Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[OH:15].[CH3:20][N:21]1CCCC1=O>>[C:20]([C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH:4]=[CH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[OH:15])#[N:21]
Reactant: COc1ccc(O)c(CC=Cc2ccccc2Br)c1
Reactant: CN1CCCC1=O
Product: COc1ccc(O)c(CC=Cc2ccccc2C#N)c1
Yield: 39 %

Procedure:
Cuprous cyanide (1.03 g; 11.5 mM) and 2-(o-bromocinnamyl)-4-methoxyphenol (1.03 g; 3.23 mM) were combined in 12 ml of anhydrous N-methylpyrrolidinone. Nitrogen was bubbled through the resulting suspension for five minutes and it was then heated to 175° under positive nitrogen pressure for 2 hours. The reaction was poured into 50 ml of conc. NH4OH and 50 ml of water. The emulsion was extracted three times with ether and the ether extracts were washed once with water. Drying over magnesium sulfate was followed by solvent removal leaving a brown oil. This crude product was purified by flash chromatography with 35% ethyl acetate in hexane on a 30 mm×6" column of silica gel. Recrystallization from ethyl acetate/hexane gave 2-(o-cyanocinnamyl)-4-methoxyphenol as a tan solid (335 mg, 39% yield) m.p. 72-74° .
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 3-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (44 mg, 39%). MS (ISP) 449.3 [(M+H)+]; mp 236-237° C.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]=[C:6]1[NH:11][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:9][C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]1[CH:24]([CH2:28][CH2:29][CH3:30])[C:25]([OH:27])=[O:26].[CH3:31]O>>[O:5]=[C:6]1[NH:11][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:9][C:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:7]1[CH:24]([CH2:28][CH2:29][CH3:30])[C:25]([O:27][CH3:31])=[O:26]
Reactant: CCCC(C(=O)O)c1c(-c2ccccc2)nc(N2CCCCC2)[nH]c1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCC(C(=O)OC)c1c(-c2ccccc2)nc(N2CCCCC2)[nH]c1=O

Procedure:
To a solution cold solution of methanol (20 mL) was added thionyl chloride (2.90 mL; 40 mmol) dropwise. The acidic solution was added to a flask containing 2-(6-oxo-4-phenyl-2-(piperidin-1-yl)-1,6-dihydropyrimidin-5-yl)pentanoic acid (1.67 g; 4.71 mmol) and the mixture was heated to reflux for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and neutralized with a saturated solution of sodium hydrogen carbonate. The suspension was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The product was used as such in the next reaction.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[CH3:32][C:33]1[N:34]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH:35]=[CH:36][N:37]=1>O1CCCC1>[CH3:32][C:33]1[N:34]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:23](=[O:24])[CH2:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=3)=[CH:40][CH:39]=2)[CH:35]=[CH:36][N:37]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Reactant: Cc1nccn1-c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2ccc(-n3ccnc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a solution of 5.0 g of p-tetradecyloxyphenylacetyl chloride in 50 ml of tetrahydrofuran is added to a solution of 4.31 g of pyridine and 2.36 g of 4-(2-methyl-1H-imidazol-1-yl)benzenamine in 50 ml of tetrahydrofuran over 5 minutes. The mixture is stirred at ambient temperature for 1 hour, heated to reflux and allowed to stir at room temperature for 2 hours. The solvent is evaporated to a residue which is partitioned between chloroform and dilute sodium bicarbonate. The organic layer is separated, washed with water, dried and filtered through a pad of magnesium silicate. The solvent is evaporated to an oil which crystallizes from methyl alcohol:water to give 4.0 g of white solid which is chromatographed on silica gel using ethyl acetate containing 0.1% ammonium hydroxide to give 3.9 g of the desired product as a white solid, m.p. 106°-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23]C(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.[NH2:47][C:48]1[CH:60]=[CH:59]C(N)=[CH:57][C:49]=1[C:50]([O:52]C(C)(C)C)=[O:51]>>[ClH:1].[NH2:47][C:48]1[CH:60]=[CH:59][C:23]([NH:22][C:20](=[O:21])[C@H:19]([NH:18][C:16]([N:13]2[C:14](=[O:15])[CH:8]([CH2:7][C:6]3[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]2)=[O:17])[CH2:31][CH3:32])=[CH:57][C:49]=1[C:50]([OH:52])=[O:51]
Reactant: CC(C)(C)OC(=O)c1cc(N)ccc1N
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1ccc(N)c(C(=O)O)c1

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, tert-butyl 2,5-diaminobenzoate was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.[NH2:43][CH2:44][C:45]([NH:47][CH2:48][CH:49]1[CH2:52][N:51]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[C:56]([Cl:61])[CH:55]=2)[CH2:50]1)=[O:46]>CN(C)C=O.C(Cl)(Cl)Cl.CO>[Cl:61][C:56]1[CH:55]=[C:54]([CH:59]=[CH:58][C:57]=1[Cl:60])[CH2:53][N:51]1[CH2:50][CH:49]([CH2:48][NH:47][C:45]([CH2:44][NH:43][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[O:46])[CH2:52]1
Reactant: NCC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: COc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccccc1C(=O)NCC(=O)NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reaction time: 1.5 h

Procedure:
A solution of 2-methoxybenzoic acid in dimethylformamide is treated with triethylamine (2 M equivalents) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (1 M equivalent). To the reaction mixture is added a solution of 2-Amino-N-[1-(3,4-dichloro-benzyl)-azetidin-3-ylmethyl]-acetamide (1 M equivalent) in dimethylformamide and left to stir for 1.5 hours. The reaction mixture is diluted with chloroform/methanol 50:50 and applied to a SCX-3 1 g cartridge. The cartridge is washed with chloroform/methanol 50:50, and the compound eluted with a solution of 10% ammonia in methanol. The solvent is evaporated to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[C:27]2[CH3:34].Cl>C(O)(C)C>[ClH:1].[CH3:33][C:28]1[NH:29][C:30]2[C:26]([C:27]=1[CH3:34])=[CH:25][C:24]([NH:23][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)=[CH:32][CH:31]=2
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 70 °C
Yield: 79 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 10), and 5-amino-2,3-dimethylindole (55 mg, 0.34 mmol) in isopropanol (6 ml) containing 5.5M hydrogen chloride in isopropanol (60 μL) was heated for 30 minutes at 70° C. After cooling, the solid was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 4-(2,3-dimethylindol-5-ylamino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline hydrochloride (118 mg, 74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[Br:16])([CH3:4])([CH3:3])[CH3:2].[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[N:7]([C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[Br:16])[CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)OC(C)(C)C)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 144A (12.37 g, 40.1 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added cesium carbonate (19.62 g, 60.2 mmol) and iodomethane (5.02 mL, 80 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and was partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 40% to 100% ethyl acetate in hexane) to provide the title compound. MS (ESI+) m/z 322 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](N(OC)C)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg+].[Br-]>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9](=[O:10])[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., to a solution of (S)-tert-butyl(2-(methoxy(methyl)amino)-2-oxo-1-phenylethyl)carbamate (0.9 g, 3.06 mmol) in anhydrous THF (15 mL), was added MeMgBr (3M solution in Et2O, 2.0 mL, 6.1 mmol) and resultant mixture was allowed to warm and stirred at ambient temperature. After 2 hrs, the reaction was carefully quenched with saturated aqueous NH4Cl solution (10 mL), and the organic contents were extracted with CH2Cl2 (3×25 mL). The volatiles were removed under reduced pressure to afford (S)-tert-butyl(2-oxo-1-phenylpropyl)carbamate. The compound obtained is pure and no further purification is necessary. 1H NMR (300 MHz, CDCl3) δ 7.40-7.33 (m, 5H), 5.88 (bs, 1H), 5.28 (bs, 1H), 2.08 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:19]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43].[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:19]([C:30]4[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:34][CH:35]=4)=[N:18]3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:40][CH2:41][C:42]([OH:44])=[O:43]
Reactant: CCOC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3CCc3ccccc3)cc2)cc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccc(C(F)(F)F)cc4)cc3CCc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[4-({5-(2-phenylethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)benzyl]amino}phenyl)propanoate in ethanol (10 mL) and tetrahydrofuran (10 mL) was added 1 M aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (620 mg, yield 51%, 2 steps) as a yellow oil.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:9][CH2:8][C@H:7]([O:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]2[C:20]3[C:27]([CH3:28])=[C:26]([C:29](O)=[O:30])[S:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH2:6]1)(=[O:3])[CH3:2].[NH2:32][CH2:33][CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][NH:32][C:29]([C:26]1[S:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([NH:18][C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[O:10][C@H:7]3[CH2:8][CH2:9][C@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]3)[C:20]=2[C:27]=1[CH3:28])=[O:30]
Reactant: NCCO
Reactant: CC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)C1
Product: CC(=O)N[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCCO)c(C)c23)C1

Procedure:
Synthesized analogously to example 225.3 from 4-[2-((1S,3S)-3-acetylamino-cyclopentyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (111 mg) and 2-aminoethanol (18 μl). The reaction mixture was concentrated, the residue was partitioned between DCM and water and the organic layer was dried and concentrated again. The crude was purified by chromatography to give the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[C:11]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20](F)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:9][C:10]1[C:11]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([N:5]3[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 95.2 %

Procedure:
(R)-(+)-3-(Dimethylamino)pyrrolidine (0.111 mL, 0.87 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 300 mg, 0.73 mmol) and DIPEA (0.151 mL, 0.87 mmol) in DMA (3 mL) and the mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated and further purification by FCC, eluting with 1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (353 mg, 96%) as an orange foam; 1H NMR: 1.78-1.91 (1H, m), 2.16-2.27 (7H, m), 2.70-2.85 (1H, m), 3.12-3.29 (3H, m), 3.41-3.55 (1H, m), 3.89 (3H, s), 6.57 (1H, s), 6.95 (1H, t), 7.17 (1H, t), 7.46 (1H, d), 8.09 (1H, s), 8.24 (1H, br s), 8.37 (1H, s), 8.50 (1H, d), 8.54 (1H, s), 11.88 (1H, s); m/z: ES+ MH+ 508.5.
Reaction SMILES: [F:1][CH2:2][C:3]([O:5]CC)=O.[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH2:14][Mg]Br)=[CH:11][CH:10]=1>O1CCCC1.[Cl-].[NH4+]>[Cl:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][CH2:14][C:3](=[O:5])[CH2:2][F:1])=[CH:11][CH:10]=1
Reactant: Clc1ccc(CC[Mg]Br)cc1
Reactant: CCOC(=O)CF
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CF)CCc1ccc(Cl)cc1
Temperature: -50 °C
Reaction time: 5 h
Yield: 18 %

Procedure:
To a stirred solution of ethyl fluoroacetate (0.59 ml; 6.0 mmol) in tetrahydrofuran (6 ml) under nitrogen at −76° C. was added dropwise a 0.5 M solution of 4-chlorophenethylmagnesium bromide in tetrahydrofuran (10 ml; 5.0 mmol). The suspension obtained was stirred at −50° C. during 5 h. The mixture was poured in ammonium chloride sat. solution (20 ml) and extracted with dichloromethane (3×20 ml). Combined organics were dried over sodium sulfate and evaporated. The crude obtained was subject flash chromatography (eluant: c-hexane/ethyl acetate 95:5) to afford 0.13 g (18% of theory) of 4-(4-chloro-phenyl)-1-fluoro-butan-2-one as a yellow oil.
Reaction SMILES: [CH:1]1([S:6]([C:8]2[CH:9]=[C:10]([CH:42]=[CH:43][CH:44]=2)[CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]3[CH2:28][C@@H:27]([C:29]4[CH:40]=[CH:39][C:32]5[O:33][C:34]([CH3:38])([CH3:37])[O:35][CH2:36][C:31]=5[CH:30]=4)[O:26][C:25]3=[O:41])=[CH:18][CH:17]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:50]>C(Cl)Cl>[CH:1]1([S:6]([C:8]2[CH:9]=[C:10]([CH:42]=[CH:43][CH:44]=2)[CH2:11][O:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][N:24]3[CH2:28][C@@H:27]([C:29]4[CH:40]=[CH:39][C:32]5[O:33][C:34]([CH3:38])([CH3:37])[O:35][CH2:36][C:31]=5[CH:30]=4)[O:26][C:25]3=[O:41])=[CH:20][CH:21]=2)(=[O:50])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(S(=O)C6CCCC6)c5)cc4)C(=O)O3)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(S(=O)(=O)C6CCCC6)c5)cc4)C(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 121.9 %

Procedure:
A solution of (5R)-3-{2-[4-(2-{[3-(cyclopentylsulfinyl)benzyl]oxy}ethoxy)phenyl]ethyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (56 mg) in CH2Cl2 (2 ml) was cooled in an ice bath under a nitrogen atmosphere. To this was added 3-chloroperoxybenzoic acid (30 mg) and the resulting solution was allowed to warm to room temperature and stirred for 2 h. The solution was then washed with sodium sulphite, to remove any excess peroxide, and water. The combined organic layers were then dried (MgSO4) and concentrated in vacuo to give the title compound (70 mg). LCMS RT=3.70 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(OCC)C>CO>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)([O-:31])(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
Clopidogrel base was dissolved in methanol. p-Toluene sulphonic acid was added to the solution at 20° C. The reaction mixture was heated to reflux temperature for 2 hrs. The solution was cooled to room temperature and was added drop-wise to diethyl ether. The suspension was stirred at RT. The solid was filtered and dried at about 50° C. in a vacuum oven to give Clopidogrel tosylate similar to that obtained above.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].O1CCCC1.[CH:18]([CH:20]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:21][CH:22]([CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[CH:31]=[C:30]2[CH2:37][CH2:38][CH2:39][O:40][CH3:41])[CH:23]([CH3:25])[CH3:24])=[O:19]>CS(C)=O>[CH3:41][O:40][CH2:39][CH2:38][CH2:37][C:30]1[C:29]2[C:33](=[CH:34][CH:35]=[C:27]([CH2:26][CH:22]([CH:23]([CH3:24])[CH3:25])[CH2:21][CH:20]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH:18]3[CH2:7][O:19]3)[CH:28]=2)[N:32]([CH3:36])[CH:31]=1
Reactant: CC(C)(C)[O-]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(C=O)NC(=O)OC(C)(C)C)C(C)C)cc12
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Temperature: 0 °C

Procedure:
1.29 g of trimethylsulphoxonium iodide and 0.66 g of potassium tert-butoxide are stirred under high vacuum overnight, admixed with 8 ml of tetrahydrofuran and subsequently cooled to 0° C. A solution of 1.01 g of tert-butyl {1-formyl-3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methylpentyl}carbamate in 8 ml of dimethyl sulphoxide is added dropwise. On completion of reaction (TLC monitoring), the reaction mixture is partitioned between water and tert-butyl methyl ether, and the aqueous phase is extracted once more with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water (3×) and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].C(N(CC)CC)C.CN([C:21]([O:25][N:26]1N=NC2C=CC=N[C:27]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC>CC#N.CCOC(C)=O>[F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4]([N:26]([O:25][CH3:21])[CH3:27])=[O:5]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C(=O)O)C(F)(F)F
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)C(C)(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a clear solution of 3,3,3-trifluoro-2,2-dimethylpropionic acid (5.000 g, 32.0 mmol) in MeCN (22.88 ml) was added triethylamine (9.82 ml, 70.5 mmol) followed by HATU (12.79 g, 33.6 mmol) and the mixture was stirred at room temperature. After 15 min, to the dark clear mixture was added N,O-dimethylhydroxylamine hydrochloride (3.44 g, 35.2 mmol) and the mixture was stirred at room temperature. After 18 h, the reaction mixture was diluted with EtOAc (100 mL) and washed with 1 N HCl (2×100 mL), and sat. NaCl (5×100 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a orange solid. The orange solid was absorbed onto a plug of silica gel and purified by silica gel chromatography eluting with a gradient of 0% to 25% EtOAc in heptane to provide 3,3,3-trifluoro-N-methoxy-N,2,2-trimethylpropanamide (5.0503 g, 25.4 mmol, 79% yield) as yellow liquid. 1H NMR (300 MHz, CDCl3) δ 3.71 (3H, s), 3.22 (3H, s), 1.51 (6H, d, J=0.7 Hz); LCMS (ESI) m/z 200.1 (M+H)+.