Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[CH2:35][CH2:36][NH2:37]>ClCCl>[F:31][C:32]1[CH:33]=[C:34]([CH2:35][CH2:36][NH:37][C:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])[CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: NCCc1cccc(F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1cccc(F)c1)c1ccc(Cl)nn1
Reaction time: 0.25 h
Yield: 37.8 %

Procedure:
To a solution of 6-chloropyridazine-3-carboxylic acid (0.31 g, 1.94 mmol) in dichloromethane (15.5 mL) was added diisopropylethylamine (0.73 mL, 4.19 mmol), followed by 1-hydroxybenzotriazole monohydrate (0.28 g, 2.1 mmol) and 1-(3-dimethylamino)propyl-3-ethylcarbodiimide (0.37 mL, 2.1 mmol). The resulting mixture was stirred for 15 minutes, followed by the addition of 3-fluorophenethylamine (0.28 mL, 2.1 mmol). After stirring for 27 hours at ambient temperature, the reaction mixture was diluted with dichloromethane (200 mL), washed with water (4×25 mL), dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography eluted with dichloromethane: ethyl acetate (2:1) afforded the product as a white powder (0.205 g). 1H NMR (400 MHz, CDCl3) δ 8.26, 8.12, 7.67, 7.28-7.23, 6.95-6.89, 3.80-3.75, 2.95.
Reaction SMILES: C/C=C/C1C=C(OC)C(OC)=CC=1OC.COC1C=C(OC)C(OC)=CC=1CCC.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[BH4-].[Na+].[CH3:47][O:48][C:49]1[CH:54]=[C:53]([O:55][CH3:56])[C:52]([O:57][CH3:58])=[CH:51][C:50]=1[CH:59]([OH:62])[CH2:60][CH3:61]>>[CH3:61][CH2:60][C:59]([C:50]1[C:49]([O:48][CH3:47])=[CH:54][C:53]([O:55][CH3:56])=[C:52]([O:57][CH3:58])[CH:51]=1)=[O:62]
Reactant: CCC(O)c1cc(OC)c(OC)cc1OC
Agent: C/C=C/c1cc(OC)c(OC)cc1OC
Agent: CCCc1cc(OC)c(OC)cc1OC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: CCC(=O)c1cc(OC)c(OC)cc1OC

Procedure:
In order to further increase the yield of α-asarone, an alternative route appears to prepare intermediate 1-(2,4,5-trimethoxy)phenyl-1-propanone (isoacroramone) by treating 2,4,5-trimethoxyphenylpropane with DDQ in aqueous organic solvent which upon treatment with sodium borohydride into 1-(2,4,5-trimethoxyphenyl-1-hydroxypropane followed by acidic dehydration towards formation of α-asarone. The structure of 1-(2,4,5-trimethoxy)phenyl-1-propanone, a crystalline solid (mp 109-110° C.), was confirmed on the basis of spectral data (Example IV) which is later on discovered as a naturally occurring rarer phenylpropanoid, isolated from Acorus tatarinowii as a light yellowish viscous gum, however, our method afforded isoacoramone as a crystalline solid with the similar spectral data as natural isoacoramone (Jinfeng, Hu and Xiaozhang, Feng, Planta Medica, 66, 662-664 (2000)). It is also worthwhile to mention that the formation of 1-(2,4,5-trimethoxyphenyl)-1-propanone in a single step from phenylalkane i.e. 2,4,5-trimethoxypropane opens new route for the synthesis of phenylpropanone derivatives which is, in fact, a mild, simple and free from drawbacks generally exist with reported synthetic methods and some of reported methods are:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.Br.[CH2:17]([O:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29]Br)[CH2:23]1)=[O:21])[CH3:18].C(O)(=O)C(C(C(O)=O)O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH2:17]([O:19][C:20]([C@@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][O:3][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: Br
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CCCN(CCOc2cccc(-c3ccccc3)c2)C1
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
Sodium hydride (0.46 g, 11.6 mmol, 60% oil dispersion) was added portionwise to a stirred solution of 3-hydroxybiphenyl (0.99 g, 5,8 mmol) in toluene (30 ml) placed under an atmosphere of nitrogen. The mixture was stirred for 30 minutes and (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (2.0 g, 5.8 mmol, EP 374801) was added portionwise. The reaction mixture was stirred overnight at ambient temperature and water was added (50 ml). The phases were separated and the aqueous phase was extracted with toluene (20 ml). The solvent was evaporated in vacuo from the combined organic phases to give a residue which was dissolved in ethyl acetate (100 ml). Water (50 ml) was added and pH was adjusted to 4 with a 34% tartaric acid solution. The phases were separated and the organic phase extracted with 34% tartaric acid (2×5 ml). To the combined aqueous phases was added ethyl acetate (30 ml) and pH was adjusted to 7.5 with 2N sodium hydroxide. The organic phase was washed with brine (10 ml) and dried (Na2SO4). The solvent was evaporated in vacuo to give 1.5 g of (R)-1-(2-(3-Phenylphenoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]([OH:16])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].CCOC(C)=O>CN(C=O)C.O>[CH3:34][O:33][C:31](=[O:32])[CH2:30][O:16][C:7]1[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)COc1c(-c2ccccc2)cc([N+](=O)[O-])cc1-c1ccccc1
Yield: 99.1 %

Procedure:
To a stirred solution of 5′-nitro-[1,1′;3′,1″]terphenyl-2′-ol (0.250 g, 0.858 mmol) and K2CO3 (0.130 g, 0.944 mmol) in DMF (9 mL) at room temperature was added dropwise methyl bromoacetate (0.162 mL, 1.72 mmol). After 72 h at this temperature, it was diluted with H2O (20 mL) followed by excess EtOAc (200 mL). The organic layer was washed with 1 N HCl (50 mL), sat., aq. NaHCO3 (50 mL), and brine (50 mL) and then dried (MgSO4). After concentration, the residue was purified by flash chromatography (5 to 30% acetone/hexane gradient) to afford the product (0.309 g, 99%) as a clear oil; 1H NMR (DMSO-d6) δ 3.37 (s, 3H), 4.03 (s, 2H), 7.43-7.53 (m, 6H), 7.60-7.64 (m, 4H), 8.14 (s, 2H); IR (film) 3420, 3080, 2950, 1770, 1745, 1590, 1530, 1500, 1455, 1440, 1410, 1350, 1305, 1210, 1110, 1070, 910, 745, and 700 cm−1; mass spectrum [EI], m/z 363 (M)+; Anal. Calcd. for C21H17NO5.0.75H2O: C, 66.93; H, 4.95; N, 3.72, Found: C, 66.89; H, 4.67; N, 3.51.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[F:27][C:25]1[CH:24]=[CH:23][C:19]([C:20]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:21])=[C:18]([C:17]([F:16])([F:28])[F:29])[CH:26]=1
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)c1ccc(F)cc1C(F)(F)F
Reaction time: 48 h

Procedure:
30.7 g (0.22 mol) of ethyl glycinate hydrochloride were suspended in CH2Cl2. At 0° C., 86.3 g (0.854 mol) of triethylamin and 50 g (0.22 mol) of 2-trifluoromethyl-4-fluorobenzoylchlorid dissolved in 250 ml of CH2Cl2 were successively added dropwise. After 48 h at RT, the solution was washed and dried, and the solvent was removed. This gave 62.2 g (97% of theory) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([C:5]1[C:6](Cl)=[N:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11])[CH2:2][CH2:3][CH3:4].[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][CH3:18]>>[NH2:12][C:8]1[N:7]=[C:6]([NH:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:10]([CH3:11])[N:9]=1
Reactant: CCCCc1c(C)nc(N)nc1Cl
Reactant: CCCCCN
Product: CCCCCNc1nc(N)nc(C)c1CCCC
Yield: 78 %

Procedure:
A mixture of 5-butyl-4-chloro-6-methylpyrimidine-2-yl amine (100 mg, 0.5 mmol) and amylamine (2 ml) was refluxed for 11 hours. The reaction mixture was cooled and the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (MeOH:CHCl3=1:20) to give the object compound (98 mg, 78%) as an oil.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[F:59]C1C=C(C=CC=1)C(Cl)=O>>[F:59][C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][CH:5]=1)[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Reactant: O=C(Cl)c1cccc(F)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4cccc(F)c4)cc3)cc2C1=O

Procedure:
The compound of example 105 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3-fluorobenzoyl chloride. The compound of example 105 was used directly without isolation for the preparation of compound of example 106.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]([OH:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.C(=O)([O-])O.[Na+].[H][H].Cl>O.[Pd]>[NH2:1][C:4]1[C:5]([C:10]([OH:12])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(O)c1ncccc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: Nc1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 50 h

Procedure:
3-nitropyridine-2-carboxylic acid (2.72 g, 16.2 mmol) and sodium hydrogencarbonate (1.34 g, 16.2 mmol) were dissolved in distilled water (20 mL), and the atmosphere in the system was replaced by nitrogen. After adding 10% palladium charcoal (1.72 g), the atmosphere in the system was replaced by hydrogen, and the mixture stirred at room temperature for 50 hours. 1N hydrochloric acid aqueous solution was added, and the pH of the reaction solution was adjusted to weak acidity. The solvent was distilled off under reduced pressure, a small amount of ethanol and ethyl acetate were added to the residue, and the precipitate produced was filtered off. The filtrate was concentrated, and the target substance (1.50 g, 67%) was thus obtained as a light yellow solid.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([O-:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].[K+].S(=O)(=O)(O)O>C(OCC)(=O)C>[CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([OH:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]
Reactant: O=C([O-])[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Temperature: 0 °C

Procedure:
A solution of potassium clavulanate in ice cold water was stirred with ethyl acetate under cooling with ice-water. With a solution of about 10% (w/w) sulphuric acid the pH was brought at about 2, the water layer separated and twice extracted with ethyl acetate. The collected extracts were dried with magnesium sulphate, filtered and washed with ethyl acetate, yielding a solution of clavulanic acid of about 2% (w/w). The clavulanic acid was diluted with an equal volume of acetone and diamine was added.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:30])[N:15]([CH2:17][CH2:18][N:19]4C(=O)C5C(=CC=CC=5)C4=O)[N:16]=[C:10]3[C:9]=2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:4][CH:3]=1.O.NN>C(O)C.C(OCC)(=O)C>[NH2:19][CH2:18][CH2:17][N:15]1[C:14](=[O:30])[N:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[C:10]2=[N:16]1
Reactant: O=C1c2ccccc2C(=O)N1CCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Reaction time: 8 h
Yield: 16.2 %

Procedure:
2-(2-(7,8-Bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)ethyl)isoindoline-1,3-dione (180 mg, 0.34 mmol) was reacted with hyrazine hydrate (0.9 ml, 18.5 mmol) in ethanol (10 ml) and stirred overnight. After this time, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-(2-aminoethyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (22 mg, 13%) as a yellow foam. MS M+H=400; 1H NMR (CDCl3) δ 8.12 (broad, 2H), 7.38-7.15 (6H), 7.05 (2H), 4.45 (2H), 3.59 (2H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([N:12]([CH2:19][C:20]1[CH:21]=[C:22]([CH:41]=[CH:42][CH:43]=1)[O:23][CH2:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([N:31]3[CH2:34][CH:33]([C:35](OC)=[O:36])[CH2:32]3)=[O:30])=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH2:2]2.[OH-].[Li+].Cl.[Cl:47][C:48]1[CH:49]=[N+:50]([O-:73])[CH:51]=[C:52]([Cl:72])[C:53]=1[CH2:54][C@@H:55]([C:57]1[CH:62]=[CH:61][C:60]([O:63][CH:64]([F:66])[F:65])=[C:59]([O:67][CH2:68][CH:69]2[CH2:71][CH2:70]2)[CH:58]=1)[OH:56].Cl.CN(C)CCCN=C=NCC>C1COCC1.CO.CN(C)C1C=CN=CC=1>[CH:69]1([CH2:68][O:67][C:59]2[CH:58]=[C:57]([C@@H:55]([O:56][C:35]([CH:33]3[CH2:32][N:31]([C:29](=[O:30])[C:28]4[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:22]5[CH:41]=[CH:42][CH:43]=[C:20]([CH2:19][N:12]([C:10]([O:9][C@@H:3]6[CH:4]7[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]7)[CH2:2]6)=[O:11])[C:13]6[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=6)[CH:21]=5)=[CH:40][CH:39]=4)[CH2:34]3)=[O:36])[CH2:54][C:53]3[C:52]([Cl:72])=[CH:51][N+:50]([O-:73])=[CH:49][C:48]=3[Cl:47])[CH:62]=[CH:61][C:60]=2[O:63][CH:64]([F:66])[F:65])[CH2:71][CH2:70]1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COC(=O)C1CN(C(=O)c2ccc(COc3cccc(CN(C(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)C1CN(C(=O)c2ccc(COc3cccc(CN(C(=O)O[C@H]4CN5CCC4CC5)c4ccccc4)c3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.9 %

Procedure:
A solution of methyl 1-[4-[[3-[(N-[(3R)-quinuclidin-3-yl]oxycarbonylanilino)methyl]phenoxy]methyl]benzoyl]azetidine-3-carboxylate (Intermediate 7 above described) (190 mg, 0.32 mmol) in THF (3 mL) and methanol (3 mL) was added with an aqueous solution of 1N lithium hydroxide (0.64 mL, 0.64 mmol). The reaction was stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and acidified by addition of 2N hydrochloric acid dropwise to pH≈2-3. The mixture was allowed to warm to room temperature and the solvent removed in vacuo and azeotroped with toluene to dryness. The crude material was redissolved in dimethylformamide (3 mL). (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (161 mg, 0.38 mmol), 4-(dimethylamino)pyridine (20 mg, 0.16 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (123 mg, 0.64 mmol) were added, and reaction mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between EtOAc (50 mL) and water (50 mL) The organic phase was dried over MgSO4, filtered and the solvent was removed in vacuo. The residue was purified twice by preparative HPLC to yield the title compound as white solid (40 mg, 13% yield over two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12].[CH:16]([O-])=[O:17].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:16]=[O:17])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([CH:13]1[CH2:15][CH2:14]1)=[O:12]
Reactant: O=C(NCc1ccc(I)cc1Cl)C1CC1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(CNC(=O)C2CC2)c(Cl)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a solution of 2.20 g of N-[(2-chloro-4-iodophenyl)methyl]cyclopropanecarboxamide and 0.57 g of sodium formate in 20 mL of N,N-dimethylformamide in an autoclave, 0.26 g of dichlorobis(triphenylphosphine) palladium (II) was added, and stirred under carbon monoxide atmosphere of 1.5 MPa at 90° C. for 1 hour. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, and diluted with 60 mL of ethyl acetate and washed with water (30 mL×2). The organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluted with ethyl acetate to obtain 1.20 g of the aimed product as white crystal.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH:2]=[CH2:3].C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[CH2:22]([O:25][C:26]1([CH3:55])[CH2:31][CH2:30][N:29]([C:32]2[N:37]3[N:38]=[C:39]([CH2:41][NH2:42])[CH:40]=[C:36]3[N:35]=[C:34]([CH3:43])[C:33]=2[C@H:44]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:28][CH2:27]1)[CH:23]=[CH2:24].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:42][CH2:41][C:39]1[CH:40]=[C:36]2[N:35]=[C:34]([CH3:43])[C:33]([C@H:44]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:32]([N:29]3[CH2:30][CH2:31][C:26]([O:25][CH2:22][CH:23]=[CH2:24])([CH3:55])[CH2:27][CH2:28]3)[N:37]2[N:38]=1)=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN)nn23)CC1
Reactant: C=CCc1ccccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CNC(=O)c4ccccc4CC=C)nn23)CC1
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.10 g, 0.200 mmol) and Ph3P (0.063 g, 0.240 mmol) in 9:1 THF/H2O (5 mL) stirred at rt for 1 h and at 45° C. for 4 h. Then, diluted with Et2O (25 mL) and extracted with 0.5M HCl (2×5 mL). The combine aqueous layers neutralized with sat Na2CO3 and extracted with CH2Cl2 (2×20 mL). The combine CH2Cl2 layers dried (MgSO4), filtered and concentrated to give (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as viscous pale yellow oil which was used in the subsequent step without purification. To a stirred solution of 2-allylbenzoic acid (0.065 g, 0.400 mmol) in CH2Cl2 (5 mL) containing cat. DMF was added 2M oxalyl chloride/DCM (0.400 ml, 0.801 mmol) at rt. After 1 h, concentrated and the resulting residue was re-dissolved in CH2Cl2 (3 mL) and added to a solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(aminomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate and DIEA (0.105 ml, 0.600 mmol) in CH2Cl2 (2 mL) at rt. After 2 h the reaction was quenched with a drop of MeOH, concentrated and purified prep-HPLC to afford (S)-ethyl 2-(2-((2-allylbenzamido)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.059 g, 0.096 mmol, 47.7% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.50 (dd, J=1.2, 7.7 Hz, 1H), 7.37-7.41 (m, 1H), 7.24-7.30 (m, 3H), 6.46-6.53 (m, 1H), 6.49 (s, 1H), 5.98-6.06 (m, 1H), 5.83-5.98 (m, 2H), 5.39 (dd, J=1.6, 17.2 Hz, 1H), 5.14 (d, J=9.8 Hz, 1H), 5.06 (qd, J=1.5, 10.1 Hz, 1H), 5.01 (qd, J=1.7, 17.2 Hz, 1H), 4.84 (d, J=5.4 Hz, 2H), 4.15-4.28 (m, 2H), 3.97 (d, J=4.6 Hz, 2H), 3.64 (d, J=6.3 Hz, 2H), 2.61 (s, 3H), 1.98 (d, J=13.2 Hz, 1H), 1.84-1.94 (m, 2H), 1.70 (d, J=9.3 Hz, 1H), 1.31 (s, 3H), 1.21-1.26 (m, 12H). LCMS (M+H)=618.5.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11](CC4C=CC(OC)=CC=4)[C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C1COCC1.O>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn(Cc4ccc(-c5ccccc5)cc4)nc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(biphenyl-4-ylmethyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (300 mg, 0.663 mmol) in THF (9 mL), a solution of ammonium cerium (IV) nitrate (1.82 g, 3.32 mmol) in water (3 mL) is added. The resulting orange solution is stirred at room temperature overnight. Another batch of CAN (1.82 g, 3.32 mmol) is added and the mixture is stirred for 6 hours, and then the third batch of CAN (1.82 g) is added, and the mixture is stirred at r.t. overnight. The reaction mixture is evaporated to dryness. The residue is treated with brine, and extracted with methylene chloride five times. The organic phase is combined and concentrated. The residue is purified by chromatography to give product as white solids with a high yield. 1H NMR (400 MHz, DMDO-d6) δ 3.16 (s, 3H), 5.37 (s, 2H), 7.38 (m, 3H), 7.46 (m, 2H), 7.65 (m, 4H), 8.59 (s, 1H), 11.6 (s, 1H). MS (FAB) m/z 333.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12]P(=O)(OC)OC)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[Li+].CC([N-]C(C)C)C.[C:33]([N:40]1[CH2:43][C:42](=O)[CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=[C:42]3[CH2:41][N:40]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:43]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(C=C2CN(C(=O)OC(C)(C)C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a cold (−78° C.) suspension of dimethyl (2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methylphosphonate (1.1 g, 2.9 mmol) in THF (26 mL) was added a 2.0M solution of LDA in THF (1.6 mL). The resulting solution was allowed to warm to room temperature before the addition of a solution of 1-Boc-3-azetidinone (0.58 g, 3.4 mmol) in THF (12 mL). The reaction mixture was stirred at room temperature for 2 hours and partitioned between brine and DCM. The organic layer was isolated, washed with brine, dried over MgSO4 and concentrated. The crude residue was then purified by flash chromatography (0-100% EtOAc in heptane) to give the title compound (1.15 g, 93%). LCMS m/z: 421.3 (MH+).