Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](Cl)=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N)CC1C=CC=CC=1.OP(O)(O)=O>C(O)(C)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:22]=1[O:21][CH3:20])=[N:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc2cc(SCc3ccccc3)ccc12
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Product: COc1cc(C(F)(F)F)ccc1-c1nccc2cc(SCc3ccccc3)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A three-neck 2 L flask equipped with an overhead stirrer, a thermocouple, a condenser and a nitrogen inlet was charged with 6-(benzylthio)-1-chloroisoquinoline (23 g, 80 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (22.1 g, 101 mmol), potassium phosphate (51.2 g, 241 mmol) and Amphos (2.85 g, 4.02 mmol) in that order. The flask was evacuated. In a separate flask was charged with dioxane (230 mL) and water (57.5 mL). The solvent solution was sparged with nitrogen and charged to the reaction flask. The reaction flask was purged with nitrogen and warmed to reflux. After 1 hr, the reaction was complete according to LC/MS. The whole was cooled to 0° C., charged with DCM and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated down to afford black oil. Isopropanol was added into the black oil and the whole was concentrated again to fully remove DCM and dioxane. The black residue was charged with 200 mL of isopropanol. The product crystallized out of solution. The slurry was stirred for 2 hrs at RT and cooled to 0° C. for 1 hr. The product was filtered off, washed with 30% isopropanol/heptane solution, and dried under vacuum with a nitrogen sweep. The product was obtained as gray solids (24.1 g, 70.4%; >99% purity via LC/MS at 215 nm). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.58 (d, J=5.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.56-7.47 (m, 3H), 7.45-7.26 (m, 8H), 4.31 (s, 2H), 3.76 (s, 3H); m/z (ESI) 426.2 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9](=[O:22])[N:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O)(OO)(=O)=[O:30]>>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][S:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:30])[C:9](=[O:22])[N:8]2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)OO
Reactant: O=C1C(CCSc2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1
Product: O=C1C(CCS(=O)c2ccccc2)C(=O)N(c2ccccc2)N1c1ccccc1

Procedure:
Herein is described a process for oxidizing 1,2-diphenyl-4-[2-(phenylthio)ethyl]-3,5-pyrazolidinedione with peroxymonosulfuric acid to obtain 1,2-diphenyl-4-[2-(phenylsulfinyl)ethyl]-3,5-pyrazolidinedione.
Reaction SMILES: [N:1]1([CH:6]([CH3:10])[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:35]([O:37][C:38](=[O:46])[C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)[CH3:36].CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[N:1]1([CH:6]([CH3:10])[C:7]([NH:45][C:42]2[CH:41]=[CH:40][C:39]([C:38]([O:37][CH2:35][CH3:36])=[O:46])=[CH:44][CH:43]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C(=O)O)N1CCCC1
Reactant: CCOC(=O)c1ccc(N)cc1
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: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(NC(=O)C(C)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the 2-pyrrolidin-1-yl-propanoic acid (200 mg, 1.4 mmol) in DMF (10 mL), was added HATU (586 mg, 1.5 mmol), 4-amino-benzoic acid ethyl ester (231 mg, 1.4 mmol) and DIPEA (0.5 mL, 2.8 mmol). The reaction mixture was stirred at room temperature for 16 hours, diluted with water and acetonitrile, purified by preparative HPLC, and lyophilized to give ethyl 4-(2-(pyrrolidin-1-yl)propanamido)benzoate.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]([CH3:32])[C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[Cl:31])=[O:21])[CH2:11][C@@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-]>C1COCC1>[Cl:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][NH:22][C:20](=[O:21])[N:19]([C@H:10]([CH2:9][OH:8])[CH2:11][C@@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[O:13]1)[CH3:32]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO[Si](C)(C)C(C)(C)C)C[C@@H]1COC(C)(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO)C[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of the above crude 1-((S)-1-(tert-butyldimethylsilyloxy)-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-yl)-3-(2-chloro-3-fluorobenzyl)-1-methylurea in THF (300 mL) was added tetrabutylammonium fluoride (10.0 mL, 1 M in THF, 10.0 mmol). The resulting solution was then stirred at RT for 1 h. The reaction mixture was added into a saturated aqueous solution of NH4Cl (350 mL) and extracted with EtOAc (2×350 mL). Combined organic layers were washed with Brine (2×400 mL) and dried over MgSO4. The solution was then concentrated. The resulting residue was purified on a silica gel column using a mixture of DCM and MeOH to give 3-(2-chloro-3-fluorobenzyl)-1-((S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxypropan-2-yl)-1-methylurea (2.3 g, 61% over two steps). LRMS (M+H+) m/z 375.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:15]1[CH:16]=[C:12]([CH3:11])[N:13]=[CH:14]1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(C=O)cc2F)cn1
Temperature: 90 °C
Reaction time: 6 h
Yield: 17.6 %

Procedure:
To a solution of 3,4-difluorobenzaldehyde (40.0 g) in DMF (533 mL), 4-methylimidazole (46.4 g) and potassium carbonate (78.0 g) were added at room temperature, and the reaction solution was stirred at 90° C. for six hours. The reaction solution was left to cool to room temperature. Ethyl acetate was added to the reaction solution, which was then sequentially washed with water and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and solidified with tert-butyl methyl ether to obtain 10.1 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](O)(=[O:20])[C:17]([CH3:19])=[CH2:18]>>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C(O)c1ccc(OCCCCO)cc1
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OCCCCOc1ccc(C(=O)O)cc1

Procedure:
4-(4-Hydroxybutoxy)benzoic acid (prepared by the method of Whitcombe et al., Polymer Comm., 32, 380-381 (1991)) was esterified with methacrylic acid by the method described in Portugall et al., Makromol. Chem 183, 2311 (1982) to give an oil which was precipitated into water, filtered, dried and recrystallized from 2-propanol to give 4-(4-methacryloxybutoxy)benzoic acid, melting point 103°-106° C. acid was converted to the desired acid chloride by the method described in the aforementioned Portugall et al. paper; the acid chloride was obtained as a clear, colorless oil, which was recrystallized from dry hexanes to give the final product (84% yield) as fluffy white needles, melting point 30°-31° C.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.Cl.[OH-].[Na+]>C1COCC1>[NH2:11][CH2:10][C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][C:2]([CH3:15])([CH3:14])[CH3:1])=[N:7][CH:8]=1
Reactant: CC(C)(C)CCOc1ccc(C#N)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)CCOc1ccc(CN)cn1
Reaction time: 8 h
Yield: 52766.5 %

Procedure:
Dissolve 6-(3,3-dimethyl-butoxy)-nicotinonitrile (1.4 g, 6.86 mmol) in anhydrous THF (10 mL) under nitrogen and add 1M BH3-THF complex in THF (20.6 mL, 20.6 mmol). Stir the mixture overnight under nitrogen and then pour the reaction carefully into 5N aqueous HCl (20 mL). Stir the resulting suspension for 6 h at room temperature. Then basify by adding 2N aqueous NaOH (50 mL) and extract with dichloromethane (3×100 mL). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Take-up the resulting oil in methanol and filter it through an SCX column eluting with methanol followed by 3M ammonia in methanol. Concentrate in vacuo to obtain the title compound (754 g, 50%). GC-MS m/z: 208 (M>).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].N1C2C(=CC=CC=2)C=CC=1.[S]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].C1(C)C=CC=CC=1>[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3]
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(c1)COC2=O
Reaction time: 7 h
Yield: 72 %

Procedure:
In a hydrogenator a mixture of 7 g (0.036 mole) of 5-chlorocarbonylphthalide, 50 ml of toluene, 0.1 ml of the quinoline/sulfur mixture and 0.7 g of previously reduced 5% Pd/BaSO4 is charged. The mixture is hydrogenated at 80° C. under 3.5 bar for 7 hours. At this point the reaction no longer proceeds because of the co-precipitation of the formed product Thus, it is stopped and the mixture is filtered in the warm in order to put the product. into solution again. A second amount of 0.7 g of 5% Pd/BaSO4 is added to the filtrate and the hydrogenation starts again under the above described conditions. After 15 minutes, no more absorption of hydrogen is observed. Hydrogenation is stopped and the catalyst is filtered off in the warm. After cooling, the solution is concentrated under vacuum to a residue which is taken up with ethyl acetate. The organic phase is washed with a 5% aqueous solution of NaHCO3, concentrated to a little volume and the separated product is filter. There is obtained 4.2 g of 5-formylphthalide with a purity (HPLC)=42% (yield 30%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].Cl>O1CCOCC1.[OH-].[Na+]>[CH2:5]([O:4][C:2]([NH:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.16 g (0.103 mmol) of benzyl chloroformate in 100 ml of dry dioxan is added dropwise over a period of 30 minutes to a solution of 10.60 g (0.1 mmol) of 4-aminobutyric acid in 300 ml of 1 N sodium hydroxide solution in an ice bath. The reaction mixture is stirred for 30 minutes at room temperature, acidified with 2 N hydrochloric acid and extracted with methylene chloride. The organic phase is dried with sodium sulphate and concentrated in vacuo. The 4-benzyloxycarbonylaminobutyric acid obtained is recrystallised from ethyl acetate, methylene chloride and hexane; melting point 61°-62°.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8](I)[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:5])C.[NH2:31][C:32]1[CH:33]=[N:34][N:35](C(OC(C)(C)C)=O)[CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[NH:34]1[CH:33]=[C:32]([NH:31][C:8]2[O:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[C:6]([C:4]([OH:3])=[O:5])[N:7]=2)[CH:36]=[N:35]1
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Reactant: CCOC(=O)c1nc(I)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(Nc4cn[nH]c4)nc3C(=O)O)cc2)CC1
Yield: 26.1 %

Procedure:
A mixture of tert-butyl 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1-carboxylate (0.150 g, 0.28 mmol), tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.261 g, 1.42 mmol), cesium carbonate (0.462 g, 2.39 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.013 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.0165 g, 0.029 mmol) tBuOH (4.5 ml) and dioxane (4.5 ml) was degassed, placed under a nitrogen atmosphere and then stirred under reflux overnight. The reaction mixture was passed through a MP-SH cartridge and the solvent removed in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase extracted with EtOAc and DCM. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(1H-pyrazol-4-ylamino)-5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)oxazole-4-carboxylic acid (0.033 g, 0.073 mmol, 26%). LCMS (2) Rt: 1.68 min; m/z (ES+) 455.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([F:25])[C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[F:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][C:2]1([CH3:1])[C:6]([C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[C:15]([F:25])[C:16]=2[C:58]2[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:57]=2[F:56])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(F)c(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(-c2cc(OC)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 75 °C
Reaction time: 21 h
Yield: 95 %

Procedure:
A stirred mixture of T25.6 (0.9464 g, 2.39 mmol), ground S-Phos (0.1977 g, 0.482 mmol), palladium acetate (0.0555 g, 0.247 mmol), 2-fluoro-5-methoxyphenylboronic acid (0.8114 g, 4.77 mmol) (commercially available from Aldrich), and potassium phosphate tribasic (1.2888 g, 6.072 mmol) in dry DMF (7.000 mL) was purged with argon and placed under vacuum and the process repeated three times. The mixture was then heated to 75° C. and the reaction was stirred for 21 hours. The reaction was then cooled to room temperature, diluted with water and extracted three times with EtOAc. The organic layers were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified on an 80 g column of silica gel (0-20% EtOAc in hexanes) to afford T25.7 as a colorless oil that was used without further purification (850.5 mg, 95% yield). MS ESI (pos.) m/e: 373.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:13].C(O)(=O)C.C(C1C=CC=CC=1)(=O)C>C1(C)C=CC=CC=1.O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH2:11][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[CH:15][CH:16]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1
Reaction time: 0.08 h

Procedure:
Simultaneous reactions were run in both a 65-L reactor and a 35-L reactor that share the same reflux system. A nitrogen atmosphere was maintained in both. 4.0 kg (100 moles) of 60% sodium hydride in mineral oil and 32 L toluene were charged into the ambient temperature reactors. The mixture was agitated for 5 minutes and allowed to settle. 20 L of the toluene solution was aspirated. 28 L of toluene was added, agitated for 5 minutes, allowed to settle and 28 L of the toluene solution was aspirated. 68 L of toluene and 8.4 L (69.7 moles) diethyl carbonate were added. The agitation was begun and the flow of Syltherm (Note 4) in reactor jackets was initiated. A solution of 5.0 kg (33.3 moles) 4-methoxyacetophenone in 12 L toluene was added over 20 minutes. When additions were complete, the jacket temperature was reduced to 10° C. and stirring continued for 16 hours. A solution of 6.7 L (117 moles) glacial acetic acid in 23 L deionized water was fed at the same rate that was previously used for the acetophenone solution. When addition was complete, agitation was stopped and the layers separated. The aqueous layer was washed once with 13 L toluene. The combined organic layers were washed twice with 6.7 L portions of 7% (w:w) aqueous sodium bicarbonate. The toluene solution was washed once with 6.7 L of 23% (w:w) aqueous sodium chloride. The organic solution was dried over 10 kg sodium sulfate, filtered, and the solvent removed on the rotary evaporator to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].P(Cl)(Cl)([Cl:15])=O>O>[Br:1][C:2]1[C:3]([Cl:15])=[N:4][CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Oc1ncnc(C(F)(F)F)c1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1ncnc(Cl)c1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
24.3 g (100.0 mmoles) of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine was suspended in 18.5 g (120.0 mmoles) of phosphorus oxychloride. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water gradually, followed by extraction with chloroform. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 21.5 g (yield: 82.4%) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[CH:6][N:7]=1.[Cl:13]C1N=CC(OC)=C(Cl)N=1.C([Mg]Br)=C.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[C:6]([Cl:13])[N:7]=1
Reactant: C=CC1(Cl)NC(Cl)=NC=C1OC
Reactant: COc1cnc(Cl)nc1Cl
Agent: C=C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: C=Cc1nc(Cl)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using 2,6-dichloro-5-methoxy pyrimidine, which is commercially available. To a solution of 2,6-dicholoro-5-methoxy pyrimidine (100 g, 0.55 mol) in dry tetrahydrofuran (THF) solvent was added, dropwise, 1M vinyl magnesium bromide in THF solvent (124 g, 0.94 mol) for one hour at room temperature. The mixture was then stirred for 4 h at room temperature. Excess Grignard reagent was quenched by addition of acetone (200 mL) while the temperature of the mixture was maintained at a temperature below 20° C. Thereafter, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (151 g, 0.67 mol) was added at once and stirred overnight. A yellow solid precipitated out. The solid was filtered and washed with ethyl acetate (500 mL) The filtrate was concentrated under reduced pressure and the resulting crude compound was diluted with ethyl acetate (2 L). The resulting undissolved, dark, semi-solid was separated by filtration using ethyl acetate. It was further concentrated under reduced pressure to provide a crude compound, which was purified by column chromatography. The compound was eluted with 5% to 10% ethyl acetate in hexane mixture to provide the title compound (70 g, 60% yield): mp 60-61° C.; 1H NMR (CDCl3) δ 3.99 (s, 3H), 5.85 (d, 1H), 6.75 (d, 1H), 6.95 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[CH:6][N:7]=1.[Cl:13]C1N=CC(OC)=C(Cl)N=1.C([Mg]Br)=C.C(N1C=CC=NC1)=C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.ClC1N=C(C=C)C(C=O)=C(Cl)N=1>C1COCC1.C(OCC)(=O)C.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:3]=[C:4]([CH:10]=[CH2:11])[C:5]([O:8][CH3:9])=[C:6]([Cl:13])[N:7]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C=CC1(Cl)NC(Cl)=NC=C1OC
Agent: [Mn+4]
Agent: C=CN1C=CC=NC1
Agent: C=C[Mg]Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1nc(Cl)nc(Cl)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 4 %

Procedure:
2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using 2,6-dichloro-5-methoxy pyrimidine, which is commercially available. 2,6-Dichloro-5-methoxy pyrimidine (10 g, 56 mmol) was dissolved in THF (15 mL). The solution was added dropwise to vinyl magnesium bromide (60 mL of 1 M, 60 mmol) over approximately 15 minutes while keeping the temperature of the mixture below 30° C. by external cooling. Rapid, clean formation of a dihydro-vinyl pyrimidine intermediate (having a molar weight of 206 g/mol) was observed using GC-MS and HPLC. The mixture was stirred for approximately 3 h at room temperature. Conversion of greater than 95% was observed by GC/FID. The mixture was cooled to below 10° C. and treated in portions with citric acid (150 mL of 10% citric acid). It was then diluted with ethyl acetate (75 mL). The phases were separate and the organic phase extracted using ethyl acetate (1×50 mL). The organic phases were then combined and washed with saturated sodium chloride (1×50 mL), then dried, and evaporated to provide a crude dihydro intermediate. This material was dissolved in DCM (200 mL) and treated with manganese dioxide (10.4 g, 120 mmol) while stirred at room temperature. The rapid formation of 2,6-dichloro-5-methoy-4-vinyl pyrimidine (having a molar weight of 204 g/mol) was observed. After about 1 h, an additional amount of manganese dioxide (15 g) was added and the mixture stirred overnight. The manganese dioxide was removed by filtration through celite. The filtrate was washed with DCM and acetone. The filtrate was then concentrated by allowing the solvents to evaporate and purified by column chromatography using silica with a ramp of 0-10% ethyl acetate/hexane. This provided the title compound (approximately 500 mg, approximately 4% yield): mp 59-60° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][C:11]([NH2:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CC#N>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:14][C:11]([CH3:13])([CH3:12])[CH3:10])[CH:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1cc(Cl)nc(N)n1
Temperature: 170 °C
Yield: 89.9 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (400 mg, 2.44 mmol) in CH3CN (5 mL) were added (1,1-dimethylethyl)amine (0.34 mL, 3.17 mmol) and triethylamine (1.36 mL, 9.76 mmol), and the reaction mixture was heated in a microwave at 170° C. for a total of 2.25 hours, checking the progression of the reaction at regular intervals. The mixture was cooled down and evaporated. The resulting residue was partitioned between EtOAc and water, and extracted with EtOAc (2×) and CH2Cl2 (2×). The organics were washed with water and brine, dried (MgSO4), filtered and evaporated. The resulting solid was triturated with Et2O and dried in vacuo to afford the title compound (440 mg). LC-MS (ES) m/z=201, 203 [M+H]+.