Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:35])C(=O)C1>>[Br:35][CH2:20][C:13]1[NH:12][C:11]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2ncccc2F)=NC1c1ccc(F)cc1Cl
Yield: 60.7 %

Procedure:
Ethyl 4-(2-chloro-4-fluorophenyl)-2-(3-fluoropyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (3 g, 7.7 mmol) was reacted with NBS (1.51 g, 8.47 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (2.2 g, 62%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: O1CCCC1.[N+:6]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH2:17]([O:19][P:20]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])([O:22][CH2:23][CH3:24])=[O:21])[CH3:18].CN1CCOCC1>[Ti](Cl)(Cl)(Cl)Cl.O>[CH2:23]([O:22][P:20](/[C:25](/[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1)([O:19][CH2:17][CH3:18])=[O:21])[CH3:24]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C(=C\c1ccc([N+](=O)[O-])cc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a mixture of titanium tetrachloride (20.0 g) and tetrahydrofuran (100 ml) were added 4-nitrobenzaldehyde (8.00 g) and ethyl diethylphosphonoacetate (11.9 g) under ice-cooling, and N-methylmorpholine (21.4 g) was added. 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 ethyl acetate layer was concentrated to give crystals of 4-[(E)-2-(diethylphosphono)-2-ethoxycarbonylethenyl]nitrobenzene (15.7 g, yield 83%), which were recrystallized from dichloromethane-isopropyl ether to give a colorless prism (14.0 g). melting point: 60–61° C. A mixture of this compound (5.00 g), iron (3.13 g), conc. hydrochloric acid (7 ml) and ethanol (30 ml) was stirred at room temperature for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was subjected to silica gel column chromatography to give crystals of 4-[(E)-2-(diethylphosphono)-2-ethoxycarbonylethenyl]aniline (2.40 g, yield 52%) from a fraction eluted with ethyl acetate-hexane (2:1, v/v), which were recrystallized from acetone-isopropyl ether to give a pale yellow needle (1.75 g). melting point: 79–80° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][CH:12]1[O:17][CH:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(NC(C)C)(C)C>O>[CH3:18][C@H:16]1[O:17][C@H:12]([CH3:11])[CH2:13][N:14]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15]1.[CH3:18][C@H:16]1[O:17][C@@H:12]([CH3:11])[CH2:13][N:14]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15]1
Reactant: CC1CNCC(C)O1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CC(C)NC(C)C
Solvent: O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@@H](C)O1
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2)C[C@H](C)O1
Temperature: 110 °C

Procedure:
A mixture of 1-fluoro-4-nitrobenzene, 2,6-dimethylmorpholine (Purchased from Aldrich) and diisopropylamine was heated at 110° C. for 16 h. After being cooled to room temperature, the mixture was added water and extracted with EtOAc. The organic phase was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatograghy eluted with EtOAc:hexanes (5 to 35% EtOAc) to give trans-2,6-dimethyl-4-(4-nitro-phenyl)-morpholine (258 mg) and cis-2,6-dimethyl-4-(4-nitro-phenyl)-morpholine (838 mg) both as yellow solids. Trans-isomer: MS (ES+): m/z=237.2; 1H NMR (CDCl3, 500 MHz): δ 1.30 (d, 6H), 3.17 (dd, 2H), 3.46 (dd, 2H), 4.15-4.22 (m, 2H), 6.77 (d, 2H), 8.14 (d, 2H). Cis-isomer: MS (ES+): m/z=237.2; 1H NMR (CDCl3, 500 MHz): δ 1.29 (d, 6H), 2.62 (dd, 2H), 3.67 (dd, 2H), 3.73-3.81 (m, 2H), 6.84 (d, 2H), 8.14 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C:10]([CH3:23])([CH3:22])[C:9]=2C(=C)C=O)=[CH:4][C:3]=1[CH3:28].[Li+].CC([N-]C(C)C)C.[C:37]([O:43][CH3:44])(=[O:42])[CH2:38][C:39]([CH3:41])=[O:40].[CH2:45]1C[O:48][CH2:47][CH2:46]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH:12]([O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:17])[CH3:16])[CH2:11][C:10]([CH3:23])([CH3:22])[C:9]=2/[CH:45]=[CH:46]/[CH:47]([OH:48])[CH2:41][C:39](=[O:40])[CH2:38][C:37]([O:43][CH3:44])=[O:42])=[CH:4][C:3]=1[CH3:28]
Reactant: C=C(C=O)C1=C(c2ccc(F)c(C)c2)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Reactant: COC(=O)CC(C)=O
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)CC(=O)CC(O)/C=C/C1=C(c2ccc(F)c(C)c2)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C

Procedure:
In a manner similiar to Scheme I, 19 (13.45 g, 33.4 mmol) was treated with LDA-derived dianion of methyl acetoacetate (40.1 mmol) in THF and, after workup and purification by HPLC using 4:1 hexanes:EtOAc as eluent provided 7.8 g of an orange color oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1nn(C)cc1N
Yield: 96 %

Procedure:
A mixture of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (500 mg, 2.7 mmol) and 10% palladium on carbon (50 mg) in methanol (25 mL) was subjected to 60 psi pressure of hydrogen gas in a Parr apparatus for 24 h. At this time, the reaction mixture was filtered through a pad of celite and washed with methanol. The filtrate was concentrated in vacuo to afford 4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (402 mg, 96%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz) δ7.10 (s, 1H), 4.65 (broad s, 2H), 3.73 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]CCCC.C1(C)C=CC=C[C:18]=1[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1>[OH:28][CH:27]([C:26]1[CH:29]=[CH:30][C:23]([CH3:18])=[CH:24][CH:25]=1)[C:7]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1ccccc1-c1ccc(C=O)cc1
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2nccn2S(=O)(=O)N(C)C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A suspension of N,N-dimethyl-1H-imidazole-1-sulfonamide (2.02 g) in THF (50 mL) was cooled to −78° C., and thereto was added dropwise n-BuLi (4.77 mL, 2.66 M hexane solution), and the mixture was stirred for 30 minutes. To the mixture was added p-tolyl benzaldehyde (2.08 g), and the mixture was warmed to room temperature over a period of 1 hour, and then stirred for 16 hours. The mixture was extracted with aqueous hydrochloric acid solution, washed with Et2O, and basified with an aqueous NaOH solution. This solution was extracted with Et2O, and the organic layer was dried and filtered. The solvent was evaporated under reduced pressure to give 2-[hydroxy(4-methylphenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: C([CH:3]([Cl:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=C.[CH3:11][C:12]([CH3:14])=O.C(C(CC)=O)C.[CH3:21][N:22](C)[CH3:23]>O>[Cl-:10].[CH:12]([CH2:14][N+:22]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:23])[CH3:21])=[CH2:11]
Reactant: CN(C)C
Reactant: C=CC(Cl)c1ccccc1
Reactant: CC(C)=O
Solvent: CCC(=O)CC
Solvent: O
Product: C=CC[N+](C)(C)Cc1ccccc1
Product: [Cl-]
Temperature: 26 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
477 Grams (3.05 mole) of 98% vinylbenzyl chloride is dissolved in 2070 ml. of acetone:diethylketone (1:1 vol). While maintaining a batch temperature of 19°-24° C., 200 grams of trimethylamine is added to this solution over a period of 6 hours by bubbling the gaseous amine into the stirred, cooled solution. After stirring the resulting batch at ambient temperature (26° C.) for 1 hour, 1300 ml. of solvent is removed under vacuum. (This solvent mixture is saved and reused in subsequent preparations). The resulting hydroscopic solid is dried in the reaction flask at reduced pressure and ambient temperature. 634 Grams (90% yield) of resulting solid product is then carefully transferred to a tightly sealed bottle for storage to prevent water pickup.
Reaction SMILES: [Na:1].C(C1(C[CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([CH2:23][S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=[O:25])[C:18]=2[CH3:35])OCC2(OCCO2)CO1)C.ClC1C=CC=C(C(OO)=O)C=1.[CH3:47][C:48]1(CO)[O:52][CH2:51][CH2:50][O:49]1>>[Na:1].[CH3:35][C:18]1[C:19]([CH2:23][S:24]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[N:27]=2)=[O:25])=[N:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][C:48]1([CH3:47])[O:52][CH2:51][CH2:50][O:49]1
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reactant: CC1(CO)OCCO1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: Cc1c(OCC2(C)OCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 12.9 %

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using (2-methyl-1,3-dioxolan-2-yl)methanol obtained in the step (67b) above to obtain the title compound (263 mg, total 12.9% yield) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].C(Cl)(Cl)Cl.[CH3:19][CH2:20]OCC>C(O)(=O)C>[CH3:19][C:20]1[NH:1][C:2]2[C:3](=[O:14])[NH:4][C:5](=[O:13])[N:6]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7]=2[N:8]=1
Reactant: CCOCC
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2CC(C)C

Procedure:
10 g of 5,6-diamino-1-(2-methylpropyl)-2,4-(1H,3H)-pyrimidine dione was refluxed in 50 ml of acetic acid for 1 hour. 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 10.8 g. The amide was refluxed in 30 ml of 2N NaOH for 1 hour and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 50 ml of acetic acid. Yield 3.3 g. NMR (see Table I).
Reaction SMILES: [F:1][CH:2]([F:21])[C@H:3]1[CH2:8][C@@H:7]([C:9](=[O:16])[CH2:10][C:11](OCC)=[O:12])[CH2:6][CH2:5][N:4]1[C:17]([O:19][CH3:20])=[O:18].[OH-].[Na+].[NH2:24]O.Cl>CO.O.C(Cl)Cl>[F:1][CH:2]([F:21])[C@H:3]1[CH2:8][C@@H:7]([C:9]2[O:16][NH:24][C:11](=[O:12])[CH:10]=2)[CH2:6][CH2:5][N:4]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](C(F)F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1C(F)F
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
Cis-methyl 2-(difluoromethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.38 g, 4.49 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.180 g, 4.49 mmol) dissolved in water (2.000 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.275 mL, 4.49 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (23.20 mL, 139.22 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 5-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(difluoromethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (650 mg, 52%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.77-1.88 (m, 1H), 2.03-2.24 (m, 3H), 2.93-3.03 (m, 1H), 3.22-3.33 (m, 1H), 3.75 (s, 3H), 3.92-4.02 (m, 1H), 4.21-4.34 (m, 1H), 5.73 (s, 1H), 5.92 (dt, 1H). MS m/z 275 (M−H)−
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[Li]CCCC.[C:15]([N:19]=[C:20]=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])=[N:3][CH:4]=1
Reactant: CC(C)(C)N=C=O
Reactant: Cc1cc(Br)ncc1Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)NC(C)(C)C)ncc1Br
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2,5-Dibromo-4-methylpyridine (1.83 g, 7.29 mmol) was dissolved in toluene (100 mL), cooled to −78° C. and a solution of nBuLi (4.4 mL, 8.8 mmol, 2.0 M in pentane) was added dropwise and stirred at −78° C. for 2 h. A solution of tBuNCO (1.1 mL, 9.5 mmol) in toluene (3 mL) was added dropwise and stirred for 1 h at −78° C. then warmed to −10° C. and quenched by addition of NH4Cl (aq). After warming to r.t. the reaction was extracted with ether and the organics dried over Na2SO4 and concentrated. The product was used without further purification. MS [M+H]+: 271.0; tR=2.44 min. (method 1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=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>[CH3:28][N:29]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)[C:25]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:11]=1)=[O:27]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Reactant: CNc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N(C)c3ccncc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (50 mg, 0.134 mmol) in N,N-dimethylformamide (1 mL) were added N-methylpyridin-4-amine (40 mg, 0.37 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([NH:15][C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[C:19]2[C:14]([N:15]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[C:16](=[O:29])[N:17]([CH3:28])[C:18]2=[O:27])=[N:13]1
Reactant: Cn1ccnc1-c1c2c(=O)n(C)c(=O)[nH]c2nn1Cc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1ccccc1CBr
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccccc1Cn1c(=O)n(C)c(=O)c2c(-c3nccn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 2-[(5-chloro-1H-indol-3-yl)methyl]-5-methyl-3-(1-methyl-1H-imidazol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione and 1-(bromomethyl)-2-methylbenzene using DBU as a base in DMF at 80° C., Mass: 514.11 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24](F)(F)F)[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.F[B-](F)(F)F.[CH3:33][O+](C)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:24])[O:13][N:12]([CH3:33])[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)=[CH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Product: Cc1cc(C2=CC(C)(c3cc(Cl)cc(Cl)c3)ON2C)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 29.9 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide (200 mg) in 1,2-dichloroethane (3 ml) was added trimethyloxonium tetrafluoroborate (85 mg) and the reaction mixture was stirred at room temperature for 19 hours then more trimethyloxonium tetrafluoroborate (210 mg). After 4 hours 30 minutes, more trimethyloxonium tetrafluoroborate (0.5 ml) was added and after 2 hours, the reaction mixture was heated at (85° C.) for 18 hours. The solution was then concentrated under vacuo to give a crude residue (210 mg). Part of this residue (100 mg) of the crude was extracted between AcOEt and saturated NaHCO3. The organic phases were gathered, dried over anhydrous MgSO4, filtered and evaporated to give the desired compound (54 mg). 1H-NMR (CDCl3, δ in ppm): 7.50-7.31 (m, 6H), 5.75 (bs, 2H), 5.41 (s, 1H), 2.99 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.I[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16].CCN(CC)CC.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)=[O:16])[C:3]=12
Reactant: CCOC(=O)N1CCN(C(=O)CI)CC1
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)COc2nsc3nc(C)cc(C)c23)CC1
Yield: 10.8 %

Procedure:
Pyridinothiazolone 4 (300 mg, 1.66 mmol) was treated with ethyl 4-(2-iodoacetyl)piperazine-1-carboxylate (541 mg, 1.66 mmol), Et3N (840 mg, 8.30 mmol) and Cs2CO3 (500 mg, 1.54 mmol) in anhydrous CH2Cl2 (25 mL) at room temperature for 24 h, and then washed with H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (EtOAc/hexane (1:1)) to give the title compound (68 mg, 11% yield) in addition to the main N-alkylation product 21 (YMU1, 60%). The purity of product 28 was 99.5% as shown by HPLC on an HC-C18 column (Agilent, 4.6×250 mm, 5 μM), t R=4.9 min (gradients of 40-90% aqueous CH3CN in 15 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:11])([F:12])[F:13])=[C:6]([CH:7]=1)[CH:8]=[O:9]
Reactant: OCc1cc(Cl)ccc1C(F)(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1cc(Cl)ccc1C(F)(F)F
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Dissolve (5-chloro-2-trifluoromethylphenyl)-methanol (347 mg, 1.66 mmol) in dichloromethane (10 mL). Add pyridinium chlorochromate (717 mg, 3.32 mmol) and stir for 2 h. Dilute with diethyl ether and stir for 1 h. Filter and concentrate. Chromatograph on silica gel eluting with 10% ethyl acetate in hexane to give the title compound as a clear oil (285 mg, 82%). 1H NMR (400 MHz, MeOH-d4) 10.33 (s, 1H), 7.90 (s, 1H), 7.69 (d, 1H, J=8.4 Hz), 7.54 (d, 1H, J=8.4 Hz).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[NH2:13][C:14]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:15]=1[OH:16].[N:22]1([C:28]2[NH:29][CH:30]([CH2:35][C:36]([O-])=[O:37])[NH:31][C:32](=[O:34])[CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[Na+]>N1C=CC=NC=1>[OH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:14]=1[NH:13][C:36](=[O:37])[CH2:35][C:30]1[NH:31][C:32](=[O:34])[CH:33]=[C:28]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:29]=1
Reactant: Nc1c(O)cccc1O
Reactant: O=C([O-])CC1NC(=O)C=C(N2CCOCC2)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1cncnc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.7 %

Procedure:
1.19 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 946 mg of 2-aminoresorcinol are added to a solution of 1 g of sodium [4-(morpholin-4-yl)-6-oxo-dihydropyrimidin-2-yl]acetate in 8 ml of pyrimidine. The reaction mixture is stirred at ambient temperature for 18 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 904 mg of N-(2,6-dihydroxyphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-acetamide are obtained in the form of a red solid, which is used as it is in the next stage.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[O:16])([CH3:13])([CH3:12])[CH3:11].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:24])[NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Phenethylamine (340 μL, 4.3 mmol), 6-tert-butoxycarbonylamino-hexanoic acid (1.0 g, 4.3 mmol) and 1-hydroxybenzotriazole (700 mg, 5.1 mmol) were dissolved under nitrogen in N,N-dimethylformamide and cooled to 0° C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added and the mixture stirred overnight, allowing to warm to room temperature. The mixture was partitioned between water and isopropyl acetate. The organics were washed with 0.5 M citric acid, then saturated sodium hydrogen carbonate, dried over sodium sulfate and evaporated to dryness. The residue was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](O)(=O)CC(O)=O>C(O)(=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)=[CH2:10]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)O
Product: C=Cc1ccc(O)cc1
Yield: 40 %

Procedure:
A mixture of 4-hydroxybenzaldehyde (1.0 g, 0.0082 mol), malonic acid (1.69 g, 0.0163 mol), triethylamine(2–4 mL) and acetic acid (10–15 mL) were taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside the microwave oven and irradiated for 2–8 minutes in parts. The cooled mixture was poured into ice cold water and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate, dil HCl., saturated sodium chloride and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel column chromatography using mixture of hexane and ethyl acetate (9:1 to 6:4), provided sweet and pleasant smelling liquid in 40% yield; 1H NMR (CDCl3) δ 7.31 (2H, d, J=8.5 Hz, H-2 and H-6), 6.81 (2H, d, J=8.8 Hz, H-3 and H-5), 6.67 (1H, dd, J=17.8 Hz, 11.3 Hz, (CH═CH2), 5.51 (1H, s, OH), 5.2 (1H, d, J=17.8, cis-CH═CH2), 5.14 (1H, d,J=11.3 Hz, trans-CH═CH2); 13C NMR (CDCl3) δ 155.5 (C-1), 136.5 (CH═CH2), 130.9 (C-4), 128.0 (C-3 and C-5), 115.8 (C-2 and C-6), 112.0 (CH═CH2).