (40 ml) for 2 hrs. The reaction mixture was diluted slowly with 30 ml of water and evaporated under vacuum at 35° C. Water (30 ml) was added to the residue and evaporated again at 35° C. The same procedure was repeated twice with toluene (30 ml each) to obtain the desired crude product as a dark brown oil [MS: m/e=227.4 (M+H+)], which could be used without any further purification for the next step.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[CH:26](=O)[CH3:27].C([BH3-])#N.[Na+]>CO.C(Cl)(Cl)Cl>[F:25][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:26][CH3:27])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: CC=O
Reactant: O=C(OC1CCNCC1)[C@](O)(c1ccc(Cl)cc1)[C@@H]1CCC(F)(F)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN1CCC(OC(=O)[C@](O)(c2ccc(Cl)cc2)[C@@H]2CCC(F)(F)C2)CC1
Reaction time: 2 h

Procedure:
To a solution of 25 mg of piperidin-4-yl (2R)-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-chlorophenyl)ethanoate in 1 ml of methanol, 50 mg of acetaldehyde and 10 mg of sodium cyanoborohydride were added at room temperature, followed by two hours' stirring at the same temperature. The reaction liquid was diluted with chloroform, washed successively with saturated sodium hydrogencarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on preparative thin layer chromatography (Kieselgel™60F254, Art5744 (Merck), chloroform/methanol=10/1) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]2[CH:26]([CH3:32])[C:27]([O:29]CC)=[O:28])=[CH:4][CH:3]=1.[Li+].[OH-].Cl>O1CCCC1.CO.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=3)[C:9]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:8]2[CH:26]([CH3:32])[C:27]([OH:29])=[O:28])=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(C)c1c(Sc2ccccc2)c2cc(C(C)C)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccc2c(c1)c(Sc1ccccc1)c(C(C)C(=O)O)n2Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To 306 mg of the ethyl ester from Step 1 in 3 mL tetrahydrofuran and 1.5 mL methanol was added 1.5 mL of 2 N LiOH. After 1 h at reflux the mixture was cooled to room temperature, acidified with 1 N HCl and diluted with ether. The ether layer was washed with brine (2×) and dried over MgSO4. Filtration and concentration gave the title compound, mp 181°-181.5°.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:31][CH2:27][CH2:28][CH2:29][CH3:30])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (489 mg, 1.26 mmol) in CH2Cl2 (5 mL) was added neat butylamine (197 μL, 2.00 mmol) and the resulting mixture was stirred for 30 min. Saturated aqueous NaHCO3 (20 mL) was added, then the resulting mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic extracts were dried (MgSO4) and concentrated. The resulting crude material was purified by flash chromatography on silica gel (hexane/EtOAc 1:1) to give (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-butylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white foam (566 mg, 97% yield). 1H NMR (500 MHz, CDCl3) δ 0.94 (t, 3H, J=7.5 Hz), 1.35-1.41 (m, 2H), 1.53-1.59 (m, 2H), 2.06 (s, 3H), 2.08 (s, 3H), 2.10 (s, 3H), 2.14 (s, 3H), 3.38 (br s, 2H), 3.82-3.85 (m, 1H), 4.13-4.16 (m, 2H), 4.20-4.25 (m, 1H), 4.29 (dd, 1H, J=4.5, 12.5 Hz), 5.17-5.22 (m, 2H), 5.73 (d, 1H, J=8.0 Hz), 6.10 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:12]=2[O:11][CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26]>>[C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[C:15]([CH:18]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])[CH:16]=[CH:17][C:12]=2[O:11][CH:10]=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C=COc2ccc(C=O)cc21
Reactant: O=C1CSC(=O)N1
Product: CC(C)(C)OC(=O)N1C=COc2ccc(C=C3SC(=O)NC3=O)cc21

Procedure:
Following the general method as outlined in Example 1, starting from 6-Formyl-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (intermediate 63) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:14][C:15]([C:19]([NH2:21])=[O:20])=[N:16]2)=[CH:11][CH:10]=1.[N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[NH:31][CH:30]=1>CN(C=O)C>[N:29]1([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:14][C:15]([C:19]([NH2:21])=[O:20])=[N:16]3)=[CH:11][CH:10]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[CH:30]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cn3cnc4ccccc43)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
Cs2CO3 (91 mg, 0.278 mmol, 2.0 equiv.) was added to a solution of 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1, 50 mg, 0.139 mmol, 1.0 equiv.) and benzimidazole (18.09 mg, 0.153 mmol, 1.1 equiv.) in DMF (696 μl) and the reaction stirred at rt for 2 hours. The crude residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier). A Waters Porapak® Rxn CX (6 cc) was conditioned with MeOH (5 mL). Fractions containing the desired product were loaded onto the cartridge and the cartridge was washed with MeOH (10 mL). The desired product was eluted with 2M NH3 in MeOH (5 mL) and the solvent removed in vacuo to afford 7-((1H-Benzo[d]imidazol-1-yl)methyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-2, 23.6 mg, 43%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.40 (s, 1H); 8.09 (s, 1H); 8.00-7.91 (m, 2H); 7.73-7.70 (m, 1H); 7.61-7.55 (m, 3H); 7.47 (dd, J=7.2, 2.0 Hz, 1H); 7.33-7.23 (m, 4H); 5.80 (s, 2H). LRMS m/z (M+H)+ 397.17 found, 397.42 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]2[CH2:25][CH:24]3[N:26](C(OC(C)(C)C)=O)[CH:21]([CH2:22][CH2:23]3)[CH:20]=2)[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](=[O:42])[N:14]2[C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:41]>FC(F)(F)C(O)=O>[CH:21]12[NH:26][CH:24]([CH2:23][CH2:22]1)[CH2:25][C:19]([C:17]1[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][C:13](=[O:42])[N:14]3[C:34]3[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=3[Cl:40])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])[N:18]=1)=[CH:20]2
Reactant: CC(C)(C)OC(=O)N1C2C=C(c3cc4c(ccc(=O)n4-c4c(Cl)cccc4Cl)c(-c4ccc(F)cc4Cl)n3)CC1CC2
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc2c(-c3ccc(F)cc3Cl)nc(C3=CC4CCC(C3)N4)cc2n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-butyl 3-[5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (103 mg) was dissolved in 1 mL of trifluoroacetic acid and stirred under nitrogen at rt for 0.75 h. The resulting reaction mixture was concentrated under reduced pressure and purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in methanol to yield 7-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one. Mass spectrum (ESI) 526 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([CH2:18][CH3:19])[CH:12]=1)[CH:5]=[O:6].[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[C:30]2[N:26]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[N:27]=[CH:28][CH:29]=2)=[CH:12][C:13]=1[CH2:18][CH3:19]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: CCc1cc(Oc2ccc(C=O)cc2Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(Oc2ccc(C=O)cc2-c2ccnn2C2CCCCO2)ccc1Cl
Temperature: 75 °C
Yield: 49.1 %

Procedure:
3-bromo-4-(4-chloro-3-ethylphenoxy)benzaldehyde (Preparation 9, 336 mg, 1.08 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (300 mg, 1.08 mmol) and cesium carbonate (1.05 g, 3.24 mmol) were suspended in dioxane (4 mL) and water (2 mL). The suspension was degassed 40 minutes with nitrogen then tetrakis-triphenylphosphine palladium (62 mg, 0.054 mmol) was added and the reaction mixture was heated for 18 hours at 75° C. The solution was concentrated in vacuo to a quarter of its volume then diluted with water (20 mL) and extracted by ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography eluting with a gradient from 15% diethyl ether in heptane to 50% diethyl ether in heptane to afford the title compound as a colourless oil (218 mg, 49%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3][C:2]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CN(C=O)C>O>[CH2:19]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[C:2]([OH:12])[CH:3]=[CH:4]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Oc1ccc2cccc(O)c2n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccc2cccc(OCc3ccccc3)c2n1
Temperature: 65 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
A flask was charged with quinoline-2,8-diol (20.0 g, 124.1 mmol), K2CO3 (17.15 g, 124.1 mmol), benzyl bromide (14.76 ml, 124.1 mmol) and DMF (124.1 ml, 124.1 mmol). The resulting mixture was heated to 65° C. overnight, then poured into 1000 ml water and stirred for 5 hours. The solids were filtered and washed with 1000 ml diethyl ether to yield 26.5 g (85% yield) of desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[CH:15]1([CH2:20][CH2:21][OH:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:20][CH2:21][O:22][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCCC1CCCC1
Product: CN1c2cc(OCCC3CCCC3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 2-cyclopentylethanol.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:10]([OH:17])(=[O:16])/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:11]1[C:12]2[C:13](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:2][N:3]([CH3:4])[CH2:10]1.[C:10]([OH:17])(=[O:16])/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:11]1[C:12]2[C:13](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:2][N:3]([CH3:4])[CH2:10]1
Reactant: c1ccc2ocnc2c1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CN1Cc2ccccc2C(c2nc3ccccc3o2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Racemic 4-benzooxazol-2-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline was prepared by a method similar to the one described in Example 132, starting from benzooxazole (Steps A to B). The free base (20 mg, 0.076 mmol) was dissolved in methanol (5 mL) was added a solution of maleic acid (8 mg, 0.076 mmol) in methanol (2 mL) at 0° C. The solution was stirred at room temperature for 12 h, concentrated, and the residue was slurried with diethyl ether. Filtration provided the as a 4-benzooxazol-2-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline, maleate salt as a white powder (28 mg, 98%): 1H NMR (CD3OD, 500 MHz) δ 7.69 (dd, J=8.3, 6.8 Hz, 2H), 7.62 (dd, J=8.3, 1.3 Hz, 2H), 7.48-7.36 (m, 5H), 7.28 (d, J=2.9 Hz, 1H), 5.42 (s, 2H), 4.98-4.97 (m, 1H), 4.43-4.33 (m, 2H), 4.03 (s, 1H), 3.81-3.77 (m, 1H), 3.04 (s, 3H); ESI-MS m/z=265 [M+H]+; mp 135-140° C.; HPLC 97.5% AUC.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH:7]([NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]3[O:36][CH:37]=[CH:38][CH:39]=3)=[O:34])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>ClC(Cl)C>[O:36]1[CH:37]=[CH:38][CH:39]=[C:35]1[C:33]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:18]([NH:17][CH:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:6]([OH:40])=[O:5])=[O:19])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)c3ccco3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)c3ccco3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
2-({4′-[(Furan-2-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-pentanedioic acid di-tert-butyl ester (369 mg, 0.67 mmol) was dissolved in dichloroethane (10 mL) and added to TFA (5 mL) at 0° C. The cooling bath was removed after the addition was complete. The mixture was stirred at room temperature for 3 hrs. and the reaction was complete as determined by TLC. After removing solvent, the residue was washed 3 times with EtOAc. The solid was then dried under vacuum to give 2-({4′-[(Furan-2-carbonyl)-amino]-biphenyl-4-carbonyl}-amino)-pentanedioic acid in 85.6% yield (251 mg). MS (ESI) m/z 437.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]([CH3:25])=[CH2:24])[C:3]=1[OH:26].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH2:22][C:23]2([CH3:25])[O:35][CH2:24]2)[C:3]=1[OH:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)Cc1c(O)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Solvent: ClC(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2CC2(C)CO2)c1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 88.4 %

Procedure:
First, 50 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2-methyl-2-propenyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione was dissolved in 500 ml of chloroform, to which 30.0 g of m-chloroperbenzoic acid was added, and the reaction was allowed to proceed at 60° C. for 4.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and subjected to phase separation with chloroform and aqueous sodium sulfite solution. The organic layer was successively washed with saturated aqueous sodium bicarbonate solution and water, dried and concentrated. The residue was recrystallized to afford 46 g of 1-[4-chloro-6-fluoro-3-hydroxy-2-(2,3-epoxy-2-methylpropyl)phenyl]-3-methyl-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9].N>C1COCC1>[NH2:6][C:7]([CH3:13])([CH:10]([CH3:12])[CH3:11])[C:8]([NH2:9])=[O:2]
Reactant: CC(C)C(C)(N)C#N
Reactant: O=S(=O)(O)O
Agent: N
Solvent: C1CCOC1
Product: CC(C)C(C)(N)C(N)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Concentrated sulfuric acid (29.7 ml) is cooled with stirring in an ice-acetone cooling bath. To the acid is added 11.8 g (-)-2-amino-2,3-dimethylbutyronitrile with [α]D25 =-7.31° (c=0.0368 g/ml THF) at such a rate that the temperature does not go above 25° C. After the addition, the temperature of the reaction mixture is slowly raised to 100° C. and held at that temperature for one hour. After cooling the mixture in an ice-acetone bath, 85 ml concentrated ammonia is added at such a rate that the temperature does not exceed 75° C. The mixture is extracted five times with methylene chloride, the combined extracts dried and concentrated. This gives 11.95 g of white solid, mp 79°-81° C. and [α]D25 =+57.43° (c=0.0213 g/ml THF). This solid is recrystallized from methylene chloride-hexane to give 11.2 g of (+)-2-amino-2,3-dimethylbutyramide, mp 81°-82° C. [α]D25 =+59.38° (c=0.0162 g/ml THF).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[Cl:22][CH2:23][C:24]([CH2:26]Cl)=[CH2:25]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH2:26][C:24]([CH2:23][Cl:22])=[CH2:25]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: C=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(CCl)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
20 g of 2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenol and 28.8 g of potassium carbonate are introduced into 150 ml of acetonitrile. 26 g of 3-chloro-2-chloromethyl-propene are then added and the mixture is stirred for 2.5 hours at 80° C. The reaction mixture is cooled to room temperature and filtered, and the filtrate is concentrated. After purification over silica gel, 1,3-dichloro-2-(2-chloromethyl-allyloxy)-5-(3,3-dichloro-allyloxy)-benzene is obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Temperature: 25 °C
Yield: 143.5 %

Procedure:
Sodium hydride (60%, 18.11 g, 452 mmol) in mineral oil was triturated with 35 hexanes, dried under a stream of nitrogen and taken up in 1500 mL of THF. To the slurry at 0° C. was added 3-oxo-piperazine-1-carboxylic acid tert-butyl ester (75.057 g, 200.4 mmol) in portions over 15 min. After 90 minutes benzyl bromide (71.01 g, 415.1 mmol) was added and the mixture was warmed to room temperature for 18 hours. The solution was quenched with H2O and extracted with Et2O. The combined organic layers were washed with H2O, washed with brine, dried over MgSO4. Concentration in vacuo gave a crude solid which was recrystallized from hexane to afford 4-benzyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (83.5 g, 76%) as a white crystalline solid.
Reaction SMILES: [H-].[Na+:2].C[O:4][C:5]([C:7]1[S:8][C:9]([C:29]#[C:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:10][C:11]=1[N:12]([CH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[C:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]1)=[O:14])=[O:6].Cl[C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[CH:43][N:44]=2)[N:41]=1.[OH-].[Na+]>C1COCC1>[CH3:33][C:31]([CH3:34])([CH3:32])[C:30]#[C:29][C:9]1[S:8][C:7]([C:5]([O-:4])=[O:6])=[C:11]([N:12]([CH:22]2[CH2:27][CH2:26][CH:25]([O:28][C:36]3[CH:37]=[CH:38][C:39]4[N:40]([CH:42]=[CH:43][N:44]=4)[N:41]=3)[CH2:24][CH2:23]2)[C:13]([CH:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:10]=1.[Na+:2]
Reactant: Clc1ccc2nccn2n1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C2CCC(Oc3ccc4nccn4n3)CC2)CC1
Temperature: 80 °C
Yield: 14 %

Procedure:
NaH (30 mg of a 60% oil dispersion, 0.75 mmol) was added to a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(4-hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.22 mmol) and 6-chloro-imidazo[1,2-b]pyridazine (167 mg, 1.08 mmol) in THF (4.0 mL) at room temperature. The reaction was heated at 80° C. overnight, cooled, aqueous NaOH (1.0 mL of a 1.0 N solution) was added and the reaction evaporated to dryness to give a brown solid. Purification by column chromatography on reverse phase C18 silica gel (100% water to 30% acetonitrile/water) provided the desired product as a solid (17 mg, 14%) after lyophilization. MS (m/z): 563.0 [M+H]; HPLC retention time: 5.55 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).