Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22]>CC(C)=O>[CH2:19]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CCBr
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CCC(C)C)CCCC1=O
Yield: 72.6 %

Procedure:
Under vigorous agitation, 34.67 g (purity of 90%) of ethyl 2-oxocyclopentane carboxylate was added to 112.65 g (purity of 98%,) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for about 15 minutes, then thereto was dropwise added 51.36 ml (purity of 98%) of 1-bromo-iso-pentane. Upon the completion of the addition, the reaction mixture was heated for reflux for 6 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 32.80 g of colorless liquid as a distillate cut of 142-147° C./15 mmHg was collected. Yield: 72.60%. MS: m/e 227(M30 +1), 226(M+), 211 (M+—CH3) 198(M+—CH2CH2) 171 (M+—OCH2CH3), 156 (M+—C5H11, base), 153(M+—CO2 CH2CH3), 127(155-CH2CH2), 111(156-OCH2CH3), 55.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[C:4]([F:13])[CH:3]=1.II.[CH3:16][C:17]([S:20](/[N:22]=[CH:23]/[C:24]1[O:28][CH:27]=[N:26][CH:25]=1)=[O:21])([CH3:19])[CH3:18]>C1COCC1.C1(C)C=CC=CC=1>[F:13][C:4]1[CH:3]=[C:2]([CH:23]([C:24]2[O:28][CH:27]=[N:26][CH:25]=2)[NH:22][S:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH:7]=[CH:6][C:5]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: CC(C)(C)S(=O)/N=C/c1cnco1
Agent: II
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC(c1ccc(OC(F)(F)F)c(F)c1)c1cnco1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-bromo-2-fluoro-1-(trifluoromethoxy)benzene (582 g, 2247 mmol), Mg (54.6 g, 2247 mmol) and iodine in THF (10 mL) was heated at reflux for 2 h. The reaction was cooled to 0° C. and added to a solution of (E)-2-methyl-N-(oxazol-5-ylmethylene)propane-2-sulfinamide (300 g, 1498 mmol, step 1 of example 1) in toluene (10 mL) cooled to 0° C. The reaction was stirred at 0° C. for 30 min. The reaction was quenched with water and extracted with DCM. The organic layer was concentrated to afford crude N-((3-fluoro-4-(trifluoromethoxy)phenyl)(oxazol-5-yl)methyl)-2-methylpropane-2-sulfinamide (55) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]([CH3:14])[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21]O)=[C:17]([CH3:23])[CH:16]=3)=[CH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:30])=O>ClCCl.CN(C)C=O>[Cl:30][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2[N:12]([CH3:14])[O:13][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[CH:16][C:17]=1[CH3:23]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C2=CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1CCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
690 mg of {4-[5-(3,5-Dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-methanol was dissolved in 20 ml dichloromethane and one drop of N,N-dimethylformamide was then added. Thionylchloride (216 mg) was then added very slowly at room temperature. The mixture turned slight yellow before the end of the addition. The mixture was stirred for 3 hours at ambient temperature and then evaporated to dryness. The residue was dissolved in diethylether, washed with aqueous sodium bicarbonate, then with water and finally dried over anhydrous sodium sulfate. The organic phase was then evaporated to dryness affording 3-(4-chloromethyl-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-2,5-dihydro-isoxazole as a resinous product (99% yield), which was used immediately for the further step without purification. 1H-NMR (CDCl3, δ in ppm): 7.29-7.44 (m, 6H), 5.36 (s, 1H), 4.60 (s, 2H), 2.99 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:40][O:41][CH2:42][C:43]1[N:44]=[C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH2:54])[CH:51]=[N:50]2)[O:46][CH:47]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:41][CH2:42][C:43]1[N:44]=[C:45]([CH2:48][N:49]2[N:53]=[C:52]([NH:54][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:51]=[N:50]2)[O:46][CH:47]=1
Reactant: COCc1coc(Cn2ncc(N)n2)n1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCc1coc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (50 mg, 0.26 mmol) in CH2Cl2 (1.3 mL) was treated at rt with DMAP (8 mg, 0.07 mmol), HOBt (43 mg, 0.32 mmol), EDC (127 mg, 0.67 mmol) and DIPEA (0.18 mL, 1.06 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(methoxymethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (55 mg, 0.26 mmol) in CH2Cl2 (1.3 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (5 mL), the layers were separated and the org. phase was washed with water (5 mL), dried over Na2SO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a white solid: TLC: rf (4:6 hept-EA)=0.13. LC-MS-conditions 07: tR=0.81 min, [M+H]+=381.14.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]([S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:9].[Cl-].[Cl-].C([Al+2])C>ClCCCl.C(Cl)Cl>[O:5]=[C:4]1[O:6][C:1](=[O:7])[CH:2]2[CH:3]1[CH2:9][CH:8]2[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=CSc1ccccc1
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1OC(=O)C2C(Sc3ccccc3)CC12
Yield: 90.7 %

Procedure:
To a solution of maleic anhydride (0.39 g, 4 mmol) and phenyl vinyl sulfide (0.52, 4 mmol) in 17 mL of 1,2-dichloroethane under nitrogen, was added 2 mL (0.5 equiv) of ethylaluminum dichloride. The resultant solution was stirred at ambient temperature for 0.5 h and then diluted with 75 mL of methylene chloride. The methylene chloride solution was washed three times with saturated aqueous ammonium chloride solution and once with brine, dried over anhydrous sodium sulfate and concentrated to give 0.85 g of the title compound; EI-MS, m/e (rel intensity): 234 (M+, 23), 136 (100), 109 (12), 91 (21).
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[NH:17][CH:16]=1)(=[O:14])[CH3:13]>CCO>[CH2:10]([O:9][C:2](=[O:8])[C:3]([OH:5])=[CH:13][C:12]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[NH:17][CH:16]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c[nH]c2ccc(Cl)cc12
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(O)=CC(=O)c1c[nH]c2ccc(Cl)cc12
Reaction time: 3 h
Yield: 80.7 %

Procedure:
In 100 ml of EtOH was dissolved 2.99 g (126 mmol) of sodium under heating. The EtOH was evaporated under reduced pressure and the residue was suspended in THF (200 ml). The THF was evaporated. To the suspension of the residue in THF (124 ml) was added 18.1 g (124 mmol) of diethyl oxalate. Subsequently, to the above suspension was added at room temperature, 12 g (62 mmol) of 3-acetyl-5-chloroindole. After stirring for 3 hours, the mixture was stirred at 50° C. for additional 16 hours. The solvent was removed under reduced pressure. The resulting residue was washed with ether, and added to 1N hydrochloric acid (120 ml). The precipitated crystal was collected by filtration, and washed with water and ethyl acetate. Then the crystal was purified by recrystallization from dioxane and dried at 80° C. under reduced pressure to give 14.7 g of the titled compound. Yield: 81%.
Reaction SMILES: NC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](N)=O)[CH:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:26])[CH:20]=1.ClC1C=CN=C(C#N)C=1>>[F:26][C:21]1[CH:20]=[C:19]([NH2:18])[CH:24]=[CH:23][C:22]=1[O:25][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[CH:7]=1
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Reactant: Nc1ccc(O)c(F)c1
Agent: N#Cc1cc(Cl)ccn1
Product: Cc1cc(Oc2ccc(N)cc2F)ccn1

Procedure:
{3-Fluoro-4-[(2-methylpyridin-4-yl)oxy]phenyl}-amine (2J) was prepared by a method analogous to that described for 4-(3-aminophenoxy)pyridine-2-carboxamide (2C), starting from 4-amino-2-fluorophenol and 4-chloro-2-cyanopyridine, MS ES: 219 (M+H)+, calcd 219, RT=1.07 min.
Reaction SMILES: C([Si](C(C)C)(C(C)C)N1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[CH:6]1)(C)C.[O:30]1C=CC(B(O)O)=C1>>[O:30]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[CH:6]1
Reactant: OB(O)c1ccoc1
Reactant: CCOC(=O)c1cn2cc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)ccc2n1
Product: CCOC(=O)c1cn2cc(-c3ccoc3)ccc2n1

Procedure:
This product is prepared under conditions similar to those described for the preparation of Intermediate 15 (step 15.1), replacing the 1-(triisopropylsilyl)pyrrole-3-boronic acid with furan-3-boronic acid.
Reaction SMILES: Br[CH:2]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH:3](Br)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1.[CH3:23][O-:24].[Na+].[K+].[Br-]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([CH:3]([O:24][CH3:23])[CH2:2][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(Br)cc1)C(Br)C(Br)C(=O)c1ccc(Br)cc1
Reactant: C[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COC(CC(=O)c1ccc(Br)cc1)C(=O)c1ccc(Br)cc1

Procedure:
To a solution of 1,2-dibromo-1,2-di(4-bromobenzoyl)ethane (11.1 g, 0.02 mole) in 150 mL dry methanol was added a solution of sodium methoxide in methanol (0.92 g sodium in 50 mL methanol). The yellow brown mixture was refluxed for 1-1.5 hr. The solvent was removed by distillation, the residue was suspended in water and the mixture was extracted with 100 mL chloroform. The chloroform extract was washed with water, dried (Na2SO4) and concentrated. The residue obtained was titrated with dry methanol-ether (3:1) to yield off-white crystalline solid, 6.6 g (78%), mp 153°-154° C. IR (KBr): 3106, 3062, 2932, 1689, 1649, 1583, 1556, 1403, 1223, 1202, 1182, 1086, 1010, 1000, 857, 814, 738, 618, 472 cm-1. 1H (DMSO-d6 /40° C.): 7.95 (d, 2H, J=7.8), 7.77 (4H, J=8.8), 7.72 (d, 2H, J=7.8), 6.89 (s, 1H), 4.03 (s, 3H). 13C (DMSO-d6 /40° C.): 189.9, 187.2, 168.8, 139.9, 135.9, 133.1, 132.2, 131.8, 130.3, 128.1, 127.4, 98.6, 58.5. MS m/e 424 (M+).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[C:10]([NH:12][C@@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]([C@:16]1([CH3:19])[CH2:18][O:17]1)=[O:15])=[O:11].[O:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]([NH:47][C@@H:48]([CH3:52])[C:49]([O-])=[O:50])=[O:46])[CH2:40][CH2:39]1.[K+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:37][O:36][C:30]1[CH:29]=[C:28]([CH2:27][C@H:9]([NH:8][C:49](=[O:50])[C@H:48]([NH:47][C:45](=[O:46])[CH2:44][N:41]2[CH2:42][CH2:43][O:38][CH2:39][CH2:40]2)[CH3:52])[C:10]([NH:12][C@@H:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([C@:16]2([CH3:19])[CH2:18][O:17]2)=[O:15])=[O:11])[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: C[C@H](NC(=O)CN1CCOCC1)C(=O)[O-]
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@]2(C)CO2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](NC(=O)[C@@H](C)NC(=O)CN2CCOCC2)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@]2(C)CO2)cc1OC
Reaction time: 0.25 h
Yield: 34.2 %

Procedure:
To (S)-2-amino-3-(3,4-dimethoxyphenyl)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)propanamide TFA salt (784 mg, 1.54 mmol) in DMF (5 mL) was added potassium (S)-2-(2-morpholinoacetamido)propanoate (470 mg, 1.85 mmol), HATU (702 mg, 1.85 mmol), DIEA (1.02 mL, 6.16 mmol). The mixture was allowed to stir for 15 min at which time it was quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) followed by trituration from ethyl acetate/heptane (1:1) provided (S)-3-(3,4-dimethoxyphenyl)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((R)-2-(2-morpholinoacetamido)propanamido)propanamide (322 mg, 34%) as a colorless amorphous solid. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=7.7 Hz, 1H), 7.26-7.20 (m, 2H), 6.99 (dd, J=7.5, 1.8 Hz, 2H), 6.86-6.68 (m, 3H), 6.64 (d, J=7.3 Hz, 1H), 6.16 (d, J=7.0 Hz, 1H), 4.78-4.64 (m, 1H), 4.48 (q, J=7.1, 7.1, 7.0 Hz, 1H), 4.42-4.28 (m, 1H), 3.86 (d, J=4.0 Hz, 6H), 3.69 (t, J=4.6, 4.6 Hz, 4H), 3.27 (d, J=5.0 Hz, 1H), 3.08 (dd, J=14.0, 4.9 Hz, 1H), 3.02-2.79 (m, 5H), 2.64 (dd, J=14.0, 8.3 Hz, 1H), 2.45 (q, J=4.0, 3.9, 3.9 Hz, 4H), 1.49 (s, 2H), 1.30 (d, J=7.1 Hz, 3H). MS (EI) for C32H42N4O8, found 611.3 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[CH2:16]Br>C([O-])C.[Na+]>[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[CH2:16][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Cc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium ethanolate [prepared from 1.35 g Na in ethanol (30 ml)] were added diethyl malonate (9.2 ml) and then dropwise 3-methyl-4-nitrobenzyl bromide (13.4 g). The mixture was stirred 30 minutes at room temperature, then 30 minutes under reflux and then concentrated. The residue is treated with water and hexane, the precipitate filtered and the filtrate extracted with diethyl ether. The organic extract was dried on sodium sulfate and concentrate to give the title compound as an oil (4 g).
Reaction SMILES: [OH-].[Na+].[C@@H]1([N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[S:14])O[C@H](CO)[C@@H](O)[C@H]1O.CI.[C:22](O)(=O)C>O.C1COCC1>[CH3:22][S:14][C:13]1[NH:15][C:16](=[O:17])[CH:18]=[CH:19][N:12]=1
Reactant: CC(=O)O
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
To a solution of sodium hydroxide (6.24 g, 156.07 mmol) in H2O (55 mL) at room temperature is added thiouridine (10 g, 78.03 mmol). The resulting mixture is stirred at room temperature for 20 min. Methyl iodide (5.45 mL, 87.40 mmol) in THF (10 mL) is added dropwise slowly and the mixture is stirred at room temperature for 18 hours. A white solid forms upon acidifying the mixture to pH 5 with glacial acetic acid. The mixture is allowed to stand at 0° C. (ice bath) for 2 hours and filtered to afford 7.4 g (67% yield) of the desired compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 2.45 (s, 3H), 6.07 (d, J=6.6 Hz, 1H), 7.85 (d, J=6.6 Hz, 1H).
Reaction SMILES: IC.[O:3](CC)[CH2:4]C.[Li].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2([C:32]([OH:34])=[O:33])[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:15][CH:16]=1.[OH2:35]>>[C:32]([OH:34])(=[O:33])[C:18]([OH:3])=[O:35].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:17][C:18]2([C:32](=[O:33])[CH3:4])[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:15][CH:16]=1
Reactant: CCOCC
Reactant: O
Reactant: COc1cccc(NC2(C(=O)O)CCN(CCc3ccccc3)CC2)c1
Agent: [Li]
Solvent: CI
Product: COc1cccc(NC2(C(C)=O)CCN(CCc3ccccc3)CC2)c1
Product: O=C(O)C(=O)O
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To start the reaction, a small amount of a solution of 101.4 parts of iodomethane in 81 parts of dry 1,1'-oxybisethane is dropped to a stirred solution of 8.95 parts of lithium in 81 parts of dry 1,1'-oxybisethane. After the addition of 244 parts of dry 1,1'-oxybisethane, the remainder of the solution is added dropwise at reflux temperature. Stirring at reflux is continued for 1 hour. Then there are added portionwise 23 parts of 4-[(3-methoxyphenyl)amino]-1-(2-phenylethyl)-4-piperidinecarboxylic acid (a violent reaction occurs whereby reflux temperature is maintained). Upon completion, stirring at reflux is continued for 1 hour. The reaction mixture is decomposed by the dropwise addition (carefully) of water. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and 6% of methanol and then a mixture of trichloromethane and 4% of methanol is eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is converted into the ethanedioate salt in 2-propanol. The salt is filtered off, dried and crystallized twice from methanol, yielding 3.08 parts (96.5%) of 1-{4-[(3-methoxyphenyl)amino]-1-(2-phenylethyl)-4-piperidinyl}ethanone ethanedioate; mp. 188° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([Cl:19])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](C(OC(C)(C)C)=O)[CH:7]=[CH:6]2.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[NH:30][N:29]=2)[CH:24]=[CH:23][N:22]=1.[C:36](O)(=O)CCCCC(O)=O.N1C2C(=CC(C(N)C)=CC=2)C=C1>>[Cl:19][C:4]1[C:3]([CH2:2][NH:1][C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:32]=[C:31]([CH:33]4[CH2:35][CH2:34]4)[NH:30][N:29]=3)[CH:24]=[C:23]([CH3:36])[N:22]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN)ccc21
Reactant: O=C(O)CCCCC(=O)O
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Agent: CC(N)c1ccc2[nH]ccc2c1
Product: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2ccc3[nH]ccc3c2Cl)n1

Procedure:
N2-((4-chloro-1H-indol-5-yl)methyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methylpyrimidine-2,4-diamine (I-19) was prepared in accord with the procedure in example 19 except in step 1, 185 and tert-butyl 5-(aminomethyl)-4-chloro-1H-indole-1-carboxylate were used in place of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine and 1-(1H-indol-5-yl)ethanamine adipic acid salt to afford I-19.
Reaction SMILES: CS[C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:5]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1.O[O:28][S:29]([O-:31])=O.[K+].[C:33](=O)([O-])O.[Na+]>>[CH3:33][S:29]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:5]([NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:4]=1)(=[O:31])=[O:28]
Reactant: CSc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: O=C([O-])O
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Product: CS(=O)(=O)c1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Yield: 118.4 %

Procedure:
The title compound was prepared by a similar method to preparation 8 from 2-(methylsulfanyl)-N-phenethyl-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine (16.7 g, 45 mmol) (preparation 42), Oxone (trade mark) (42.0 g, 136 mmol) and solid sodium hydrogen carbonate (20 g, 238 mmol). This gave the title compound (21.4 g) as a white solid. MS: 402 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[C:19]([CH3:22])[N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].[NH2:23][C:24]1[N:32]=[C:31]2[C:27]([NH:28][CH:29]=[N:30]2)=[C:26](Br)[N:25]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:23][C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][NH:30]2)=[C:26]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:21][CH:20]=[C:19]([CH3:22])[N:7]3[C:8](=[O:18])[C:9]=2[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[CH3:3])[N:25]=1
Reactant: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(F)c3)c(=O)n12
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3nc(N)nc4[nH]cnc34)c(-c3cc(F)cc(F)c3)c(=O)n12
Temperature: 110 °C
Yield: 52.3 %

Procedure:
A mixture of optical pure 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.13 g, 0.40 mmol) made from above, 2-amino-6-bromopurine (0.10 g, 0.47 mmol), and N,N-diisopropylethylamine (0.085 mL, 0.49 mmol) in ethanol (1 mL) was heated at 110° C. overnight. LCMS showed incomplete conversion. An additional 0.5 equivalent of 2-amino-6-bromopurine and 1.0 equivalent of N,N-diisopropylethylamine was added, and the mixture was stirred at 110° C. for another day. The solid was shown to be 2-amino-6-bromopurine by LCMS. The mixture was filtered, and the filtrates were purified on preparative-LCMS ((XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (0.095 g, 52%). LCMS calculated for C20H17F2N8OS (M+H)+: m/z=455.1. Found: 455.1 1H NMR (DMSO-d6, 400 MHz) δ 7.67 (1H, s), 7.27 (1H, m), 7.17 (3H, m), 7.07 (1H, s), 6.89 (1H, br s), 5.45 (2H, br s), 5.03 (1H, m), 2.63 (3H, s), 1.30 (3H, d, J=6.8 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −111 ppm.