Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O:15][C:16]([NH:18][CH:19]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12]>CCOC(C)=O.C(#N)C>[Br-:1].[C:11]([O:15][C:16]([NH:18][CH:19]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[C:20]([O:22][C@@H:23]1[CH:28]2[CH2:27][CH2:26][N+:25]([CH2:2][C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)([CH2:30][CH2:29]2)[CH2:24]1)=[O:21])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccc(F)c1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1cccc(F)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.1 %

Procedure:
2-Bromo-1-phenylethanone (63.1 mg, 0.32 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(3-fluorophenyl)acetate (C53) (100 mg, 0.26 mmol) in EtOAc (3 ml) and acetonitrile (3 ml). The reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The crude was purified by flash chromatography (DCM/MeOH=94/6) to obtain (3R)-3-(2-(tert-butoxycarbonylamino)-2-(3-fluorophenyl)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (70.7 mg; 46% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=O.[F:8][C:9]([F:19])([F:18])[C:10](=[O:17])[C:11]#CC(F)(F)F>O>[CH2:11]([C:3]([C:2]([F:7])([F:6])[F:1])=[O:5])[C:10]([C:9]([F:19])([F:18])[F:8])=[O:17]
Reactant: O=C(C#CC(F)(F)F)C(F)(F)F
Reactant: O=C([O-])C(F)(F)F
Solvent: O
Product: O=C(CC(=O)C(F)(F)F)C(F)(F)F

Procedure:
In view of the above circumstances, the present inventors have made extensive researches and resultantly found that: it is possible to form a 1,1,1,5,5,5-hexafluoroacetylacetone hydrate by reacting a 3,3,3-trifluoropropynyl metal with a trifluoroacetate and then bringing the resulting reaction mixture (A), in which at least 1,1,1,5,5,5-hexafluoro-3-pentyn-2-one or an equivalent thereof is contained, into contact with water in the presence of an acid; and it is possible to produce 1,1,1,5,5,5-hexafluoroacetylacetone by dehydration of the thus-formed hydrate.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)C([N:8]1[C@H:11]([S:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][CH3:17])[C:9]1=[O:18])=O>CO.C(OC)(=O)C.O>[C:13]([S:12][C@H:11]1[NH:8][C:9](=[O:18])[C@@H:10]1[O:16][CH3:17])(=[O:15])[CH3:14]
Reactant: CO[C@H]1C(=O)N(C(=O)C(=O)OCC(Cl)(Cl)Cl)[C@@H]1SC(C)=O
Solvent: O
Solvent: CO
Solvent: COC(C)=O
Product: CO[C@H]1C(=O)N[C@@H]1SC(C)=O

Procedure:
A solution of 1.52 g of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-oxoacetic acid 2,2,2-trichloroethyl ester (crude product) in 290 ml of methanol, 40 ml of methyl acetate and 5.9 ml of water is refluxed for 20 minutes under nitrogen. The solvent is evaporated off in vacuo. After chromatography over silica gel with toluene/ethyl acetate (3:1) the residue yields the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:8]([CH3:22])=[CH:9][C:10]2[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12](=[O:19])[C:11]=2[C:20]=1[CH3:21].[CH2:23](O)[CH3:24]>>[Cl:6][C:7]1[C:8]([CH3:22])=[CH:9][C:10]2[O:15][C:14]([C:16]([O:18][CH2:23][CH3:24])=[O:17])=[CH:13][C:12](=[O:19])[C:11]=2[C:20]=1[CH3:21]
Reactant: CCO
Reactant: Cc1cc2oc(C(=O)O)cc(=O)c2c(C)c1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(=O)c2c(C)c(Cl)c(C)cc2o1

Procedure:
10 Parts of concentrated sulphuric acid were added to a suspension of 66.1 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxylic acid in 600 parts of ethanol, and the mixture was heated at reflux for 24 hr. Most of the ethanol was removed by evaporation under reduced pressure, and 1500 parts of water were added to the reaction mixture. The precipitated solid was filtered, dissolved in chloroform and the solution, dried and evaporated, leaving 58.5 parts of 6-chloro-5,7-dimethyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester as a colourless solid. On recrystallisation from ethanol, the product had melting point 114.5°-115.5°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+]([O-])=O)=[C:11]([Cl:18])[C:10]=2[Cl:19])=[C:4]([CH3:20])[N:3]=1.CO.C(Cl)(Cl)[Cl:24]>Cl[Cu]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:24])=[C:11]([Cl:18])[C:10]=2[Cl:19])=[C:4]([CH3:20])[N:3]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl
Agent: Cl[Cu]
Solvent: CO
Product: Cc1nc(N)nc(N)c1-c1ccc(Cl)c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 47 by reduction to the amine (PtO2, H2, AcOH), formation of the diazonium salt (NaNO2, H2SO4), and reaction of this with CuCl (as for Example 57). Sublimes at 275° C. Homogenous on TLC (methanol/chloroform, 1:9) Rf=0.36.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=O)([F:7])[F:6]>C(O)C.N1C=CC=CC=1.O>[F:4][C:5]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[N:2][OH:3])([F:7])[F:6]
Reactant: NO
Reactant: O=C(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: O
Product: ON=C(c1cccc(C(F)(F)F)c1)C(F)(F)F

Procedure:
7.8 g of hydroxylamine hydrochloride are dissolved in 250 ml of a mixture of ethanol and pyridine and to this solution 7 g (m-trifluoromethyl phenyl) trifluoromethyl Ketone are added. The mixture is heated to reflux for 16 hours, then cooled and diluted with 100 ml water. The oxime precipitates and is separated by filtration, dried, washed with water many times, and dried again. The yield amounts to 42%.
Reaction SMILES: [OH-].[Na+].P(=O)(O)(O)O.C([O:11][CH2:12][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:23]([NH:24][C:25](=[O:35])[C:26](=[N:32][O:33][CH3:34])[C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)[C:22](=[O:36])[N:17]2[C:18]=1[C:19]([OH:21])=[O:20])(=O)C>O>[OH:11][CH2:12][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:23]([NH:24][C:25](=[O:35])[C:26](=[N:32][O:33][CH3:34])[C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)[C:22](=[O:36])[N:17]2[C:18]=1[C:19]([OH:21])=[O:20]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1ccco1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Reaction time: 16 h

Procedure:
Sodium hydroxide (16.0 g) an orthophosphoric acid (13.5 ml) were dissolved in distilled water (750 ml). (6R,7R)-3-Acetoxymethyl-7-[2-methoxyimino-2-(fur-2-yl) acetamido]ceph-3-em-4-carboxylic acid (syn isomer ) (50g.), was added, and this dissolved to give a solution with a pH of 6.4. The pH was adjusted to 6.3 by addition of 20% orthophosphoric acid, and a suspension of Rhodosporidium toruloides CBS 14 cells (150 g.) was added. The mixture was stirred and aerated for 8 hours at 25° during which time M sodium hydroxide solution (105 ml.) had to be added to keep the mixture in the pH range 5.8 to 6.3. Thin layer chromatography showed that the conversion was complete. The mixture was stirred and aerated for a further 16 hours then the yeast removed by centrifugation. The yeast was washed by suspending in water (200 ml.) and recentrifuging. The main function was stirred with charcoal (2 g.) for 30 minutes then filtered through a Hyflo Supercel bed. The bed was washed with the yeast washings. Sodium chloride (250 g.) and 4-methylpentan-2-one (500 ml.) were added to the filtrate, and the pH was adjusted to 2.0 by addition of 20% orthophosphoric acid over 20 minutes. The mixture was cooled in an ice-bath during the acidification. The stirrer was stopped and the layers were allowed to settle. The clear aqueous layer was rejected and the precipitated solid was filtered off and washed with 4-methylpentan-2-one (50 ml) and water (3 × 40 ml.). The product was dried at 40° in vacuo for 24 hours to give the title compound as an off-white solid (38.39 g.) purity by h.p.l.c. 99.1%, total impurities by t.l.c. 2.5%.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH3:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=O.[C:15](Cl)(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][O:9][C:10]([C:11]1([CH3:13])[N:1]([C:15](=[O:17])[CH3:16])[CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]1)=[O:14]
Reactant: CC(=O)Cl
Reactant: N[C@@H](CS)C(=O)O
Reactant: COC(=O)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C1(C)SCC(C(=O)O)N1C(C)=O

Procedure:
In the same manner as in Reference Example 2, L-2-methylthiazolidine-2,4-dicarboxylic acid 2-methyl ester was synthesized from L-cysteine and pyruvic acid methyl ester, and the compound was subjected to acetylation with acetyl chloride in the presence of potassium carbonate to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-methyl ester (with the ratio of cis form:trans form of about 44:56 as confirmed by NMR) as a white solid (80.2%). 1H-NMR (DMSO-d6,400 MHz): δ;
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>ClCCCl>[CH2:1]([C:8]1[C:9]([NH:22][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[O:33])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Solvent: ClCCCl
Product: COc1ccc(NC(=O)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 19 h
Yield: 59.2 %

Procedure:
Under an argon atmosphere, to a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (306 mg, 1.05 mmol) in anhydrous 1,2-dichloroethane (10 mL) was added 4-methoxyphenyl isocyanate (13) (191 μL, 1.00 mmol) at room temperature, and the mixture was heated with stirring at 80° C. for 19 hours. After cooling to room temperature, the solid precipitated was collected by filtration and dried in vacuo to give the crude product (293 mg, <664 μmol, <63.2%) as a colorless solid. An aliquot (93.0 mg, <211 μmol) was recrystallized from methanol to give Compound 11u (54.9 mg, 125 μmol, 59.2%) as a colorless solid. Rf=0.50 (n-hexane/ethyl acetate=1/1); 1H NMR (400 MHz, DMSO-d6) δ 3.73 (s, 3H), 3.81 (s, 3H), 4.36 (s, 2H), 6.98-6.93 (AA′BB′, 2H), 7.02-7.08 (AA′BB′, 2H), 7.17-7.25 (m, 1H), 7.28-7.32 (m, 4H), 7.43-7.48 (AA′BB′, 2H), 7.95-8.01 (AA′BB′, 2H), 8.79 (s, 1H), 9.04 (s, 1H), 10.58 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ 38.5, 55.18, 55.24, 114.0 (2C), 114.4 (2C), 121.1 (2C), 126.3, 127.2 (2C), 128.2, 128.3 (2C), 129.0 (2C), 131.7, 134.5, 137.9, 144.4, 145.0, 145.4, 152.2, 155.1, 160.1; IR (KBr, cm−1) 704, 746, 824, 1038, 1173, 1242, 1329, 1369, 1416, 1481, 1510, 1570, 1607, 1668, 2833, 3030, 3261; Anal. Calcd. For C26H24N4O3: C, 70.89; H, 5.49; N, 12.72. Found: C, 70.66; H, 5.49; N, 12.61.
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C[CH2:26][N:27](C(C)C)C(C)C.C(Br)#N>C(Cl)Cl.C1COCC1>[C:26]([N:22]1[CH2:23][CH2:24][CH:19]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:9][CH:8]=2)=[O:6])[CH2:20][CH2:21]1)#[N:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Agent: N#CBr
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nccn1-c1ncc(C(=O)N(C2CC2)C2CCN(C#N)CC2)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide (310 mg, Intermediate 20) and DIPEA (0.42 mL) in CH2Cl2 (10 mL) and THF (10 mL) is added bromocyane (120 mg) and the mixture is stirred at room temperature for 12 h. The mixture is concentrated, ethyl acetate and water are added, the organic layer is dried (MgSO4) and concentrated to yield the title compound. LC (method 3): tR=1.07 min; Mass spectrum (ESI+): m/z=352 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[O:11][C:10]=2[CH3:20])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[ClH:23].[Cl:23][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[O:11][C:10]=1[CH3:20]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccn2)cc1C(O)C1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccn2)cc1C(Cl)C1CCCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl[2-methyl-5-(pyridin-2-yl)furan-3-yl]methanol (0.7 g) in toluene (20 mL) was added thionyl chloride (1.3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (0.8 g, 100%) as a yellow crystal.
Reaction SMILES: [CH:1]([C:4]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:5]#[N:6])([CH3:3])[CH3:2].C=O.[CH:36](O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH:1]([C:4]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)([CH2:7][CH2:8][N:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH3:36])[C:5]#[N:6])([CH3:3])[CH3:2]
Reactant: O=CO
Reactant: COc1ccccc1OCCCNCCC(C#N)(c1cc(OC)c(OC)c(OC)c1)C(C)C
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccccc1OCCCN(C)CCC(C#N)(c1cc(OC)c(OC)c(OC)c1)C(C)C

Procedure:
A mixture of 0.39 g of alpha-isopropyl-alpha-[2-[N-[3-(2-methoxyphenoxy)propyl]amino]ethyl]-3,4,5-trimethoxyphenylacetonitrile, 1 ml of 37% formalin, and 1 ml of 90% formic acid was refluxed for 1 hour. After cooling, to the mixture were added water and potassium carbonate to make it alkaline. The solution was extracted with chloroform. The extract was washed with water, dried, and evaporated to give 0.23 g of desired compound as a yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N+:8]=1[O-:14].[N+:15]([O-])([OH:17])=[O:16]>[OH-].[Na+]>[CH3:6][C:7]1[CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]([CH3:13])=[CH:9][N+:8]=1[O-:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C)[n+]([O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 52 %

Procedure:
To 75 mL of concentrated sulfuric acid at 0° C. was added 2,5-dimethylpyridine N-oxide (10 g, 0.08 mol) dropwise. 5.6 mL of fuming nitric acid (0.13 mol) was added to the mixture. The mixture was heated at 90° C. for 6 h, cooled, poured onto 500 mg ice, and neutralized with 120 mL of 50% sodium hydroxide solution. The solution was extracted with DCM (250 mL×5), and the combined organic phase was dried with anhydrous sodium sulfate and concentrated to give 7.0 g of the crude product as a yellow solid, which was used for the next step without further purification. MS (ESI): m/z 169.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:31]([C:27]2[N:28]=[CH:29][O:30][C:26]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:32])[CH:13]=[N:12]1)(=[O:6])[CH3:1]
Reactant: CC1(c2cccc(Cn3cc(N)cn3)c2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1cccc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)c1

Procedure:
Following general procedure B followed by C, starting from 1-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.00 min; [M+H]+=387.06.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[N:34]1([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([C:48]([O:50][CH3:51])=[O:49])[CH2:44][CH2:43]2)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:31])[F:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:37]3[CH2:38][CH2:39][N:34]([CH2:40][CH2:41][N:42]4[CH2:43][CH2:44][CH:45]([C:48]([O:50][CH3:51])=[O:49])[CH2:46][CH2:47]4)[CH2:35][CH2:36]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: COC(=O)C1CCN(CCN2CCNCC2)CC1
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: COC(=O)C1CCN(CCN2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (150 mg, 0.32 mmol) in DMF (10 mL) was added methyl 1-[2-(piperazin-1-yl)ethyl]piperidine-4-carboxylate hydrochloride (190 mg, 0.65 mmol), DIEA (126 mg, 0.97 mmol), HATU (148 mg, 0.39 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 4% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (22.0% up to 31.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 22.0% in 2 min); Detector, UV 254/220 nm. This resulted in 96.5 mg (40%) of the formic acid salt of methyl 1-[2-[4-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]acetyl)piperazin-1-yl]ethyl]piperidine-4-carboxylate as a light yellow solid. LCMS (Method 24) [M+H]+=700.2, RT=2.21 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.6, 6.8 Hz), 8.69-8.68 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.46 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 6.8 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.59 (s, 3H), 3.49-3.46 (m, 4H), 2.84-2.81 (m, 2H), 2.54-2.52 (m, 6H), 2.50-2.40 (m, 2H), 2.33-2.27 (m, 1H), 2.04-1.99 (m, 2H), 1.88-1.70 (m, 2H), 1.55-1.50 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2([CH3:11])[O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>CN(C1C=CN=CC=1)C.ClCCl>[CH3:11][C:6]1([C:3]2([CH2:2][O:1][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[CH2:4][CH2:5]2)[O:7][CH2:8][CH2:9][O:10]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C2(CO)CC2)OCCO1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C3(C)OCCO3)CC2)cc1
Temperature: 0 °C

Procedure:
To a stirred and ice-cooled solution of 3 (5.0 g, 31.6 mmol), N,N-dimethyl-4-aminopyridine (386 mg, 8.16 mmol) and triethylamine (22 mL, 158 mmol) in dichloromethane (25 mL) was added p-toluenesulfonyl chloride (7.23 g, 37.9 mmol) portionwise and the mixture was stirred in a cold room at 4° C. overnight. The mixture was poured into ice water, and the organic layer was separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water and brine, and dried over sodium sulfate. Filtration and concentration gave 16.70 g of crude 4, as a pale yellow oil, which was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1COCC1.[I:44]N1C(=O)CCC1=O>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[CH2:12][C@@H:11]([O:23][C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[C:27]([I:44])[N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2ncn3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ncnc3c2nc(I)n3C2CCCCO2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 70 °C

Procedure:
To a solution of 6-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (288 mg, 0.000512 mol) in THF (10 mL, 0.1 mol) was added N-Iodosuccinimide (0.576 g, 0.00256 mol), and the mixture was heated at 70° C. overnight. The reaction was cooled, quenched by addition of saturated aqueous NaHSO3 and the mixture was extracted with DCM (3×), washed with water, brine dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 10% EtOAc/hexanes) to obtain 271 mg (76.9%). Reference: Nolsoe, J. M. J.; Gundersen, L-L.; Rise, F. Acta Chemica Scandinavica, 1999, 53, 366-372.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:19]SC)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[O:40][S:41]([O-:43])=O.[K+].[CH3:45]O>O>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:19][S:41]([CH3:45])(=[O:43])=[O:40])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccccc3)oc2CSC)C2CCCCC2)cc1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(-c3ccccc3)oc2CS(C)(=O)=O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{2-[(methylsulfanyl)methyl]-5-phenylfuran-3-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (267 mg) was dissolved in methanol (9 mL) and water (1 mL), OXONE (0.6 g) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 75% ethyl acetate/hexane) to give the title compound (229 mg, 81%) as an amorphous compound.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[C:12]([N:14]([CH3:16])[CH3:15])=O>CN(C=O)C>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1/[CH:1]=[CH:12]/[N:14]([CH3:16])[CH3:15]
Reactant: CC(=O)N(C)C
Reactant: Cc1nc2ccccc2o1
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1nc2ccccc2o1
Temperature: 145 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
A mixture of 2-methylbenzo[d]oxazole (3 g, 22.6 mmol) in DMF (3.2 g) and dimethyl acetamide (3.5 g, 29.3 mmol) was stirred under N2 at 145° C. overnight. Then the solution was poured into ice-water and extracted with EtOAc (100 mL×2). The organic phase was washed, dried and concentrated. The residue was purified by column chromatography to get the title compound (2.2 g). MS (ESI) m/z 134 (M+H+).