Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:9]1=[O:13]
Reactant: Brc1cccs1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cccs2)C1=O
Yield: 109.3 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 2-bromo-thiophene (0.08 mL, 0.847 mmol), 1,4-dioxane (10 mL), copper iodide (16.13 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL) and potassium carbonate (233 mg, 1.694 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in DCM) afforded 240 mg of the product (48.4% yield).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][CH2:10][CH2:11][N:5]2[CH2:4]1.[C:12]([O-:15])(=[O:14])[CH3:13].[K+]>>[C:12]([O:15][CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][CH2:10][CH2:11][N:5]2[CH2:4]1)(=[O:14])[CH3:13]
Reactant: ClC[C@@H]1CN2CCC[C@H]2CO1
Reactant: CC(=O)[O-]
Agent: [K+]
Product: CC(=O)OC[C@@H]1CN2CCC[C@H]2CO1
Yield: 96.9 %

Procedure:
(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (2.30 g, 13.1 mmol) and potassium acetate (12.8 g, 131 mmol) were stirred in dimethylfomamide (25 mL) at 140° C. for 20 h. The mixture was partitioned between ethyl acetate and water. The organic portion was washed twice with water, then with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate as a brown oil (2.53 g, 12.7 mmol, 97% yield). 1H NMR (400 MHz, CDCl3): 4.14-4.02 (m, 3H), 3.81-3.72 (m, 1H), 3.37-3.31 (m, 1H), 3.09 (dt, 1H), 3.00 (dd, 1H), 2.21-2.00 (m, 3H), 2.10 (s, 3H), 1.90-1.67 (m, 3H), 1.39-1.24 (m, 1H); MS (EI) for C10H17NO3: 200 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[N:12][C:6]2[O:7][CH2:8][C:9](=O)[NH:10][C:5]=2[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1>[F:14][C:2]([F:1])([F:15])[C:3]1[CH:13]=[N:12][C:6]2[O:7][CH2:8][CH2:9][NH:10][C:5]=2[CH:4]=1
Reactant: O=C1COc2ncc(C(F)(F)F)cc2N1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)c1cnc2c(c1)NCCO2
Reaction time: 1 h
Yield: 50.7 %

Procedure:
In a 5 ml flask, 7-trifluoromethyl-1H-pyrido[2,3-b][1,4]oxazin-2-one (60 mg, 0.28 mmol) was dissolved in tetrahydrofuran (1.0 ml), and then 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (0.33 ml, 0.33 mmol) was added thereto dropwise and stirred for 1 hour at 0□. Water and saturated solution of sodium hydrogen carbonate were added and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of methanol:dichloromethane=1:50. The fractions containing the product were collected and evaporated to obtain white solid (29 mg, 52%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH2:30])[CH:29]=1)=[CH:17]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:1][NH:30][C:28]2[CH:29]=[C:24]([C:18]3[NH:19][C:20]4[C:16]([CH:17]=3)=[CH:15][C:14]([F:13])=[C:22]([F:23])[CH:21]=4)[CH:25]=[CH:26][C:27]=2[O:31][CH3:32])=[CH:4][CH:5]=1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNc2cc(-c3cc4cc(F)c(F)cc4[nH]3)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
Methyl 4-formylbenzoate (0.21 g, 1.28 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.34 g, 1.24 mmol) in methylene chloride (125 mL), followed by acetic acid (0.3 g, 3.33 mmol). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.3 g, 1.42 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 4 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated, and dried over Na2SO4. The solvent was evaporated to give a brown gum. Recrystallization from methanol gave the product as off-white crystals (140 mg), mp 168-170° C.
Reaction SMILES: C(O[C:4](=[O:25])/[C:5](=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1)/[CH2:6][CH2:7][CH:8]=O)C.[CH3:26][C@H:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)(=O)C.C(Cl)Cl>[CH3:24][O:23][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1)/[CH:10]=[C:5]1/[C:4](=[O:25])[N:34]([C@H:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:26])[CH2:8][CH2:7][CH2:6]/1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(/C=C2\CCCN([C@@H](C)c3ccccc3)C2=O)ccc1-n1cnc(C)c1
Reaction time: 8 h

Procedure:
To a methylene chloride (2 mL) solution of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-oxovaleric acid ethyl ester (162 mg), (S)-(−)-alpha-methylbenzylamine (183 μL), acetic acid (1.0 mL) and sodium triacetoxy borohydride (120 mg) were added one by one. After agitating reaction solution at room temperature overnight, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in acetic acid (2 mL), and heat-refluxing of the reaction solution was carried out overnight. After cooling reaction solution to 0° C., neutralized with a saturated sodium bicarbonate water, ethyl acetate was added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate=1:1->ethyl acetate: ethanol=10:1), and 13.7 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C([O-])(=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+].C(O)(=O)C=CC1C=CC=CC=1>>[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:1])[CH3:14]
Reactant: O=C([O-])C=Cc1ccccc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(O)C=Cc1ccccc1
Agent: [Na+]
Product: CC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
10 Liters of medium were prepared in a 14 L fermenter and were sterilized at 121° C. for 30 minutes. After sterilization, 100 g of sterile 50% dextrose solution and 100 ml of 48 hours grown inoculum were added. Periodically, after 24 hours of incubation, aliquouts of sterile 10% sodium cinnamate solution, pH 7.0 were added to maintain an approximate concentration of 5 g/L cinnamic acid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[N:34]1([CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([O:47][CH2:48]/[CH:49]=[CH:50]\[CH2:51][NH2:52])[CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C=O.C(OCC)(=O)C>[N:34]1([CH2:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([O:47][CH2:48]/[CH:49]=[CH:50]\[CH2:51][NH:52][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: O=C(O)c1cccs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1cccs1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.4 %

Procedure:
240 mg of 2-thiophenecarboxylic acid, 390 mg of N,N'-dicyclohexylcarbodiimide and 275 mg of 1-hydroxybenzotriazole were added to a solution of 485 mg of 4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenylamine in 10 ml of dry dimethylformamide, and the resulting mixture was stirred at room temperature for 17 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate, and the urea which precipitated was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and methylene chloride as the eluent, to give 499 mg (yield 73%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])S[C@@H:5]2[C:7]([Br:11])([Br:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13].[OH-].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].P(=O)(O)(O)O.[Mn]([O-])(=O)(=O)=O.Cl.[S:35](=[O:38])(O)[O-:36].[Na+].[Cl-].[Na+]>C(OCC)(=O)C.O.ClCCl>[CH3:1][C:2]1([CH3:15])[S:35](=[O:38])(=[O:36])[C@@H:5]2[C:7]([Br:10])([Br:11])[C:8](=[O:9])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: O=S([O-])O
Reactant: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)[C@H]1C(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C(Br)(Br)[C@H]2S1(=O)=O
Reaction time: 0.83 h

Procedure:
To the dichloromethane solution of 6,6-dibromopenicillanic acid from Preparation J was added 300 ml. of water, followed by the dropwise addition over a period of 30 minutes of 3N sodium hydroxide. The pH stabilized at 7.0. The aqueous layer was removed and the organic layer was extracted with water (2×100 ml.). To the combined aqueous solutions was added, at -5° C., a premixed solution prepared from 59.25 g. of potassium permanganate, 18 ml. of concentrated phosphoric acid and 600 ml. of water, until the pink color of the permanganate persisted. The addition took 50 minutes and 550 ml. of oxidant were required. At this point 500 ml. of ethyl acetate was added and then the pH was lowered to 1.23 by the addition of 105 ml. of 6N hydrochloric acid. Then 250 ml. of 1M sodium bisulfite was added during 10-15 minutes at ca. 10° C. During the addition of the sodium bisulfite solution the pH was maintained at 1.25-1.35 using 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride and the two phases were separated. The aqueous solution was extracted with additional ethyl acetate (2×150 ml.) and the combined ethyl acetate solutions were washed with brine and dried (MgSO4). This afforded an ethyl acetate solution of 6,6-dibromopenicillanic acid 1,1-dioxide.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][C:16]3=[CH2:21])([CH3:14])[C:12](=[O:22])[CH2:11][CH2:10]4)[C@H:7]([CH3:23])[CH2:6][C:5]=2[CH:4]=1.[BH4-].[Na+].[Li].N>>[OH:22][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([C:16](=[CH2:21])[CH2:15][C@:13]12[CH3:14])[C@@H:18]1[C:5](=[CH:4][C:3](=[O:2])[CH2:20][CH2:19]1)[CH2:6][C@H:7]3[CH3:23]
Reactant: C=C1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](C)Cc3cc(OC)ccc3[C@@H]12
Agent: N
Agent: [BH4-]
Agent: [Li]
Product: C=C1C[C@]2(C)[C@@H](O)CC[C@H]2[C@H]2[C@H]1[C@H]1CCC(=O)C=C1C[C@H]2C

Procedure:
3-Methoxy-7α-methyl-11-methyleneestr-1,3,5(10)-trien-17-one (A-11) was subjected to sodium borohydride reduction of the 17-ketone function, Birch reduction with lithium/NH3 (1), and acid hydrolysis and rearrangement to the title compound. Experimental details are as follows:
Reaction SMILES: CS[C:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:17])[N:4]=1.[OH-].[NH3:19]>>[NH2:19][C:3]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:17])[N:4]=1
Reactant: N
Reactant: CCCCCn1c(SC)nc(=O)c2[nH]cnc21
Agent: [OH-]
Product: CCCCCn1c(N)nc(=O)c2[nH]cnc21
Temperature: 100 °C
Reaction time: 96 h
Yield: 68 %

Procedure:
2-(Methylthio)-3-pentyl-3,7-dihydro-6H-purin-6-one (5.0 g, 0.020 mol) was mixed with 100 ml of 28% ammonia hydroxide in a seal tube. The mixture was stirred at 100° C. for 4 days. After cooling to room temperature, the solid was filtered and dried to yield the desired product (3.0 g, 68%). LCMS calculated for C10H16N5O(M+H): 222.1; found: 222.1.
Reaction SMILES: [Br-].[CH:2]1([CH2:5][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:4][CH2:3]1.C([Li])CCC.Cl[C:31]1[C:32]2[N:33]([CH:37]=[C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[N:39]=2)[CH:34]=[CH:35][N:36]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH:2]1([CH2:5][C:31]2[C:32]3[N:33]([CH:37]=[C:38]([C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=4)[N:39]=3)[CH:34]=[CH:35][N:36]=2)[CH2:4][CH2:3]1
Reactant: Fc1ccc(-c2cn3ccnc(Cl)c3n2)cc1
Reactant: c1ccc([P+](CC2CC2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2cn3ccnc(CC4CC4)c3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a suspension of (cyclopropylmethyl)triphenylphosphonium bromide (Alfa Aesar, 20.3 g, 51 mmol) in dry DME (100 mL) kept between about −30° C. and −40° C. was added a 2.5M solution of n-butyllithium in hexanes (20.4 mL, 51 mmol) over 10 min. After stirring between about −30° C. and −40° C. for about 1 h, 8-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyrazine (5.74 g, 23.2 mmol) was added. The mixture was warmed to ambient temperature, then stirred at about 85° C. for about 2 h, at which point a solution of Na2CO3 (2.70 g, 25.5 mmol) in water (50 mL) was added and heating was continued for about 15 h. After cooling to ambient temperature, the mixture was partitioned between 0.5 N HCl and CHCl3 and the aqueous phase washed two more times with CHCl3. The combined organic phase was extracted six times with 0.5 N HCl. The combined aqueous phase was rendered alkaline with NaOH and extracted with Et2O. After drying over Na2SO4 and concentration, the crude material was purified by silica gel chromatography with heptane/EtOAc (gradient 30-100% EtOAc) to give 3.77 g (61%) of the title compound as an orange solid: LC/MS (Table 1, Method g) Rt=2.78 min; MS m/z: 268.2 (M+H)+.
Reaction SMILES: C[Si](Cl)(C)C.I[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.Br[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]2[C:47]([CH3:48])=[CH:46][CH:45]=[C:44]2[CH3:49])[N:38]=1>O1CCCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([N:43]3[C:47]([CH3:48])=[CH:46][CH:45]=[C:44]3[CH3:49])[N:38]=2)[CH2:8][CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(C)n1-c1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 60 °C
Reaction time: 0.05 h
Yield: 30.8 %

Procedure:
After stirring for 3 minutes at 60° C. the reaction medium is left to return to ambient temperature. 0.047 ml of trimethylsilyl chloride is added and stirring is carried out for 30 minutes at ambient temperature. 1 g (3.2mmol) of 2 solubilized beforehand in 2 ml of tetrahydrofuran is added. This reaction mixture is stirred for 45 minutes at ambient temperature and it is added to a solution containing 30 mg (0.032 mmol) of tris(dibenzylideneacetone) dipalladium marketed by Aldrich and 30 mg (0.13 mmol) of tris(2-furyl)phosphine marketed by LANCASTER. Then 1 g (4 mmol) of 3 solubilized beforehand in 10 ml of tetrahydrofuran is added. The reaction mixture is left under magnetic stirring at 60° C. for 2 hours, then left to return to ambient temperature, filtered on clarcel and extracted between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. After extracting the aqueous phase twice with ethyl acetate, the organic phases are combined and dried over magnesium sulphate. The ethyl acetate is evaporated off under reduced pressure (2 kPa) and the crude residue is purified by chromatography on silicagel eluting with a heptane/ethyl acetate mixture 4:1. 350 mg (yield=30%) of expected product is recovered in the form of a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:17]#[N:18])[C:10]([CH3:16])=[C:11]([CH:14]=[O:15])[C:12]=3[F:13])[N:8]=2)[CH2:3][CH2:2]1.O.O.P([O-])(O)(O)=[O:22].[Na+].CC(=CC)C.Cl([O-])=O.[Na+].Cl>C(O)(C)(C)C.O.O1CCCC1.C(OCC)(=O)C>[C:17]([C:9]1[C:7]2[N:8]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[O:5][C:6]=2[C:12]([F:13])=[C:11]([C:14]([OH:22])=[O:15])[C:10]=1[CH3:16])#[N:18]
Reactant: O=P([O-])(O)O
Reactant: Cc1c(C=O)c(F)c2oc(C3CC3)nc2c1C#N
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Cyclopropyl-7-fluoro-6-formyl-5-methyl-1,3-benzoxazole-4-carbonitrile (I-182) (160 mg, 0.66 mmol) was dissolved in tert-butanol (4.5 ml)-water (3 ml)-tetrahydrofuran (3 ml), then at 0° C., sodium dihydrogenphosphate dihydrate (153 mg, 0.98 mmol), 2-methyl-2-butene (292 μl, 2.62 mmol), sodium chlorite (purity 80%, 222 mg, 1.97 mmol) were added. This was stirred for 15 hours with gradually warming up to room temperature. At 0° C., aqueous 1 N hydrochloric acid solution and ethyl acetate were added to the reaction liquid, followed by stirring at the same temperature for 10 minutes. The aqueous layer was separated, and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away to obtain the entitled compound. This was used in the next reaction as such.
Reaction SMILES: C([C:4]1([O:18][C@H:17]([CH2:19][Cl:20])[C@H:16]([Cl:21])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])[OH:5])(=O)C.C(O)(=O)C.NN>CN(C=O)C.ClCCl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:16]([Cl:21])[C@@H:17]([CH2:19][Cl:20])[O:18][CH:4]1[OH:5])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@H]1[C@@H](Cl)[C@@H](CCl)OC(O)(C(C)=O)[C@@H]1OC(C)=O
Agent: NN
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1[C@@H](Cl)[C@@H](CCl)OC(O)[C@@H]1OC(C)=O
Yield: 105.8 %

Procedure:
A solution of acetyl 2,3-di-O-acetyl-4,6-dichloro-4,6-dideoxy-D-galactopyranose (compound 82) (2.24 g, 6.5 mmol) and hydrazine acetate (903 mg) in DMF (22 mL) was stirred for 2 hours at room temperature. The reaction mixture was then diluted with dichloromethane (250 mL) and washed 4 times with water (4×250 mL), dried over anhydrous sodium sulfate and evaporated. Flash chromatography using hexane-ethyl acetate (1:1) as an eluent gave 2,3-di-O-acetyl-4,6-dichloro-4,6-dideoxy-D-galactopyranose (~6.88 mmol). This compound was then dissolved in dichloromethane (20 mL) cooled to 0° C., and trichloroacetonitrile (3.35 mL, 34.4 mmol) was added. After stirring at 0° C. for 40 minutes, the solvent was evaporated and the residue was chromatographed on a silica gel column, eluting with hexane-ethyl acetate (5:1), to give imidate 83 (1.14 g, 39%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Nc1ccc(S)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(S)cc2)C(=O)OC1=O

Procedure:
A mixture of 2.12 g. of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 1.25 g. of p-aminothiophenol and 75 ml. of methanol is refluxed for two hours, cooled and filtered to yield 5-acetyl-4-hydroxy-3-[1-(p-mercaptophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 207°-210° C.
Reaction SMILES: C(OC([NH:11][N:12]([C@@H:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:24][CH:25]=[CH2:26])[C:13](=[O:22])[C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=1)=O)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH:27]1([C@H:23]([N:12]([C:13](=[O:22])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[CH:15]=2)[NH2:11])[CH2:24][CH2:25][CH3:26])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C=CC[C@H](C1CCCCC1)N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC[C@H](C1CCCCC1)N(N)C(=O)c1cc(C)cc(C)c1
Reaction time: 1.5 h
Yield: 101.7 %

Procedure:
(R)—N′-(1-Cyclohexyl-but-3-enyl)-N′-(3,5-dimethyl-benzoyl)-hydrazine carboxylic acid benzyl ester (2.91 g, 6.7 mmoles) was suspended in ca. 50 mL glacial acetic acid. 102 mg 10% palladium on charcoal was added as a slurry in several mL of acetic acid. The mixture was diluted with acetic acid to 75 mL, and shaken on a Parr hydrogenator for 90 minutes at 20-30 psi. The suspension was allowed to stand for two days to allow the carbon to settle out. The supernatant was filtered through a 0.45 micron syringe filter into a recrystallizing dish and solvent was evaporated to leave 2.06 g (102% mass balance) of (R)-3,5-dimethyl-benzoic acid N-(1-cyclohexyl-butyl)-hydrazide as a reddish brown viscous oil. Rf=0.24 (2:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 7.05 (1H, s), 7.0 (2H, s), 4.55+3.35 (1H, 2 t), 2.4 (6H, s), 0.8-1.9 (15H, m), 0.9 (3H, t); HRMS (ESI) m/z calcd for C19H31N2O [M+H]+ 303.2436, found 303.2441, calcd for C19H30N2NaO [M+Na]+ 325.2256, found 325.2262.
Reaction SMILES: Br[C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[N:6][CH:7]=1.[OH-].[NH4+:20]>C(=O)=O.[O-]S([O-])(=O)=O.[Cu+2]>[NH2:20][C:2]1[C:3]([C:16]([OH:18])=[O:17])=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(O)c1nc(-c2c(F)cccc2F)ncc1Br
Agent: [Cu+2]
Agent: O=C=O
Agent: O=S(=O)([O-])[O-]
Product: Nc1cnc(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 110 °C

Procedure:
CuSO4 (0.1 eq) was added to a mixture of 5-bromo-2-(2,6-difluorophenyl)pyrimidine-4-carboxylic acid (1 eq) and 28% aqueous ammonium hydroxide solution in a microwave reaction vessel. The reaction mixture was heated in a microwave reactor at 110° C. for 25 min. The reaction vessel was cooled in dry ice for 30 min then unsealed and concentrated in vacuo. To the resulting solids was added 1.0 N HCl and the mixture was extracted with EtOAc. Combined organic extracts were washed once with brine, then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 5-amino-2-(2,6-difluorophenyl)pyrimidine-4-carboxylic acid. The crude product was used for the next step without further purification. LC/MS (m/z): 252.0 (MH+). LC: Rt: 2.043 min.