Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20]2/[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:23][CH2:24]/2)=[C:16]([CH2:31][CH3:32])[C:15]([CH3:33])=[C:14]2[C:10]=1[C:11](=[O:34])[O:12][CH2:13]2)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:31]([C:16]1[C:15]([CH3:33])=[C:14]2[C:10]([C:11](=[O:34])[O:12][CH2:13]2)=[C:9]([OH:8])[C:17]=1[CH2:18]/[CH:19]=[C:20]1/[C@H:21]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:23][CH2:24]/1)[CH3:32]
Reactant: CCOC(=O)C[C@@H]1CCC/C1=C\Cc1c(CC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCC/C1=C\Cc1c(O)c2c(c(C)c1CC)COC2=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of ethyl (S)(E)-2-{2-[2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]cyclopent-1-yl}acetate (1.24 g) in tetrahydrofuran (8 ml) was cooled to 0° C. and treated with 1M tetrabutylammonium fluoride in tetrahydrofuran (3 ml). After 5 minutes, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extracts were dried, evaporated and the residue chromatographed on silica gel (20% ethyl acetate/hexane) to give ethyl (S)(E)-2-{2-[2-(1,3-dihydro-6-ethyl-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl)ethylidene]cyclopent-1-yl}acetate, m.p. 95.0°-95.7° C.
Reaction SMILES: [ClH:1].C[NH:3]O.[CH3:5][O:6][CH:7]([O:17]C)[CH:8]([CH:12](OC)[O:13]C)[C:9]([O-])=[O:10]>O.Cl>[ClH:1].[CH3:5][O:6][C:7]([C:8]1[C:9](=[O:10])[NH:3][O:13][CH:12]=1)=[O:17]
Reactant: COC(OC)C(C(=O)[O-])C(OC)OC
Reactant: CNO
Agent: Cl
Solvent: O
Product: COC(=O)c1co[nH]c1=O
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2.21 g methylhyroxylamine-hydrochloride in 2.90 g water and 0.26 g concentrated aqueous HCl, 5.81 g 3,3-dimethoxy-2-dimethoxymethyl-propionate were fed over a period of 40 minutes. External cooling with an ice-bath was required in order to keep the temperature between 15° C. and 20° C. After stirring for an additional 15 minutes and cooling to 10° C., a non-stirrable white crystal-pap was gained. The needle-shaped crystals were isolated by suction-filtration, washing with a small amount of diisopropylether and drying in vacuo. Further product-fractions could be isolated by evaporation of part of the mother liquor, filtration, washing, and drying. The total amount of methyl-3-keto-isoxazole-4-carboxylate-hydrochloride obtained in this way was 4.60 g (91% theory based on 3,3-dimethoxy-2-dimethoxymethyl-propionate). Identification of the product was based on 1H-NMR-, 13C- and IR-spectra. The 1H-NMR-spectrum did not show any impurities.
Reaction SMILES: [CH3:1][C:2](O)([C:9](O)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC(OCC)OCC)C.C(O)(=O)C1C=CC=CC=1>>[C:3]1([C:2](=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(O)(c1ccccc1)C(C)(O)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: CCOC(OCC)OCC
Product: CC(=C(C)c1ccccc1)c1ccccc1
Yield: 88 %

Procedure:
A high yield, four step synthesis process is disclosed for producing the omer, 2,3-diphenyl-1,3-butadiene, wherein in step 1 acetophenone pinacol is produced from the dimerization of acetophenone in 96% yield; in step 2 acetophenone pinacol is reacted with triethoxymethane and benzoic acid to produce 2,3-diphenyl-2-butene in about 88-96% yield. The 2,3-diphenyl-2-butene and N-bromosuccinimide (NBS) are reacted together in step 3 in an ultra violet reactor and in a CCl4 reaction solvent to produce in about 92% yield, the dibromo compound, 1,4-dibromo-2,3-diphenyl-2-butene. In step 4, 1,4-dibromo-2,3-diphenyl-2-butene is converted to the desired monomer in about 86% yield by reacting with NaI under refluxing conditions for about 90 minutes in a hot acetone solution. The monomer 2,3-diphenyl-1,3-butadiene is recovered in hexane, shaken (in the order listed) with water solutions of NaHSO3, NaHCO3, and pure water, dried over CaCl2, and the hexane is spun off. The residue is then recrystallized from hot methyl alcohol by the addition of water. The crystals which are air dried should be refrigerated as soon as possible to prevent spontaneous polymerization.
Reaction SMILES: [C:1]([C:3]1[C:8]([N:9]=[CH:10]N(C)C)=[C:7]([N+:14]([O-])=O)[C:6]([CH3:17])=[C:5]([N+:18]([O-])=O)[CH:4]=1)#[N:2]>[Pd].CO>[NH2:18][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[C:8]2[N:9]=[CH:10][NH:14][C:7]=2[C:6]=1[CH3:17]
Reactant: Cc1c([N+](=O)[O-])cc(C#N)c(N=CN(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)cc(C#N)c2nc[nH]c12
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 102.2 %

Procedure:
A mixture of N′-(6-cyano-3-methyl-2,4-dinitro-phenyl)-N,N-dimethyl-methanimidamide (8) (0.607 g, 2.42 mmol) and 10% palladium on carbon (0.23 g of 50% water wet) and methanol (60 mL) is agitated under hydrogen pressure (43 psi) for about 4.5 hours. The vessel is then flushed with nitrogen and the mixture is heated to 60° C. for about 2.5 hours. The mixture is allowed to cool to ambient temperature and is then filtered through a pad of Celite. The solvent is then evaporated in vacuo to provide 6-Amino-7-methyl-1H-benzimidazole-4-carbonitrile (10) (0.426 g, >100% crude Yield), as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:19][CH3:20])[CH2:6][C:5]([C:13](OC(C)C)=[O:14])([C:7](OC(C)C)=[O:8])[CH2:4]1.[AlH4-].[Li+].O.[OH-].[Na+]>C1COCC1>[CH3:20][O:19][C:3]1([O:2][CH3:1])[CH2:4][C:5]([CH2:7][OH:8])([CH2:13][OH:14])[CH2:6]1
Reactant: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1(OC)CC(CO)(CO)C1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
At 0° C., to a solution of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (3.0 g, 0.010 mol) in THF (20 mL) was added 2.0 M of lithium tetrahydroaluminate in tetrahydrofuran (16 mL) slowly with stirring. The mixture was stirred for 2 h, allowing warm up to rt. At 0° C., to the reaction was added dropwise water (1.2 mL), 15% NaOH solution (1.2 mL) and water (3.6 mL) successively and the resultant mixture was stirred for 20 min at rt. The mixture was filtered and the filtrate was concentration to give the desired product (1.64 g, 89%) as colorless oil which was used directly in the next step without purification.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH:28]([CH:30]3[CH2:32][O:31]3)[CH3:29])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].CCCC[N+](CCCC)(CCCC)CCCC.[FH:59].[FH:60].[F-]>ClC1C=CC=CC=1>[F:59][C:2]1[CH:3]=[C:4]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:33])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH:28]([CH3:29])[CH:30]([OH:31])[CH2:32][F:60])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17]
Reactant: F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C3CO3)CC2)c2ncnn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Clc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C(O)CF)CC2)c2ncnn12
Temperature: 120 °C
Reaction time: 24 h

Procedure:
A mixture of 3′-fluoro-4′-({4-[trans-4-(1-oxiran-2-ylethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g), tetra-n-butylammonium dihydrogentrifluoride (0.49 g) and chlorobenzene (0.5 mL) was stirred at 120° C. for 24 hr and then at room temperature for 40 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.081 g, 51%).
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([C:9]([N+:13]([O-:15])=[O:14])=[CH:10][C:11]=1[CH3:12])[NH:5][CH:6]([CH3:8])[CH3:7].[CH3:19][O-:20].[Na+]>CO>[CH:6]([NH:5][C:4]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][C:11]([CH3:12])=[C:2]([O:20][CH3:19])[C:3]=1[N+:16]([O-:18])=[O:17])([CH3:8])[CH3:7]
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C)c([N+](=O)[O-])c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C)cc([N+](=O)[O-])c(NC(C)C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirred solution of 5.47 g. (0.02 mole) of 3-chloro-N-isopropyl-4-methyl-2,6-dinitroaniline in 100 ml. of methanol is added 1.79 g. (0.033 mole) of sodium methoxide. The reaction mixture is stirred at reflux for three hours, cooled to room temperature and filtered. The filtrate is evaporated at reduced pressure and the residue partitioned between ether and dilute aqueous hydrochloric acid. The organic phase is successively washed with water, saturated sodium bicarbonate and brine. It is then dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo gives 5.0 g. of the desired product having a m.p. of 72°-77° C. Two recrystallizations from methanol give the analytical sample, m.p. 77.5°-79° C. Analysis: Calcd. for C11H15N3O5 : C, 49.07; H, 5.62; N, 15.61. Found: C, 49.35; H, 5.66; N, 15.77.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][S:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[C:23]([CH2:28][CH3:29])[N:24]2[CH3:27])=[C:20]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:19]=1)=[O:11])=O)(C)(C)C.[ClH:41]>O1CCCC1.O1CCOCC1>[ClH:41].[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][S:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[C:23]([CH2:28][CH3:29])[N:24]2[CH3:27])=[C:20]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[N:19]=1)=[O:11]
Reactant: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)c(NC(=O)CNC(=O)OC(C)(C)C)c3)nc2n1C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)c(NC(=O)CN)c3)nc2n1C
Yield: 83 %

Procedure:
2-[3-(2-tert-butoxycarbonylaminoacetylamino)-4-methoxybenzylsulfanyl]-8-ethyl-9-methyl-6-morpholino-9H-purine (Compound 62) (140 mg, 0.24 mmol) was dissolved in tetrahydrofuran (15 ml), 4N-hydrogen chloride in dioxane (2 ml) and stirred for 8 hours. After distilling away the solvent under reduced pressure, the residue was washed with ether to obtain 103 mg (83% yield) of Compound 28.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:13][C@H:12]([O:14][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](COCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cis-3-benzyloxymethylcyclobutanol (Albany Molecular Research Institute, 1.0 g, 5.2 mmol) in 50 mL of CH2Cl2 was added imidazole (2.7 g, 39 mmol) followed by tert-butyldimethylsilyl chloride (3.9 g, 26 mmol). This mixture stirred at ambient temperature for 2 hours and was quenched with 10 mL of saturated aqueous NH4Cl. The layers were separated and the aqueous layer was extracted with three 5 mL of portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 75% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 307 (M+H)+.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][O:7][C@H:6]([CH2:9][OH:10])[CH2:5][O:4]1)=[CH2:2].[H-].[Na+].I[CH3:14]>C1COCC1.O>[CH3:14][O:10][CH2:9][C@@H:6]1[CH2:5][O:4][C@@H:3]([CH:1]=[CH2:2])[CH2:8][O:7]1
Reactant: CI
Reactant: C=C[C@H]1CO[C@H](CO)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@H]1CO[C@H](COC)CO1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 36.5 %

Procedure:
To a solution of ((2R,5S)-5-vinyl-1,4-dioxan-2-yl)methanol (Preparation #17, 0.25 g, 1.734 mmol) in THF (3 mL) was added NaH (41.6 mg, 1.734 mmol) at 0° C. The reaction mixture was slowly warmed to RT and stirred for 25 min. The reaction mixture was cooled to about 0° C. and iodomethane (0.108 mL, 1.734 mmol) was added. Upon completion of addition, the reaction mixture was slowly warmed to RT and stirred for about 2.5 h. The reaction mixture was diluted with water (20 mL) and the product extracted with EtOAc (2×10 mL). The organic layer dried over sodium sulfate and concentrated under reduced pressure. The crude material obtained was purified by column chromatography eluting with 10% EtOAc in hexane to afford (2R,5S)-2-(methoxymethyl)-5-vinyl-1,4-dioxane 0.1 g (36.5%), 1H NMR (400 MHz, CDCl3): δ 5.75-5.67 (m, 1H), 5.36-5.32 (m, 1H), 5.23-5.20 (m, 1H), 4.05-4.00 (m, 1H), 3.87-3.70 (m, 3H), 3.55-3.49 (m, 1H), 3.42-3.35 (m, 6H), ES-MS: m/z 158 (m+H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[NH2:1][C:2]1[C:6]([NH:7][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:5][S:4][CH:3]=1
Reactant: Nc1cscc1N
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1cscc1N
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
3.06 g of 3,4-diaminothiophene were mixed with 45 ml of methylene chloride and 9 ml of triethylamine and a solution of 3.6 g of valeroyl chloride in 45 ml of methylene chloride was added at a temperature of 20° C. over one hour. The mixture was stirred for 30 minutes, followed by evaporation to dryness. After separation by chromatography (eluant: methanol/methylene chloride 5/95), 3.2 g of the expected monoamide were obtained which was crystallized from 15 ml of a 50/50 mixture of isopropyl ether and cyclohexane. The crystals were separated, washed with this mixture and dried under reduced pressure at 100° C. to obtain 2.14 g of the expected product melting at 110° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([O:13]C)=[O:12].C1COCC1.O[Li].O.Cl>O>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc2c(c1Cl)OCO2
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1Cl)OCO2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a vial containing methyl 4-chlorobenzo[d][1,3]dioxole-5-carboxylate (395.8 mg, 1.8 mmol, 1 equiv.) in 3:1 THF:H2O (15 mL) was added LiOH.H2O (153.3 mg, 3.7 mmol, 2 equiv.). The vial was capped and the mixture was stirred at 70° C. for 2 h, diluted with water, acidified with 1M HCl to pH <3, and extracted with ethyl acetate. The combined organic layers was dried over anhydrous Na2SO4, filtered and the solvent was removed under vacuum to give a quantitative yield of 4-chlorobenzo[d][1,3]dioxole-5-carboxylic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[O:13]=C1CCCSC1C(OCC)=O.[Na].O>C(O)C.C(O)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)C1SCCCC1=O
Reactant: Nc1nc(Cl)c2c(n1)CCCS2
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nc(O)c2c(n1)CCCS2

Procedure:
The starting material, 2-amino-4-chloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine, was prepared in the following manner. 56.4 g of ethyl 3-oxotetrahydrothiopyran-2-carboxylate was added to a solution of 6.9 g of sodium metal in 300 ml of ethanol at room temperature while stirring. After stirring overnight, water was added to the mixture, and the mixture was rendered acidic with acetic acid. The precipitated crystals were filtered, washed with water and then with a small amount of isopropyl alcohol and air-dried to obtain 45 g of 2-amino-4-hydroxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as colorless needles having a melting point above 300° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Br[CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: Brc1cccc2[nH]ccc12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccc2c(Br)cccc21

Procedure:
Add sodium hydride (4.89 g, 122.4 mmol, 60% dispersion in mineral oil) to a solution of 4-Bromo-1H-indole (12 g, 61.2 mmol) in dimethylformamide (100 ml). Cool the reaction to 0° C. and add (2-bromo-1-(tert-butyldimethylsilyloxy)ethane (17.04 g, 67.32 mmol). Stir the reaction for 1 hour at room temperature, quench with aqueous saturated sodium bicarbonate, and extract into ethyl acetate. Combine the organic layers and wash with saturated aqueous sodium chloride, dry over magnesium sulfate. Concentrate under reduced pressure to obtain the title compound, as a clear oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:2]=C.I([O-])(=O)(=O)=[O:26].[Na+].N1C(C)=CC=CC=1C>O.O1CCOCC1.[Os](=O)(=O)(=O)=O>[O:14]=[C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH:4]([CH2:1][CH:2]=[O:26])[CH2:13]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC1CC(=O)c2ccccc2N1C(=O)OCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: O=CCC1CC(=O)c2ccccc2N1C(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
Osmium tetroxide (5% in water, 2.0 mL, 0.33 mmol, 0.025 equiv) was added to a biphasic mixture of benzyl 2-allyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1A) (4.20 g, 13.1 mmol, 1 equiv), sodium periodate (11.2 g, 52.3 mmol, 4.00 equiv) and 2,6-lutidine (3.04 mL, 26.1 mmol, 2.0 equiv) in water (33 mL) and dioxane (98 mL) at 23° C. The reaction mixture was stirred at 23° C. for 3 h, and then it was partitioned between water and dichloromethane. The aqueous layer was further extracted with dichloromethane (1×), and the combined organic layers were dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (15% ethyl acetate-hexanes, grading to 70% ethyl acetate-hexanes) to afford 25A. [M+H]+: 324.1
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[F:20][C:21]([F:31])([F:32])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:7]2[C:8]([O:9][C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]2=[O:18])=[CH:25][CH:24]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2ccc(OC(F)(F)F)cc2)c(=O)[nH]c1=O
Yield: 53.6 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 4-trifluoromethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (233 mg, yield: 53.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:3]=1.[Br:15]Br.O.[OH-].[K+]>C(O)(=O)C>[Br:15][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:5]=1[NH2:7]
Reactant: BrBr
Reactant: Cc1cc(N)n(-c2ccccc2C)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1-n1nc(C)c(Br)c1N
Reaction time: 0.5 h

Procedure:
To a solution of 3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate F, 7.78 g, 41.7 mmol) in acetic acid (90 mL) was added a solution of bromine (6.64 g, 41.6 mmol) in acetic acid (10 mL). The reaction mixture was stirred for 30 min. Water was added to the reaction mixture, and the mixture was basified using a cold KOH solution (1 N). The white solid, 4-bromo-3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine, was collected and used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:31])[CH:9]([NH:11][C:12]([C:14]2[CH:30]=[CH:29][C:17]3[N:18]=[C:19]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:28])[NH:20][C:16]=3[CH:15]=2)=O)[CH3:10])=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:31][C:12]([C:14]3[CH:30]=[CH:29][C:17]4[N:18]=[C:19]([C:21]5[C:22]([Cl:28])=[CH:23][CH:24]=[CH:25][C:26]=5[Cl:27])[NH:20][C:16]=4[CH:15]=3)=[N:11][C:9]=2[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(NC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1)C(=O)c1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)oc1-c1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
A mixture of 2-(2,6-dichlorophenyl)-3H-benzimidazole-5-carboxylic acid [2-(4-chlorophenyl)-1-methyl-2-oxoethyl]-amide (480 mg, 1.02 mmol) and Burgess Reagent (848 mg, 4.06 mmol) in THF (10 mL) was heated in a microwave apparatus at 150° C. for 30 min. The mixture was poured into ethyl acetate and extracted with water and brine. The organic layer was dried, filtered, and the solvent removed under reduced pressure. The residual oil was triturated with acetonitrile to afford the title compound. H1-NMR (DMSO-d6): δ 8.40 (s, broad, 0.5H), 8.22 (s, broad, 0.5H), 8.0 (m, 1H), 7.72 (m, 8H), 2.47 (s, 3H). MS: m/z 455.9 (M+1); High resolution MS (M+H): theory: 454.0281, measured: 454.0279.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]([NH2:18])([CH3:17])[CH3:16].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:15]([NH:18][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To the solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 25.09 mmol) in methanol (35 mL) was added isopropylamine (1.07 mL, 12.54 mmol), acetic acid (0.94 mL, 16.30 mmol) and sodium cyanoborohydride (1.0 g, 16.30 mmol). The resulting solution was stirred at room temperature for 1 hour, then quenched with water. The solution was concentrated in vacuo and redissolved in ethyl ether. The organics were extracted with 0.1 N HCl. The aqueous extracts were basified with 1 N NaOH (pH>8) and extracted with ethyl ether. The organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, to afford tert-butyl 4-(isopropylamino)piperidine-1-carboxylate (1.2 g, 41%) as a clear liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12.O[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12
Reactant: O=C1CCCN1CCO
Reactant: Fc1cccc(-c2n[nH]c3nnc(-c4ccccc4)c(Cl)c23)c1
Product: O=C1CCCN1CCn1nc(-c2cccc(F)c2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIr was synthesized from 4-chloro-3-(3-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 1-(2-hydroxyethyl)pyrrolidin-2-one following the general procedure for the Mitsunobu reaction as described.