Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([C@@H:11]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])=[CH:3][CH:2]=1.[C:28]([C:35]1NC=CN=1)(C1NC=CN=1)=[O:29].C([O-])(=O)[CH2:41][C:42]([O-])=[O:43].C([Mg+2])C>C1COCC1>[CH2:42]([O:43][C:28](=[O:29])[CH2:35][C:14](=[O:16])[CH2:13][CH2:12][C@H:11]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10])[CH3:41]
Reactant: O=C([O-])CC(=O)[O-]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CC[Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Z-Glu-Obzl 3 (1.0 g, 2.7 mmol) was dissolved in dry THF (10 mL) at rt. Carbonyl diimidazole (0.48 g, 2.96 mmol) was added slowly and the mixture was then stirred for another 2 h. After the solution was cooled to 0° C., ethyl magnesium malonate solution 2 (4.7 mL, 1.2 mmol) was added, and the mixture was then stirred at rt overnight. The product was extracted with ester, and washed with 10% NaHCO3, water, and brine. After the solvent was evaporated, the residue was purified by flash chromatography on silica gel (Hexanes:EtOAc=1:1) and afford a white solid (0.9 g, 2.03 mmol, 75.2%). 1H NMR (400 MHz, CDCl3, 25° C.) δ 1.23 (t, 3H), 1.90-2.00 (m, 1H), 2.10-2.30 (m, 1H), 2.50-2.70 (m, 2H), 3.36 (s, 2H), 4.16 (q, 2H), 4.30-4.50 (m, 1H), 5.10 (s, 2H), 5.12 (s, 2H) 5.36 (m, 1H), 7.25-7.40 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:38][CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1CCCC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Cyclopentylamine (2.38 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to drynnes and the residue was treated with water. The solid was colleced by filtration, washed with water, and ddried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol-ethanol, collected by filtration, washed with cold isopropyl alcohol, and dried under high vacuum over the weekend to give 3.67 g (74%) of crystals, mp 260°-261° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([C:38]1([CH3:46])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[C:31]2=[O:47].O>CN(C)C=O>[CH3:46][C:38]1([N:32]2[C:31](=[O:47])[C:30]3[C:34](=[CH:35][CH:36]=[C:28]([CH2:27][NH:26][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][N:8]=4)=[O:12])[CH:29]=3)[C:33]2=[O:37])[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45]
Reactant: CCOc1ccc(C(=O)O)nc1
Reactant: CC1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2(C)CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A stirred mixture of 5-ethoxy-pyridine-2-carboxylic acid (0.33 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solids were filtered and dissolved in CH2Cl2 (10 mL). The crude product was purified by column chromatography (0-5% MeOH CH2Cl2, gradient, product eluted at 3% MeOH). The product fractions were combined and concentrated to give 5-ethoxy-pyridine-2-carboxylic acid[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.69 g, 77% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.98 min (95.90%); mp: 145-147° C.; 1H NMR (DMSO-d6) δ 1.37 (t, J=7.2 Hz, 3H), 1.88 (s, 3H), 2.01-2.07 (m, 1H), 2.54 2.71 (m, 3H), 4.19 (dd, J=6.9, 13.8 Hz, 2H), 4.61 (d, J=6.3 Hz, 2H), 7.53 (dd, J=3.0, 8.7 Hz, 1H), 7.77-7.82 (m, 3H), 7.99 (d, J=8.7 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 9.40 (t, J=6.3 Hz, 1H), 11.00 (s, 1H); 13C NMR (DMSO-d6) δ12.70, 19.30, 26.90, 27.40, 40.60, 57.00, 62.40, 119.60, 120.00, 121.40, 121.70, 127.80, 129.60, 131.80, 135.10, 14.050, 145.90, 155.30, 162.30, 166.10, 166.20, 170.40, 170.50; LCMS: MH=451; Anal Calcd for C23H22N4O6+0.5H2O: C, 60.13; H, 5.05; N, 12.19. Found: C, 59.95; H, 4.91; N, 12.04.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:18]([OH:20])=O)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:10]=1)[CH3:3].Cl.Cl.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:18]([NH:32][C@@H:30]([C:27]2[CH:28]=[N:29][C:24]([CH3:23])=[CH:25][CH:26]=2)[CH3:31])=[O:20])[CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:10]=1)[CH3:1]
Reactant: Cc1ccc(-c2cc(CN(C)C)cc(C(=O)O)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CN(C)C)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-((dimethylamino)methyl)-4′-methylbiphenyl-3-carboxylic acid (20 mg, 0.074 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (40 mg, 0.19 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (60 mg, 0.16 mmol), and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][O:10][CH2:11][C:5]2=[CH:4][C:3]=1[C:12]#[N:13].C(O)(=O)C>C(O)C.[Zn]>[N:7]1[CH:2]=[C:3]([C:12]#[N:13])[CH:4]=[C:5]2[CH2:11][O:10][CH2:9][CH2:8][C:6]=12
Reactant: N#Cc1cc2c(nc1Cl)CCOC2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: N#Cc1cnc2c(c1)COCC2
Temperature: 25 °C
Yield: 72.8 %

Procedure:
step 3 2-Chloro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.77 g, 9.09 mmol) obtained in step 2 was dissolved in ethanol (30 mL), acetic acid (9 mL) and zinc (2.60 g) were added thereto, and the mixture was stirred with heating under reflux for 4 hr. The mixture was allowed to cool to room temperature, then filtered through Celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added a saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50) to give 7,8-dihydro-5H-pyrano[4,3-b]pyridine-3-carbonitrile (1.06 g, 73%) as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2C=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CC[C@@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@@H:44]5[CH2:46][CH2:47][NH:48][CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-N—Boc 3-amino pyrrolidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml). The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.27 (m, 1 H) 1.28-1.47 (m, 2 H) 1.52-1.71 (m, 4 H) 1.71-1.89 (m, 4 H) 1.89-2.04 (m, 1 H) 2.64 (dd, J=11.12, 5.05 Hz, 1 H) 2.75 (ddd, J=10.74, 7.96, 6.32 Hz, 1 H) 2.83-3.03 (m, 2 H) 3.31 (s, 3 H) 3.94 (s, 3 H) 4.06 (t, J=13.52 Hz, 2 H) 4.22-4.36 (m, 1 H) 4.38-4.54 (m, 1 H) 7.47 (dd, J=8.46, 1.64 Hz, 1 H) 7.51 (d, J=1.52 Hz, 1 H) 7.90 (s, 1 H) 8.21 (s, 1 H) 8.23 (d, J=7.07 Hz, 1 H) 8.26 (d, J=8.34 Hz, 1 H). Melting point: 195-198° C. [M+H] calc'd for C26H33F2N7O3 530; found 530.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH3:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28]O)=[CH:24][CH:23]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][O:26][C:25]2[CH:30]=[CH:31][C:22]([CH3:21])=[CH:23][CH:24]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: Cc1ccc(OCCO)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(C)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(4-methylphenoxy)ethanol (1.15 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl ether-hexane to provide 0.83 g of 4-[[2-(4-methylphenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 105°-107° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Sn](C)(C)C)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3]1.Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:33][C@H:32]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[O:31][N:30]=2)=[CH:25][CH:24]=1>>[Si:36]([O:35][CH2:34][C@@H:32]1[O:31][N:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3][C:2]4=[O:1])=[CH:8][CH:9]=3)=[CH:28][CH:27]=2)[CH2:33]1)([C:39]([CH3:42])([CH3:40])[CH3:41])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC(c2ccc(Br)cc2)=NO1
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NO[C@@H](CO[Si](C)(C)C(C)(C)C)C4)cc3)cc2)C(=O)O1

Procedure:
The procedure of Example 41, but starting from N-({(5S)-2-oxo-3-[4-(trimethylstannyl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide (476 mg, 1.20 mM) and (5R)-3-(4-bromophenyl)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4,5-dihydroisoxazole (370 mg. 1.00 mM) was used to give the desired product after 7 hours at 90° C. Purification by chromatography on silica gel using 90% ethyl acetate/hexanes gave 398 mg of the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.[Sn](Cl)Cl>>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[N:4]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: O=C1C=CC(=O)O1
Agent: Cl[Sn]Cl
Product: O=C1C=CC(=O)N1c1c(Cl)cc(Cl)cc1Cl
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A mixture of 2,4,6-trichloroaniline (1.20g, 6.11 mmol), maleic anhydride (0.80g, 8.2 mmol) and tin(II) chloride (0.068g, 0.36 mmol) is heated to 140° C. with mixing and held at this temperature for 2.0 hours. The reaction mixture is cooled, extracted with xylene, filtered and the resulting filtrate water washed. Solvent removal yielded N-(2,4,6-trichlorophenyl)maleimide. HPLC analysis showed conversion of 2,4,6-trichloroaniline was 96.4% and selectivity to N-(2,4,6-trichlorophenyl)maleimide based on reacted 2,4,6-trichloroaniline was 88.0%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[F:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])=[O:19])=[C:16]([CH3:30])[CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])([OH:19])[CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[C:16]([CH3:30])[CH:15]=1
Reactant: Cc1nnnn1C
Reactant: Cc1cc(F)ccc1C(=O)c1ccc(F)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(O)(Cc1nnnn1C)c1ccc(F)cc1C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a suspension of 1,5-dimethyltetrazole (3.8 g, 39.0 mmoles) in tetrahydrofuran (40 mL) at -40° C. was added butyl lithium (17.7 mL of a 2.2M solution, 39.0 mmoles). After stirring for 10 minutes, 4,4'-difluoro-2,2'-dimethylbenzophenone (8 g, 32.5 mmoles) was added and the solution stirred for 3 hours. The reaction was quenched with 1N hydrochloric acid. The aqueous layer was separated and extracted with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give 7.5 g of the title compound; m.p.=186°-188° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[CH3:14].[OH-:18].[Na+].Cl>>[C:13]([C:12]1[C:11]([OH:18])=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)CBr
Reactant: Nc1ncccc1C=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)c1nc2ncccc2cc1O
Reaction time: 72 h
Yield: 24 %

Procedure:
2-Amino-pyridine-3-carbaldehyde (100 mg) and 1-bromo-3,3-dimethyl-butan-2-one (147 mg) were suspended in a 5 N aqueous sodium hydroxide solution (0.6 ml), and the suspension was hermtically sealed and, in this state, was allowed to stand for 3 days. The reaction solution was neutralized with 10% hydrochloric acid, and the resultant precipitate was then collected by filtration and was washed with water and chloroform. The powder as the residue was dried under the reduced pressure to give 2-tert-butyl-[1,8]naphthyridin-3-ol (40 mg, yield 24%).
Reaction SMILES: C(N(CC)CC)C.[F:8][S:9]([F:20])([F:19])([F:18])([F:17])[C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)Cl>[C:21]([O:24][CH2:25][C:26](=[O:27])[NH:14][C:13]1[CH:12]=[CH:11][C:10]([S:9]([F:17])([F:18])([F:19])([F:20])[F:8])=[CH:16][CH:15]=1)(=[O:23])[CH3:22]
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Triethylamine (13.9 g, 137 mmol) was added to a stirred solution of 4-(pentafluoro-λ6-sulfanyl)aniline (Commercially available, for example from Apollo Scientific, Stockport, UK, 10.0 g, 45.6 mmol) in DCM (100 mL) at 0° C. and the mixture was stirred for 15 mins. 2-Chloro-2-oxoethyl acetate (7.47 g, 54.7 mmol) was added at 0° C., and the temperature was raised to room temperature with stirring continued for 4 hr. The reaction mixture was diluted with DCM and washed with ice water, saturated aq NaHCO3 solution and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. This was purified by recrystallisation from ether (500 mL) to give the title compound (8.64 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:23]=[C:12]2[N:13]=[C:14]([O:17][CH2:18][C:19](F)(F)F)[CH:15]=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([S:8][C:9]1[N:23]=[C:12]2[N:13]=[C:14]([O:17][CH2:18][CH3:19])[CH:15]=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)COc1ccn2nc(SCc3ccccc3)nc2n1
Solvent: CCO
Product: CCOc1ccn2nc(SCc3ccccc3)nc2n1

Procedure:
This material was prepared by heating 2-benzylthio-5-(2,2,2-trifluoroethoxy)-1,2,4-triazolo[1,5-a]pyrimidine in boiling ethanol. The hot mixture was filtered and the filtrate was concentrated. The crude product was recrystallized from isopropanol to yield the desired product as a solid, m.p. 115°-117° C. IR and 1HNMR spectra were in agreement with the assigned structure.
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].C(=O)(O)[O-].[Na+].CC(C)=O.O.[CH2:23]([O:30][C:31](Cl)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[CH2:23]([O:30][C:31](=[O:32])[NH:9][C:8]1[CH:10]=[CH:11][CH:12]=[C:6]([C:2]2[O:1][CH:5]=[N:4][N:3]=2)[CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1cccc(-c2nnco2)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1cccc(-c2nnco2)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A solution of 3-(1,3,4-oxadiazol-2-yl)aniline (1 g, 6.2 mmol) and sodium bicarbonate (1.1 g, 13 mmol) in a 2:1 mixture of acetone/water (10 mL) was cooled to 0° C. Benzylchloroformate (0.92 mL, 6.5 mmol) was added dropwise over 5 minutes. The reaction mixture was brought to room temperature and stirred for 30 minutes at which point LCMS indicated completion of the reaction. The reaction mixture was diluted with water and filtered on a glass frit to give (3-[1,3,4]Oxadiazol-2-yl-phenyl)-carbamic acid benzyl ester as a white powder (1.7 g, 93%). M+1=296.4
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][C:29]1[C:30]([C:37](O)=[O:38])=[N:31][CH:32]=[C:33]([C:35]#[N:36])[CH:34]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C@:9]([CH3:26])([C:22]([F:25])([F:24])[F:23])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:37]([C:30]3[C:29]([NH2:28])=[CH:34][C:33]([C:35]#[N:36])=[CH:32][N:31]=3)=[O:38])[N:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1cnc(C(=O)O)c(N)c1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(N)n2)CO[C@@]1(C)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(NC(=O)c3ncc(C#N)cc3N)n2)CO[C@@]1(C)C(F)(F)F
Reaction time: 8 h

Procedure:
A mixture of [(2R,5R)-5-(6-amino-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (80 mg, 0.206 mmol), 3-amino-5-cyano-pyridine-2-carboxylic acid (40.3 mg, 0.247 mmol, Acid-4, HOAt (50.5 mg, 0.371 mmol) in DMF (1 ml) and EDC.HCl (59.2 mg, 0,309 mmol) was stirred overnight. The reaction mixture was diluted with EtOAc, washed with aq. NaHCO3 and brine, and dried with MgSO4.H2O. The title compound was obtained after chromatography on silica gel (toluene/1-3% EtOAc) to give 71 mg of the title compound as a pale yellow solid slightly contaminated with some starting material. HPLC: RtH1=3.608 min; ESIMS: 534 [(M+H)+]; 1H-NMR (600 MHz, CDCl3): 10.92 (s, 1H), 8.29 (d, 1H), 8.18 (s, 1H), 7.82 (t, 1H), 7.36 (s, 1H), 7.14 (d, 1H), 6.33 (br, 1H), 4.39 (d, 1H), 4.12 (d, 1H), 1.66 (s, 3H), 1.60 (s, 9H), 1.59 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18](=[O:19])/[C:17](=[CH:20]/[C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[C:38]([F:41])([F:40])[F:39])[N:25]=[CH:24]4)/[S:16][C:15]2=[O:42])[CH:10]([OH:43])[CH2:9]1)=O)(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:26]2[C:27]3[C:23](=[CH:22][C:21](/[CH:20]=[C:17]4/[C:18](=[O:19])[N:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][C:10]5=[O:43])[C:15](=[O:42])[S:16]/4)=[CH:29][CH:28]=3)[CH:24]=[N:25]2)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNCCC1N1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5Z)-4-{5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.13 mmol) in DCM (2 mL) was added Dess-Martin periodinane powder (0.16 mmol). The mixture was stirred at rt for 18 h, then purified by silica gel chromatography (0-30% EtOAc/hexanes). The product was obtained as pale yellow solid, which was treated with TFA/DCM following General Procedure M to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([F:18])[C:3]=1[F:19].[CH3:20]N(C(OC)OC)C.[NH2:28][C@@H:29]([CH3:32])[CH2:30][OH:31]>O1CCCC1>[Br:1][C:2]1[C:15]([F:16])=[C:14]([F:17])[C:5]([C:6]([C:8](=[CH:20][NH:28][C@@H:29]([CH3:32])[CH2:30][OH:31])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4]([F:18])[C:3]=1[F:19]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(Br)c(F)c1F
Reactant: C[C@H](N)CO
Solvent: C1CCOC1
Product: CCOC(=O)C(=CN[C@@H](C)CO)C(=O)c1c(F)c(F)c(Br)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 19.99 g ethyl 4-bromo-2,3,5,6-tetrafluorobenzoylacetate and 7.8 ml DMF dimethyl acetal in 60 ml tetrahydrofuran was stirred at room temperature for about 16 hours. The mixture was then cooled in an ice-bath and 4.6 ml (S)-2-amino-1-propanol was added. The resulting clear solution was concentrated in vacuo, and the residue was dissolved in ether and chromatographed on a column of silica gel using ether as eluant. There was obtained 22.4 g of ethyl (S)-2-(4-bromo-2,3,5,6-tetrafluorobenzoyl)-N-(1-hydroxy-2-propyl)-3-aminopropenoate as a light yellow solid, m.p. 127°-134° C., [α]D25 =+17.6°.