Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22](O)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29][CH2:28]1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:32]3)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC[C@H]1CC[C@H](N)CC1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Product: CC(C)(C)OC(=O)CC[C@H]1CC[C@H](NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)CC1

Procedure:
In the same manner as in Example 15 (3), 5-(benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (3.98 g, 11.8 mmol) and t-butyl trans-3-(4-aminocyclohexyl)propionate (2.70 g, 11.8 mmol) were condensed to give 5.04 g of t-butyl trans-3-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino]cyclohexyl]propionate as a colorless solid (78%). In the same manner as in Example 85, this solid (4.90 g, 8.95 mmol) was subjected to hydrogen reduction to give 3.52 g of compound (161) as a colorless solid (95%), which was treated with methanesulfonic acid (0.82 g, 8.52 mmol) in tetrahydrofuran solvent to give 3.82 g of methanesulfonate of compound (161) as a colorless solid (88%).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[CH3:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([O:26][C@H:27]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([C:39]([O:41][CH3:42])=[O:40])[CH2:28]3)=[CH:20][C:21](=[O:25])[NH:22]2)=[CH:17][C:16]=1[CH:43]=[CH2:44].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:6]([O:25][C:21]1[CH:20]=[C:19]([O:26][C@H:27]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:29]([C:39]([O:41][CH3:42])=[O:40])[CH2:28]2)[C:18]2[C:23](=[CH:24][C:15]([O:14][CH3:13])=[C:16]([CH:43]=[CH2:44])[CH:17]=2)[N:22]=1)[CH3:7]
Reactant: CC[O+](CC)CC
Reactant: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc(=O)[nH]c2cc1OC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1cc2c(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc(OCC)nc2cc1OC

Procedure:
Triethyloxonium tetrafluoroborate (1.28 g, 6.75 mmol) was added to a solution of the product from step 3 (2.0 g, 4.5 mmol) in DCM (41 mL). DIEA (0.236 mL, 1.35 mmol) was then added after 15 min. After 45 additional min, the reaction mixture was worked up with NaHCO3 and DCM. The organic layer was then dried over MgSO4, and the solvent was removed in vacuo. The crude material was then purified on silica (gradient elution, 10-60% EtOAc/hexanes) to yield the title compound as an oil. LRMS (M+H)+=473.4.
Reaction SMILES: C(OC([CH:8]1[S:20][C:11]23[CH:19]=[CH:18][CH:17]=[CH:16][C:12]2=[N:13][CH2:14][CH2:15][CH:10]3[CH:9]1[C:21]([OH:23])=O)=O)(C)(C)C.Cl.CN.[CH2:27]([N:29](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH3:27][NH:29][C:21]([CH:9]1[CH:10]2[C:11]3([CH:19]=[CH:18][CH:17]=[CH:16][C:12]3=[N:13][CH2:14][CH2:15]2)[S:20][CH2:8]1)=[O:23]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)C1SC23C=CC=CC2=NCCC3C1C(=O)O
Agent: CN
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)C1CSC23C=CC=CC2=NCCC13
Temperature: 50 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
In 5 ml of dimethylformamide were dissolved 0.32 g of 2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid, 0.08 g of methylamine.hydrochloride, and 0.17 ml of triethylamine, and after adding dropwise thereto 5 ml of a dimethylformamide solution of 0.33 g of diphenylphosphorylazide under ice-cooling and further adding dropwise thereto 2 ml of a dimethylformamide solution of 0.17 ml of triethylamine, the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added 50 ml of ethyl acetate and the mixture was washed thrice with 10 ml of an aqueous 5% citric acid solution, thrice with an aqueous 5% sodium hydrogencarbonate solution and then twice with a saturated sodium chloride solution, and thereafter dried with sodium sulfate. After filtering away sodium sulfate, 5 ml of a mixture of 1N hydrochloric acid in ethyl acetate were added to the filtrate and the mixture was heated to 50° C. for one hour. Then, the reaction mixture was allowed to stand overnight in a refrigerator and crystals thus deposited were collected by filtration to provide 0.23 g (yield of 65%) of N-methyl-1,2,3,4-tetrahydrobenzo[b]thieno[2,3-c]pyridine-3-carboamide. (See Table 11, Table 12).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)=[N:19][N:20]=1)(=[O:37])[CH3:36]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (200 mg, 0.508 mmol), pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Acetyl chloride (0.18 mL, 2.54 mmol) was then added dropwise and the mixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.052 g, 24%). 1H NMR (Acetone d6, 400 MHz) δ 8.23 (d, J=9 Hz, 2 H), 8.02 (d, J=9 Hz, 2 H), 7.54 (d, J=9 Hz, 1 H), 7.01 (d, J=9 Hz, 1 H), 5.74 (d, J=9 Hz, 1 H), 5.68-5.62 (m, 1H), (dd, J=9 and 5 Hz, 1H), 2.37 (s, 3 H), 2.04 (s, 3H), 1.47 (d, J=6 Hz, 3 H).
Reaction SMILES: Cl.[NH2:2]O.[CH:4]([C:6]1[S:10][CH:9]=[C:8]([N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=1)=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:4]([C:6]1[S:10][CH:9]=[C:8]([N:11]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=1)#[N:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C=O)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1csc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
Hydroxylamine hydrochloride (0.766 g, 11.03 mmol) was added to a solution of compound 11 (1.888 g, 5.51 mmol) in pyridine (5.5 mL). The solution was heated to 90 degrees for 10 minutes and then cooled to room temperature. Acetic anhydride (3.23 mL, 34.2 mmol) was then added to the solution. It was then stirred at room temperature for 30 minutes and then at 80 degrees for 1 hour. The reaction was concentrated to half the volume under reduced pressure and then diluted with 300 mL of water, extracted into ethyl acetate (3×), washed with brine, dried over Na2SO4, filtered and then concentrated. The resulting yellow oil was then purified by silica gel chromatography through a 40M Biotage column with gradient of 12-24% ethyl acetate in hexanes to give compound 12 (1.39 g, 74%) as a white crusty solid. LRMS (ESI): calc. 339.13; found 338.1 (M-H)−.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[N:23][N:24]([CH:26]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]3)[CH:25]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1>CO.CCOC(C)=O>[CH3:3][C:4]1[CH:5]=[C:6]([C:21]2[CH:22]=[N:23][N:24]([C@@H:26]3[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]3)[CH:25]=2)[CH:7]=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3CCC(=O)CC3)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn([C@H]3CC[C@@H](O)CC3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (3.39 mg, 0.09 mmol) was added to 4-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]cyclohexanone (24.8 mg, 0.06 mmol) dissolved in methanol (0.5 mL). The reaction mixture was stirred at room temperature for one hour. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (45 to 80% ACN/Water with 0.1% TFA modifier). The free base was liberated using PL-HCO3 cartridges (Stratospheres™, 0.9 mmol) and lyophilized to afford cis-4-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]cyclohexanol. MS ESI calcd. for C21H23F3N5O [M+F]+ 418. found 418. 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.80 (d, J=4.7 Hz, 1H), 8.06 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 7.38 (s, 1H), 7.25 (d, J=4.7 Hz, 1H), 7.05 (s, 1H), 4.67 (s, 1H), 4.19-4.07 (m, 1H), 3.50-3.41 (m, 1H), 2.27 (s, 3H), 2.02-1.99 (m, 2H), 1.94-1.85 (m, 2H), 1.78 (q, J=11.7 Hz, 2H), 1.35 (q, J=11.7 Hz, 2H).
Reaction SMILES: ClC1C=C(C=CC=1Cl)C(C1C=CC=CC=1)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=O)[CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24].[CH3:36][NH2:37]>[Ti](Cl)(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[N:37][CH3:36])[CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CN
Reactant: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C(c1ccccc1)c1ccc(Cl)c(Cl)c1
Product: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
There is described in U.S. Pat. Nos. 4,536,518 and 4,556,676 to W. M. Welch, Jr. et al., as well as in the paper of W. M. Welch, Jr. et al., appearing in the Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 (1984), a multi-step method for synthesizing pure racemic cis-(1S) (4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro -1-naphthaleneamine, starting from the readily available 3,4-dichlorobenzophenone and proceeding via the known racemic or (±)-4-(3,4-dichlorophenyl)-4-butanoic acid and then to (±) -4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone (see also U.S. Pat. Nos. 4,777,288 and 4,839,104 to G. J. Quallich et al. for improved methods leading to these intermediates), with the latter ketone then being condensed with methylamine in the presence of titanium tetrachloride to yield N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine. In the last step of the overall synthesis, the aforementioned imine is then readily reduced by means of catalytic hydrogenation or by the use of a metal hydride complex to yield N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine, which is actually a mixture of the cis- and trans-isomers in the form of a racemate. The aforesaid isomeric mixture is then separated into its component parts by conventional means, e.g., by fractional crystallization of the hydrochloride salts or by column chromatography on silica gel of the corresponding free base. Resolution of the separated cis-racemate free base compound while in solution with an optically-active selective precipitant acid, such as D-(-)-mandelic acid, in a classical manner then ultimately affords the desired cis-(1S)(4S)-enantiomer (sertraline).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N+:12]([CH:15]=[C:16](SC)[S:17]([CH3:19])=O)([O-:14])=[O:13].C[O-].[Na+]>C(O)C.CO>[CH3:19][S:17][C:16]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:15]=1[N+:12]([O-:14])=[O:13]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: NCC(=O)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CSc1[nH]cc(-c2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
α-Aminoacetophenone hydrochloride (6.87 g, 0.040 mol) was mixed with 1-nitro-2-methylthio-2-methylsulphinylethylene (7.25 g, 0.040 mol) in 300 ml dry ethanol and warmed at 60°. Sodium methoxide (from 0.92 g sodium, 0.080 g atom) in methanol (25 ml) was added dropwise, with stirring, over about 10 minutes. After addition, the mixture was stirred at 60° for one hour, and then filtered to give 2-methylthio-3-nitro-4-phenylpyrrole 5.66 g, m.p. 259°-261° dec.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[N:37][CH:36]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: FC(F)(F)c1cccc(Oc2ccccc2Br)n1
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3cccc(C(F)(F)F)n3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)-6-(trifluoromethyl)pyridine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H14F4N4O, 426.11; m/z found, 427.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 2H), 8.04 (m, 1H), 7.59-7.48 (m, 4H), 7.41 (m, 1H), 7.35-7.24 (m, 4H), 6.89 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[CH2:16][C:15]1([CH3:26])[CH3:25])=[O:12])=[CH:5]2.[CH3:27][O:28][CH2:29][CH:30]=O>C1COCC1.C(Cl)Cl>[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][C:15]([CH3:26])([CH3:25])[C@H:14]2[NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([NH:1][CH2:30][CH2:29][O:28][CH3:27])=[CH:10][CH:9]=3)=[O:12])=[CH:18][CH:19]=1)#[N:24]
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc(N)ccc2[nH]1
Reactant: COCC=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCNc1ccc2[nH]c(C(=O)N[C@H]3c4cc(C#N)ccc4CC3(C)C)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.1 %

Procedure:
To a solution of (R)-5-amino-N-(6-cyano-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-1H-indole-2-carboxamide (66.0 mg, 0.192 mmol) (prepared as described in Example 9) and methoxyacetaldehyde (containing 13% water, 18.0 mg, 0.211 mmol) in 1:1 THF/CH2Cl2 (4 mL) was added NaB(Oac)3H at rt in one portion. The mixture was stirred at rt for 4 hr and the reaction was quenched with saturated with NaHCO3 solution. The mixture was extracted with ethyl acetate (3×20 mL). The combined extract was washed with brine and dried over anhydrous MgSO4. The desired product (27.1 mg, 35% yield) was isolated as a pale yellow solid by prep. HPLC. LCMS (M+H)+=345.38. 1H NMR (500 MHz, DMSO-d6) δ: 11.1 (s, 1H), 8.34 (d, J=9.3 Hz, 1H, 7.69 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.03 (s, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.61 (s, 1H), 5.36 (d, J=9.3 Hz, 1H), 5.00 (t, J=5.8 Hz, 1H), 3.51 (t, J=6.0 Hz, 2H), 3.28 (s, 3H), 3.16 (dt, J=11.5, 6.0 Hz, 2H), 2.86 (dd, J=23.0, 16.5 Hz, 2H), 1.20 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]([NH:24][CH3:25])=[O:23])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>C(#N)C>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:1][C:2]2[C:3]([C:22]([NH:24][CH3:25])=[O:23])=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][C@@H:17]4[CH2:21][CH2:20][N:19]([CH2:37][C:36]5[CH:39]=[CH:40][C:33]([Cl:32])=[CH:34][CH:35]=5)[CH2:18]4)=[O:15])[CH:9]=3)=[CH:6][N:7]=2)=[CH:35][CH:34]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CNC(=O)c1nc(-c2cccc(C(=O)N[C@@H]3CCNC3)c2)cnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1nc(-c2cccc(C(=O)N[C@@H]3CCN(Cc4ccc(Cl)cc4)C3)c2)cnc1NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.3 %

Procedure:
To a solution of 3-amino-N-methyl-6-(3-{[(3R)-pyrrolidin-3-ylamino]carbonyl}phenyl)pyrazine-2-carboxamide (34.0 mg, 0.1 mmol) in acetonitrile was added K2CO3 (27.6 mg, 0.2 mmol) followed by 4-chlorobenzyl bromide (30.7 mg, 0.15 mmol). The mixture was allowed to stir at room temperature over 12 h and filtered. The acetonitrile solution was evaporated to dryness, the residue was chromatographed on silica gel using ethyl acetate/hexane 4:1 v/v and trituration of the resulting solid with hexane afforded 3-{[(4-chlorophenyl)methyl]amino}-6-{3-[({(3R)-1-[(4-chlorophenyl) methyl]pyrrolidin-3-yl}amino)carbonyl]phenyl}-N-methylpyrazine-2-carboxamide (28 mg, 47.6%yield): 1H NMR (400 MHz; DMSO-D6): 8.9 (s, 1H); 8.85 (m, 1H); 8.75 (m, 1H); 8.38 (m, 2H); 7.78-7.5 (m, 1H); 4.63 (m, 5H); 3.9 (m, 1H); 3.6 (m, 2H); 3.4 (m, 1H); 2.85 (d, 3H); 2.5 (m, 1H); 2.2 (m, 1H); MS (EI) for C31H30N6O2Cl2: 589 (MH+)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:18]([O:23][CH3:24])(=[O:22])[CH:19]([CH3:21])[OH:20]>O1CCCC1>[CH2:3]([O:10][C:11]1[C:12]([O:20][CH:19]([C:18]([O:23][CH3:24])=[O:22])[CH3:21])=[N:13][CH:14]=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C(C)O
Reactant: Clc1ncncc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)Oc1ncncc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride is added to a mixture of 5-benzyloxy-4-chloropyrimidine, methyl lactate and tetrahydrofuran at 0° C. The mixture is stirred at room temperature for 1 hour, then, stirred for 30 minutes at 90° C. The reaction solution is cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer is washed with dilute hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 5-benzyloxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine.
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH:9]=1)[OH:8].CN(C)C=O.Cl[CH2:17][CH:18]([O:21][CH3:22])[O:19][CH3:20]>O>[CH3:20][O:19][CH:18]([O:21][CH3:22])[CH2:17][O:8][C:7]1[CH:9]=[C:3]([CH3:2])[CH:4]=[C:5]([OH:10])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: COC(CCl)OC
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1cc(C)cc(O)c1)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The monosodium salt of 5-methylresorcinol prepared in Example 4 and dimethyl formamide (200 ml) were charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. 1-Chloro-2,2-dimethoxyethane (6.25 grams) was added, and the mixture was heated at 85° to 90° C. and stirred for a period of about 221/2 hours. After this time the reaction mixture was cooled to room temperature and was added to 1200 ml of water. The resulting mixture was carefully neutralized and extracted with chloroform. The organic phase was then separated from the aqueous phase and stripped of solvent, leaving a liquid residue. The residue was distilled under reduced pressure to yield a yellow viscous liquid which solidified upon cooling to -10° C. This product was then recrystallized from a methanol-water mixture, was washed with boiling water and dried to yield the desired product 3-(2,2-dimethoxyethoxy)-5-hydroxytoluene as a white solid melting at 73° to 75° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].[OH2:23].[OH2:24].O.O.O.O.C(OO)(=O)C1C(=CC=CC=1)C(O)=O.O.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>ClCCl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([F:10])[C:7]=1[S:8]([CH3:9])(=[O:24])=[O:23]
Reactant: CSc1c(F)cc(C2=C(c3ccccc3)C(=O)OC2)cc1F
Reactant: O
Agent: O=C(O)c1ccccc1C(=O)OO
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1c(F)cc(C2=C(c3ccccc3)C(=O)OC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
Unpurified 4-[3,5-difluoro-4-(methylthio)-phenyl]-3-phenylfuran-2(5H)-one (8.9 g, 27 mmol) and magnesum monoperoxyphthalate hexahydrate (17.2 g, 27 mmol) were combined in a mixture of dichloromethane (200 mL) and methanol (60 mL), and stirred overnight at room temperature. The slurry was poured into water, and extracted with dichloromethane (1×200 mL, 2×50 mL). The combined extracts were washed with water and dilute sodium bicarbonate, and the aqueous sodium bicarbonate wash extracted with dichloromethane (50 mL). The combined extracts were dried with magnesium sulfate, filtered and concentrated. The residue was treated again with magnesium monoperoxyphthalate hexahydrate (8.5 g., 25 mmol), in a mixture of dichloromethane (120 mL) and methanol (30 mL), stirring overnight at room temperature. The reaction mixture was poured into water, and extracted with dichloromethane (2×200 mL). The combined extracts were washed with dilute ammonium chloride (100 mL), and dilute sodium chloride (100 mL), dried with magnesium sulfate, and concentrated to give 6.7 g yellow solids. The crude product was dissolved in dichloromethane (20 mL), and crystallized by adding a mixture of 40% ethyl acetate/60% hexanes (15 mL). The product was filtered, and the filtrate purified by silica gel chromatography using 40% ethyl acetate/60% hexanes to give a total of 5.3 g yellow solids (56%). The 4-[3,5-difluoro-4-(methylsulfonyl)phenyl]-3-phenylfuran-2(5H)-one was recrystallized from ethyl acetate to give white solids. MP 203.5-203.8° C. 1H NMR (CDCl3/400 MHz) 7.35-7.44 (m, 5H), 6.97 (d, 2H, J=9.0), 5.11 (s, 2H), 3.29 (s, 3H). ESHRMS m/z 351.0536 (M+H+, Calcd 351.0502). Anal. Calcd for C17H12F2O4S: C, 58.28; H, 3.45. Found: C, 57.69; H, 3.72.
Reaction SMILES: O1CCNC1=O.C[Si](C)(C)Cl.[C:12]1([CH:18]2[O:22][C:21](=[O:23])[NH:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:24]([Si:26]([CH2:30][CH3:31])([CH2:28][CH3:29])Cl)[CH3:25]>>[C:12]1([CH:18]2[O:22][C:21](=[O:23])[N:20]([Si:26]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH2:24][CH3:25])[CH2:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=C1NCC(c2ccccc2)O1
Agent: C[Si](C)(C)Cl
Agent: O=C1NCCO1
Product: CC[Si](CC)(CC)N1CC(c2ccccc2)OC1=O

Procedure:
This example is performed in a similar way to example 1, with the 2-oxazolidinone and the trimethylchlorosilane being replaced by 5-phenyl-2-oxazolidinone (57.11 g; 0.35 mol) and triethylchlorosilane (63.3 g; 0.42 mol) respectively. Once the solvent has been evaporated off, the result is crude 5-phenyl-3-triethylsilyl-2-oxazolidinone with a virtually quantitative yield. By methanolysis 5-phenyl-2-oxazolidinone is obtained. Calculated: 69.33%; found: 69.05%.