Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[N:8]=[C:7]([C:22]#[N:23])[C:6]=1[C:24]#[C:25][Si](C)(C)C)(=[O:3])[CH3:2].C(=O)([O-])[O-].O.CCOCC>CO>[C:1]([NH:4][C:5]1[N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:19])([F:20])[F:18])=[CH:12][C:11]=2[Cl:21])[N:8]=[C:7]([C:22]#[N:23])[C:6]=1[C:24]#[CH:25])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C#C[Si](C)(C)C)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1NC(C)=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-acetamido-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)4-trimethylsilylethynylpyrazole (20 mg, the compound of Example B2) in methanol (1 ml) was added potassiun carbonate (20 mg). The reaction mixture was stirred at room temperature for 40 minutes and then poured into water (20 ml) and ether (20 ml). The organic layer was separated, dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica gel eluted with ether to provide the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([CH2:15]O)[CH:12]=[C:11]([CH3:17])[N:10]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>ClCCl>[Cl:20][CH2:15][C:13]1[CH:12]=[C:11]([CH3:17])[N:10]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:14]=1
Reactant: Cc1cc(CO)nc(Nc2ccc(F)cc2)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(CCl)nc(Nc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At 0° C., 225 mg (0.96 mmol) of the compound from example 6A and 137 mg (1.16 mmol) of thionyl chloride are initially charged in 10 ml of dichloromethane and, after warming to RT, stirred at this temperature for 24 h. The solvent is removed on a rotary evaporator and the product that remains is directly reacted further.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]([CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:8])[CH3:2].Br[CH2:19][CH2:20][CH2:21][Cl:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]([CH3:16])[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(C)C(=O)c1ccc(OCCCCl)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 58.6 %

Procedure:
A mixture of 4-(4-hydroxyphenyl)-3-methyl-4-oxo-butyric acid ethyl ester (12.5 g, 52.9 mmol), 1-bromo-3-chloropropane (11.3 mL, 114.6 mmol) and K2CO3 (21.9 g, 159 mmol) in acetone (200 mL) was stirred at 60° C. for 15 h. The reaction was cooled to RT and filtered over celite and the filtrate was evaporated at reduced pressure to give a crude residue. The crude residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution and the aqueous layer was extracted twice with methylene chloride. The combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude product. The crude product was purified by ISCO (330 g) chromatography using 15% EtOAc in hexane to produce 4-[4-(3-chloro-propoxy)-phenyl]-3-methyl-4-oxo-butyric acid ethyl ester (9.7 g, 56%), MS m/z 267 (M−45)
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:25]=[CH:24][C:22]([NH:23][C:34]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=4)=[O:35])=[CH:21][CH:20]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CCOCC4)n3)cc2)cc1

Procedure:
Starting from 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (0.140 g 0.40 mmoles) and 4-methylphenyl isocyanate (74 mg, 0.56 mmoles), the title compound was isolated as a white solid. Yield; 65 mg (33%) (M+H)=476.4
Reaction SMILES: C([O-])(O)=O.[Na+].[CH:6]1([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]([NH:23][C:24]2[S:25][C:26]([CH:29]=O)=[CH:27][N:28]=2)=[O:22])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.[NH2:32][OH:33]>C1COCC1>[CH:6]1([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]([NH:23][C:24]2[S:25][C:26]([CH:29]=[N:32][OH:33])=[CH:27][N:28]=2)=[O:22])=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(C=O)s2)c(C(=O)C2CCCC2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2ncc(C=NO)s2)c(C(=O)C2CCCC2)c1
Temperature: 60 °C
Yield: 75.2 %

Procedure:
To a mixture of 2M aq NaHCO3 (5 mL) and 1-(2-cyclo-pentanecarbonyl-4-methylphenyl)-3-(5-formyl-thiazol-2-yl)-urea (72 mg, 0.2 mmol) in THF (5 mL) was added hydroxylamine hydrochloride (200 mg) at room temperature with stirring. The resulting mixture was heated at 60° C. for 12 h. The reaction mixture was cooled and extracted with ethyl acetate. The organic layer was washed (brine), dried (Na2SO4) and concentrated to obtain 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(hydroxyimino-methyl)-thiazol-2-yl]-urea (56 mg, 76%) as a mixture of syn and anti-isomers.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:13][CH:14]([OH:29])[CH2:15][O:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[C:20]([C:26]([NH2:28])=O)[NH:21]4)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.N1C=CC=CC=1>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:13][CH:14]([OH:29])[CH2:15][O:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[C:20]([C:26]#[N:28])[NH:21]4)[CH2:9]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)c1cc2c(OCC(O)COC3CN(C(c4ccccc4)c4ccccc4)C3)cccc2[nH]1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: N#Cc1cc2c(OCC(O)COC3CN(C(c4ccccc4)c4ccccc4)C3)cccc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.0 g of 4-(3-(1-diphenylmethylazetidin-3-oxy)-2-hydroxypropoxy)-1H-indole-2-carboxamide are dissolved in a mixture of 112 ml of dioxane and 10 g of pyridine and 10 ml of trifluoroacetic anhydride in 10 ml of dioxane are added at 10° C. After standing for two hours at room temperature, the mixture is stirred into ice water. The mixture is extracted using methylene chloride, washed first with dilute NaOH, then with water, and the organic phase is dried over sodium sulphate and concentrated. The residue is purified by column chromatography on silica gel (eluent: chloroform).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].ClCCl.[CH2:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH:29]=[CH:28]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:19]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH:29]=[CH:28]2)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: O=c1ccc2cc(OCCCCNCc3ccccc3)ccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(OCCCCN(Cc3ccccc3)S(=O)(=O)CCCCl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6.6 ml of 3-chloropropanesulfonyl chloride was dropwise added, at 0° C., to a dichloromethane solution containing 8 g of 6-(4-benzylaminobutoxy)carbostyril and 7.6 ml of triethylamine. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with 10% hydrochloric acid and water in this order and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was dissolved in 30 ml of dioxane. To the solution was added 10 ml of a 10% potassium hydroxide solution, followed by stirring at room temperature for 30 minutes. The reaction mixture was neutralized with 10% hydrochloric acid, followed by extraction with chloroform. The extract was dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was crystallized from diethyl ether to obtain 7.3 g of 6-{4-[N-(3-chloropropylsulfonyl)-N-benzylamino]butoxy}carbostyril.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:9]=1.ClCC(O)[C@@H:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])(C)C)[CH3:30]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:30][C@H:29]1[C@H:34]([CH2:37][N:12]2[CH:11]=[C:10]([C:8]3[CH:7]=[C:6]([NH:15][C:16]4[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=4)[CH:5]=[C:4]([CH3:3])[CH:9]=3)[CH:14]=[N:13]2)[O:33][C:32](=[O:38])[NH:31]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(O)CCl
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C[C@@H]3OC(=O)N[C@H]3C)c2)c1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 28 mg, 0.71 mmol) was added to a mixture of N-(3-methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (150 mg, 0.47 mmol) in DMF (3 mL), and the mixture was stirred for 5 minutes. A mixture of tert-butyl ((2S)-4-chloro-3-hydroxybutan-2-yl)carbamate (110 mg, 0.49 mmol) in DMF (2 mL) was added and the mixture was heated to 40° C. for 4 hours. The mixture was then allowed to cool to room temperature and diluted with ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel. The purified diasteromeric mixture was separated by chiral SFC (Chiralpak ID, 21×250 (mm), 25% CO2 with methanol as the diluent) to afford (4S,5S)-4-methyl-5-((4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)methyl)oxazolidin-2-one (Isomer 1, early eluting): MS ESI calc'd. for C20H20F3N6O2 [M+H]+ 433. found 433. 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.80 (d, J=4.3 Hz, 1H), 8.06 (s, 1H), 7.85-7.76 (m, 2H), 7.73 (s, 1H), 7.35 (s, 1H), 7.24 (d, J=4.6 Hz, 1H), 7.06 (s, 1H), 4.47-4.35 (m, 3H), 3.75-3.59 (m, 1H), 2.29 (s, 3H), 1.10 (d, J=5.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].[F:30][C:31]1[CH:44]=[CH:43][C:34]([CH2:35][NH:36][CH2:37][CH:38]([O:41][CH3:42])[O:39][CH3:40])=[CH:33][CH:32]=1>O1CCCC1>[CH2:11]([NH:10][C:8]([C:4]1[S:3][C:2]([NH:1][C:18]([N:36]([CH2:37][CH:38]([O:39][CH3:40])[O:41][CH3:42])[CH2:35][C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:44][CH:43]=2)=[O:19])=[N:6][C:5]=1[CH3:7])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(CNCc1ccc(F)cc1)OC
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(CN(Cc1ccc(F)cc1)C(=O)Nc1nc(C)c(C(=O)NCc2ccccc2)s1)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (0.31 g, 1.25 mmol) in tetrahydrofuran (20 mL) was added 1,1′-carbonyldiimidazole (0.24 g, 1.50 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 6 hours, and N-(4-fluorobenzyl)-2,2-dimethoxyethanamine (0.35 g, 1.65 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 hour. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound in 77% yield (0.47 g): MS (ES+) m/z 487.4 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[C:4]([F:11])[C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[C:4]([F:11])=[CH:5][C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)cc2sccc2c1F
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc2sccc2c(F)c1CBr

Procedure:
To a solution of 0.48 g of 4,6-difluoro-5-methylbenzo[b]thiophene in 5 ml of carbon tetrachloride are added 0.92 a of N-bromosuccinimide and 0.01 g of 2,2'-azobisisobutylonitrile, and the resulting mixture is refluxed for 16 hours. After cooling, insolubles are removed from the thus cooled mixture by filtration, and the filtrate obtained is concentrated under reduced pressure. The residue obtained is purified by a column chromatography [eluent:hexane], to obtain 0.18 g of colorless, solid 5-bromomethyl-4,6-difluorobenzo[b]thiophene.
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)Cl.[O:6]1[C:10]2C=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7]1>C(Cl)Cl.CCOCC>[O:2]1[C:3]2[CH:7]=[CH:8][C:9]([CH:10]=[O:6])=[CH:14][C:13]=2[CH2:12][CH2:1]1
Reactant: COC(Cl)Cl
Reactant: c1ccc2c(c1)CCO2
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
To a stirred solution of α,α-dichloromethyl methyl ether (2.15 g, 19 mmol, 1.35 eq) in methylene chloride (30 mL) at −40° C. was added successively stannic chloride (1.65 g, 17 mmol, 1.2 eq) and 15 minutes later, a solution of 2,3-dihydrobenzofuran (1.68 g, 14 mmol) in CH2Cl2 (5 mL) maintaining the temperature at or below −35° C. The mixture was warmed to 0° C., stirred 1 hour, then poured into ice-water, and stirred a further 30 minutes. The mixture was diluted with ether, and the phases separated. The organic phase was concentrated in vacuo, and the residue purified by vacuum distillation to yield the title compound (1.25 g, 60%) as a colorless liquid. b.p. 119-121° C. at 0.3 mm Hg.
Reaction SMILES: [C:1]([SH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH2:12]>C(Cl)(Cl)(Cl)Cl>[C:1]([S:9][C:11]([CH3:12])([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(S)c1ccccc1
Reactant: C=C(C)CC(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)CC(C)(C)SC(=S)c1ccccc1
Temperature: 70 °C
Yield: 31.7 %

Procedure:
A mixture of dithiobenzoic acid (5 g), 2,4,4-trimethylpentene (7.3 g) and carbon tetrachloride (25 mL) was heated at 70° C. for two days. The resultant mixture was reduced to a crude oil. Purification of the residue, by column chromatography (Kieselgel-60, 70-230 mesh, petroleum spirit 40-60° C. eluent) gave 2,4,4-trimethylpent-2-yl dithiobenzoate (17) (2.74 g, 31.7% yield) as a dark red oil. 1H-nmr (CDCl3) d (ppm): 1.08 (s, 9H, 3×CH3), 1.77 (s, 6H, 2×CH3), 2.26 (s, 2H, CH2), 7.35 (dd, 2H, meta-ArH), 7.49 (dd, 1H, para-ArH) and 7.85 (d, 2H, ortho-ArH). 13C-nmr (CDCl3) d (ppm): 28.3, 31.5, 32.8, 50.5, 57.7, 126.6, 128.1, 131.5 and 147.9. The signal due to C═S (d>220.0 ppm) was beyond the frequency range of the spectrum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH3:14])=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[C:25]=1[CH3:35])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][N:13]([CH3:14])[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[O:33][C:29]2[CH:28]=[C:27]3[C:32]([C:24]([C:22]([NH:21][CH3:20])=[O:23])=[C:25]([CH3:35])[N:26]3[CH3:34])=[CH:31][CH:30]=2)[CH:8]=1)=[O:12]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CN(C)CCN(C)C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N(C)CCN(C)C)sc34)ccc12
Yield: 14.9 %

Procedure:
This material was prepared by the reaction of 7-chloro-N-[2-(dimethylamino)ethyl]-N-methylthieno[3,2-b]pyridine-2-carboxamide 29a (0.167 g, 0.56 mmole) with 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.123 g, 0.56 mmole) and Cs2CO3 (0.182 g, 0.56 mmole) in a manner as previously described for example 1 to give a yellow solid (0.040 g, 13%). 1H NMR (400 MHz, CD3OD) δ8.71 (1H, d, J=6.8 Hz), 8.06 (1H, s), 7.83 (1H, d, J=8.6 Hz), 7.46 (1H, d, J=2.0 Hz), 7.09 (1H, d, J=6.8 Hz), 7.05 (1H, dd, J=2.0, 8.6 Hz), 3.90 (2H, t, J=5.8 Hz), 3.64 (3H, s), 3.42 (2H, t, J=5.8 Hz), 3.23 (6H, s), 2.93 (3H, s), 2.88 (3H, s), 2.58 (3H, s). HRMS (MH+): Calcd: 480.2090; Found: 480.2069.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[C:24](=[O:25])[CH2:23][NH:22][C:21]2=[O:26])=[CH:17][CH:16]=1.[C:29](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:24](=[O:25])[CH2:23][N:22]([CH3:29])[C:21]2=[O:26])=[CH:27][CH:28]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CNC(=O)N1Cc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CC(=O)N(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{4-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]benzyl}imidazolidine-2,4-dione (Example 84, 19 mg, 0.048 mmol) was dissolved in N,N-dimethylformamide and treated with potassium carbonate (8.6 mg, 0.062 mmol, 1.3 equiv) and iodomethane (5.4 μL, 0.086 mmol, 1.8 equiv). After stirring at ambient temperature for 1 hour, additional iodomethane (5.4 μL, 0.086 mmol, 1.8 equiv) and potassium carbonate (8.6 mg, 0.062 mmol, 1.3 equiv) were added and the mixture was placed into a preheated oil bath at 50° C. for 2.5 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate (30 mL) and washed with sodium bicarbonate (2×20 mL, aqueous saturated). The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (85:15 to 36:64; water with 0.05% trifluoroacetic acid:acetonitrile with 0.05% trifluoroacetic acid) to afford the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 7.53 (1H, d, J=6.5 Hz); 7.51 (2H, d, J=6.7 Hz); 7.48 (2H, d, J=2.7 Hz); 7.45 (1H, d, J=2.9 Hz); 4.73 (2H, s); 4.55 (2H, d, J=7.2 Hz); 3.92 (2H, s); 3.02 (3H, s); 1.47-1.39 (1H, m); 0.72-0.67 (2H, m); 0.54-0.50 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 410.1380 [(M+H)+; calculated for C21H21ClN5O2: 410.1378].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.O>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=[CH:10][C:9]1=2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)CCCC2=O
Solvent: O
Solvent: c1ccncc1
Product: O=C1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Temperature: 23 °C
Reaction time: 24 h

Procedure:
To a solution of 0.46 gram (2.85 mmole) 6-amino-3,4-dihydro-2H-naphthalen-1-one in 25 mL pyridine was added 0.605 grams (3.42 mmoles) benzenesulfonyl chloride. The reaction mixture was stirred at 23° C. for 24 hours. The mixture was diluted with 100 mL water and extracted with 200 mL ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to low pressure column chromatography over silica gel 230-400 mesh eluting with 50% ethyl acetate in hexane. The title compound was obtained as a solid, 0.48 gram (56%), m.p. 164-165° C., M−H=300.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:10])=[N:4][C:5](SC)=[N:6][CH:7]=1.O[O:12][S:13]([O-:15])=O.[K+].S(=O)(O)[O-].[Na+].[CH3:22]O>O>[F:1][C:2]1[C:3]([NH2:10])=[N:4][C:5]([S:13]([CH3:22])(=[O:15])=[O:12])=[N:6][CH:7]=1
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CSc1ncc(F)c(N)n1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ncc(F)c(N)n1
Temperature: 10 °C
Yield: 63 %

Procedure:
To a solution of 5-fluoro-2-methylsulfanylpyrimidin-4-ylamine (5.02 g, 31.6 mmol) in methyl alcohol (MeOH; 105 mL) was added dropwise a solution of OXONE™ (Registered trademark of E.I. du Pont de Nemours & Co, Inc.; 42.7 g, 69.4 mmol) in H2O (210 mL) over a 20 minute (min) period at −45° C., and the resulting mixture was slowly warmed to 10° C. over a period of 14 h. The mixture was treated with sodium bisulfite (10 g) and the majority of the MeOH was removed on the rotary evaporator. The aqueous residue was extracted with EtOAc (2×250 mL), and the organic extracts were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to give 5-fluoro-2-methanesulfonylpyrimidin-4-ylamine (3.79 g, 63%) as a white solid: mp 157-159° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, J=3.6 Hz, 1H), 8.11 (s, 2H), 3.27 (s, 3H); CIMS m/z 191 ([M]+).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([CH:30]2[CH2:35][CH2:34][N:33]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:32][CH2:31]2)=[O:29])=[CH:26][CH:27]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and (4-chloro-phenyl)-piperidin-4-yl-methanone via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C24H26ClNO6 [M+H]+: 460.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:23])[CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].C([Li])CCC>C1COCC1.CCCCCC>[ClH:1].[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH:7]([CH:6]1[O:23][CH2:2][CH2:3][NH:4][CH2:5]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1OC(c1ccccc1)C(O)CNCCCl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccccc1OC(c1ccccc1)C1CNCCO1
Product: Cl
Reaction time: 2 h
Yield: 35.8 %

Procedure:
3.35 g of N-(2-chloro-ethyl)-2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propylamine was dissolved in 40 ml of anhydrous THF at -10° C. At this temperature, slow dropwise addition was made to the mixture of 6.07 ml of 15% butyl lithium in hexane. After approximately 2 hours at -10° C. the temperature was slowly allowed to return to room temperature and the whole was stirred for another 20 hours in these conditions, and then concentrated to dryness. The residue was dissolved in ethyl ether, filtered and the filtrate again concentrated to dryness. The residue was converted to the hydrochloride by treatment with gaseous HCl in ethyl ether. After three crystallizations from a mixture of isopropanol and a very small quantity of ethyl ether, there was obtained 1.2 g of 2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine hydrochloride, melting point 112°-170° C. (Yield 35.7%) as a mixture of diastereoisomers. By means of chromatographic separation, as described in Examples 42 and 44, there were obtained two distinct diastereoisomers having melting point of 211°-214° C. and 175°-178° C. respectively.