Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:12][C:13]#[N:14])[CH:7]=[N:8][C:9]=1[CH2:10][CH3:11])[CH:2]=[CH2:3].Cl.N[C:17]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[C:19]([F:25])[C:18]=1[SH:26].C(O)(=O)C.C(=O)(O)[O-].[Na+]>FC(F)(F)CO.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[CH2:1]([C:4]1[CH:5]=[C:6]([CH2:12][C:13]2[S:26][C:18]3[C:19]([F:25])=[CH:20][C:21]([F:24])=[C:22]([F:23])[C:17]=3[N:14]=2)[CH:7]=[N:8][C:9]=1[CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(CC#N)cnc1CC
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: OCC(F)(F)F
Product: C=CCc1cc(Cc2nc3c(F)c(F)cc(F)c3s2)cnc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
In a teflon screwcap glass pressure vessel a solution of 5-allyl-6-ethyl-pyridin-3-yl-acetonitrile (0.70 g, 3.76 mmol), 2-amino-3,4,6-trifluoro-benzenethiol hydrochloride (1.2 g, 5.64 mmol), 2,6-di-tert-butyl-4-methylphenol (BHT) (20 mg) and acetic acid (0.25 mL, 4.51 mmol) in 2,2,2-trifluoroethanol (5 mL, 0.8 M, degassed with nitrogen) is warmed to 90° C. and stirred overnight. The mixture is cooled to room temperature, added to saturated aq sodium bicarbonate (15 mL), extracted with ethyl acetate (2×15 mL) and dried over sodium sulfate. Purification by medium-pressure liquid chromatography (MPLC) on silica (20-40% ethyl acetate in heptane) provided 2-(5-allyl-6-ethyl-pyridin-3-ylmethyl)-4,5,7-trifluoro-benzothiazole as a yellow oil (1.14 g, 87%): Rf 0.38 (30% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 8.45 (d, J=2.1 Hz, 1 H), 7.44 (d, J=2.1 Hz, 1 H), 7.01 (ddd, J1=10.5 Hz, J2=8.7 Hz, J3=5.6 Hz, 1 H), 5.91 (ddt, J1=17.0 Hz, J2=10.3 Hz, J3=6.3 Hz, 1 H), 5.13 (dd, J1=10.3 Hz, J2=1.5 Hz, 1 H), 5.01 (dd, J1=17.0 Hz, J2=1.5 Hz, 1 H), 3.40 (d, J=6.3 Hz, 2 H), 2.83 (q, J=7.5 Hz, 2 H), 1.29 (t, J=7.5 Hz, 3 H); ESI-LCMS m/z calcd for C18H15F3N2S: 348.1; found 349.0 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(N)cc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: COc1ccc(NCc2ccccc2)cc1
Reaction time: 5 h
Yield: 83 %

Procedure:
369 parts of p-anisidine, 162 parts of benzyl alcohol and 15 parts of triphenyl phosphite are first heated to 177° C. At this temperature, the elimination of water commences. The condensation has ended after 5 hours, when the internal temperature is 231° C. 27 parts of water are removed. Excess p-anisidine and excess benzyl alcohol are distilled off under reduced pressure. 265 parts of N-benzyl-4-methoxy-aniline, corresponding to a yield of 83% of theory, distil at 190° C/5 mm Hg.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][O:17][C:18](=[O:39])[CH:19]([C:24]1[CH:29]=[C:28](O)[CH:27]=[C:26]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=1)[CH2:20][C:21]([CH3:23])=[CH2:22].N1C=CC=CC=1>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:39])[CH:19]([C:24]1[CH:29]=[C:28]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:27]=[C:26]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=1)[CH2:20][C:21]([CH3:23])=[CH2:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: C=C(C)CC(C(=O)OC)c1cc(O)cc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 131.7 %

Procedure:
Trifluoromethanesulfonic anhydride (3.3 mL, 10.1 mmol) was added dropwise to a stirred solution of 2-(3-benzyloxy-5-hydroxyphenyl)-4-methyl-pent-4-enoic acid methyl ester (4.5 g, 13.8 mmol) and pyridine (3.0 mL, 38.7 mmol) in DCM (80 mL) at 0° C. then warmed to room temperature. After 1 h, the mixture was washed with 1M HCl (50 mL), dried (MgSO4) and concentrated in vacuo to afford the title product as an orange oil (6.10 g, 96%). 1H-NMR (400 MHz, CDCl3): δ 7.42-7.30 (m, 5H), 6.97 (s, 1H), 6.85 (s, 1H), 6.78 (s, 1H), 5.05 (s, 3H), 4.75 (s, 1H), 4.64 (s, 1H), 3.77 (t, 1H), 3.66 (s, 3H), 2.77 (dd, 1H), 2.40 (dd, 1H), 1.69 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[CH3:12])[C:3]=1[C:4]#[N:5].[S:13](Cl)(=[O:16])(=[O:15])[NH2:14]>CN(C)C(=O)C>[S:13]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]/[CH3:12])[C:3]=1[C:4]#[N:5])(=[O:16])(=[O:15])[NH2:14]
Reactant: C/C=C/c1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: C/C=C/c1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
A solution of (E)-2-amino-6-(prop-1-enyl)benzonitrile (Example 130b) (0.60 g, 3.82 mmol) in N,N-dimethylacetamide (DMA) (15.5 mL), under a nitrogen atmosphere, was treated with sulfamoyl chloride (0.88 g, 7.63 mmol) at room temperature. The obtained mixture was stirred at room temperature for 2 h and the reaction was quenched with water (20 mL). The mixture was extracted with EtOAc (4×80 mL), the combined extract was washed with water (2×20 mL) and brine, and dried with MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to hexanes/EtOAc (1:1) to give 0.83 g (92%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.39 (broad s, 1H), 7.48-7.60 (m, 2H), 7.38-7.43 (m, 1H), 7.21 (broad s, 2H), 6.51-6.65 (m, 2H), 1.88-1.94 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH:28]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:40]([C:37]1[CH:36]=[CH:35][C:34]([CH:28]([O:1][C:2]2[CH:26]=[CH:25][C:5]([C:6]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:39][CH:38]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CCCCCC(Br)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCC(Oc1ccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)cc1)c1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.1 %

Procedure:
A mixture of ethyl 4-[3-(4-hydroxybenzoyl)indol-1-yl]butyrate (176 mg), 1-(1-bromohexyl)-4-isobutylbenzene (223 mg) and potassium carbonate (207 mg) in N,N-dimethylformamide (4 ml) was stirred at room temperature for 6 hours. The reaction mixture was filtered and the filtrate was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic phase was separated, washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (3:1) to give ethyl 4-[3-[4-[1-(4-isobutylphenyl)hexyloxy]benzoyl]indol-1-yl]butyrate (279 mg) as an oil.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:10](=[O:23])[NH:11][C:12](=[O:22])[N:13]([CH:21]=1)[C@@H:14]1[O:20][C@H:17]([CH2:18][OH:19])[CH2:16][CH2:15]1)=O.[O-:26][P:27]([O:30][P:31]([O:34][P:35]([O-])([O-:37])=[O:36])([O-:33])=[O:32])(=[O:29])[O-:28]>>[P:35]([O:19][CH2:18][C@H:17]1[O:20][C@@H:14]([N:13]2[CH:21]=[C:9]([C:8]#[C:7][CH2:6][NH2:5])[C:10](=[O:23])[NH:11][C:12]2=[O:22])[CH2:15][CH2:16]1)([O:34][P:31]([O:30][P:27]([OH:28])([OH:29])=[O:26])([OH:33])=[O:32])(=[O:36])[OH:37]
Reactant: O=C(NCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Reactant: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Product: NCC#Cc1cn([C@H]2CC[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]c1=O

Procedure:
Alkynylamino nucleoside 48 (0.30 mmol) was converted to the corresponding triphosphate and its trifluoroacetyl group was removed following the general procedure given in Example 1E. After addition of the second aliquot of phosphorus oxychloride, phosphorylation was allowed to proceed for a total of 210 min. Assuming an absorption coefficient for the product equal to that of the starting material (13,000), the yield of triphosphate 46, based on its UV absorption at 291.5 nm, was 18%.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>[NH4+].[Cl-].C(Cl)Cl>[Br:1][C:2]1[C:11]([O:12][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc2ccc(Br)c(O)c2n1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1ccc2ccc(Br)c(O[Si](C)(C)C(C)(C)C)c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To the product from Step A (3.0 g, 12.6 mmol) was added imidazole (1.89 g, 27.7 mmol) and CH2Cl2 (40 mL). The solution was cooled to 0° C. and then tert-butylchlorodimethylsilane (2.09 g, 13.9 mmol) was added in one portion. The reaction was gradually warmed to ambient temperature over 1 hour and then stirred overnight. The mixture was diluted with a saturated aqueous NH4Cl solution (25 mL) and CH2Cl2 (40 mL). The layers were mixed and separated and the organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (2 to 20% CH2Cl2/hexanes) to provide 3.36 g (76%) of the desired product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl.[F:30][C:31]1([F:37])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1>>[F:30][C:31]1([F:37])[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:32]1
Reactant: FC1(F)CCCNC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Agent: Cl
Product: Cc1nc2ccc(N3CCCC(F)(F)C3)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Yield: 50 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-methanesulfonyl-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 23] and 3,3-difluoropiperidine hydrochloride according to the procedure of example 51. Yield: 50%; MS: m/z=. 513 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[N:5]=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:25]=2)[C:23]#[N:24])[CH:3]=1.[NH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[N:5]=[C:4]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:25]=3)[C:23]#[N:24])[CH:3]=[C:2]([NH:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1nc(Cl)cc(-c2cncc(C#N)c2)n1)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cncc(C#N)c2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
55 mg of (S)-5-{6-chloro-2-[1-(4-fluorophenyl)ethylamino]pyrimidin-4-yl}nicotinonitrile, 16 mg of 2-aminopyrazine, 15 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 21 mg of sodium t-butoxide and 8 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 2 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 21 mg of the objective compound as white powder.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:9](=[CH:19][N:20]([CH3:22])[CH3:21])[C:10]([O:12][CH3:13])=[O:11])=[O:14])=[CH:15][CH:16]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CC(=O)NCc1ccc(Br)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=CN(C)C)C(=O)NCc1ccc(Br)cc1

Procedure:
The product of Step A (5.01 g, 17.5 mmol) in THF (30 mL) was treated to dimethylformamide dimethylacetal (4.97 mL, 35.0 mmol, 94% assay) at 60° C. for about an hour. The reaction was concentrated and used directly in Step C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:19][CH2:18]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CC1CCC(CCN)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(CCNS(=O)(=O)c2ccc(C#N)cc2)CC1
Yield: 95 %

Procedure:
by the reaction of 4-cyanobenzenesulphonylchloride with ethyl 4-(2-aminoethyl)-cyclohexylacetate hydrochloride in methylene chloride in the presence of triethylamine. Yield 95% of theory, colourless oil. 1H-NMR (300 MHz, d6 -DMSO): δ=2.12 and 2.21 (2d, J=7 Hz, addl. 2H, CH2COOEt); 2.75-2.85 (m, 2H, NHCH2); 7.78 (t, J=4 Hz, 1H, SO2NH); 7.91-8.08 (m, 4H, aromatic protons).
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1)[CH2:10][CH2:11][CH:12]([CH:27]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)[NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)C(N1C(C2C=CC=CC=2)COC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:60][O:61][C:62](=O)[O:63]C.Cl>ClCCl>[CH3:60][O:61][C:62](=[O:63])[CH:12]([CH:27]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:40][CH:41]=1)[NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)[CH2:11][CH2:10][CH:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:50]1[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=1
Reactant: O=C1OCC(c2ccccc2)N1C(=O)C(CCC(OCc1ccccc1)c1ccc(F)cc1)C(Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(CCC(OCc1ccccc1)c1ccc(F)cc1)C(Nc1ccc(F)cc1)c1ccc(OCc2ccccc2)cc1
Reaction time: 6 h

Procedure:
10 gms of 3-[5-Benzyloxy-2-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-(4-fluoro-phenyl)-pentanoyl]-4-phenyl-oxazolidin-2-one was taken in dichloromethane, to this 3.6 gms of sodium methoxide was added followed by 3.2 ml of dimethylcarbonate, and 500 ml of dichloromethane. Reaction mass was stirred for about 5-7 hours. To the reaction mass 0.1 ml of hydrochloric acid was added. Separated the layers and extract the aqueous layer with 25 ml of methylene dichloride. The organic layer was washed with water and dried over sodium sulphate. Distilled the solvent completely under reduced pressure at 50-55° C. and 85 ml of methanol was added. Stirred the reaction mass for about 1-2 hours, filtered and washed with methanol and dried at 50-55° C. to get 5 gms of 5-Benzyloxy-2-[(4-benzyloxy-phenyl)-(4-fluoro-phenylamino)-methyl]-5-(4-fluoro-phenyl)-pentanoic acid methyl ester.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:18]([S:21](Cl)(=[O:23])=[O:22])[CH2:19][CH3:20].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][N:14]2[S:21]([CH2:18][CH2:19][CH3:20])(=[O:23])=[O:22])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCN2)no1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CC[C@H]1C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-Azetidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (100 mg; 0.385 mmol) in DMF (1 mL) is added n-propylsulfonyl chloride (0.043 mL; 0.385 mmol) and N,N-diisopropylethylamine (0.201 mL; 1.155 mmol). The reaction mixture is left stirring at room temperature for 18 hours. After this time, the reaction mixture is diluted with ethyl acetate and washed with water twice then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/hexanes provides the title compound, m/z 330 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][C:14]([CH2:25][CH2:26][CH3:27])(C(OCC)=O)[C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]([CH2:25][CH2:26][CH3:27])[C:15]([OH:17])=[O:16])=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Product: CCCC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Yield: 53.7 %

Procedure:
In a similar manner to that described in Reference example 2(b), a reaction was carried out using diethyl 2-(4-benzyloxybenzyl)-2-propylmalonate (9.85 g), which is the product of Reference example 23(a), and potassium hydroxide (5.25 g) and the reaction mixture was treated to afford the desired compound (3.96 g) as brown crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][C:2]1=[O:10].C1([NH:17][C:18](=O)[O-:19])C=CC=CC=1.[H-].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[OH:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]=1[C:18]([NH2:17])=[O:19]
Reactant: O=C1Cc2ccccc2S1
Reactant: O=C([O-])Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: NC(=O)c1c(O)sc2ccccc12

Procedure:
To a stirred mixture of benzthiophene-2-one (1.50 g, 0.01 m), phenylcarbamate (1.4 g, 0.01 m), and hexamethylphosphorictriamide (2.2 ml) at 5° C. is added sodium hydride (0.24 g, from 0.4 g 60% mineral oil dispersion), and the resultant mixture stirred at ambient temperatures for 5 hours. The volatiles are removed under high vacuum, and the residue triturated well with hexane and then with water to yield 2-hydroxybenzo(b)thiophene-3-carboxamide.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:34](Cl)(=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([O:22][C:34](=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(O)c1
Reactant: CCCCCCCCCC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CCCCCCCCCC(=O)Oc1cc(C(=O)CNC(C)(C)C)ccc1OC(=O)C(C)(C)C

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with decanoyl chloride there is obtained 3-(decanoyloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 2B, there is obtained 3-(decanoyloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[CH2:7]2.Cl[CH2:32][C:33]1[N:34]=[CH:35][N:36]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=1>C1COCC1>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[C:7]2([CH2:32][C:33]1[N:34]=[CH:35][N:36]([C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:37]=1)[CH2:32][C:33]1[N:34]=[CH:35][N:36]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
The title compound of 13A (250 mg, 0.644 mmol) and 4-chloromethyl-1-trityl-1H-imidazole compound (694 mg, 1.93 mmol) were dissolved in 4 ml of anhydrous THF under an atmosphere of dry N2. To this solution was added 95% KHMDS (338 mg, 1.61 mmol) and the reaction mixture was subsequently stirred overnight. The reaction mixture was partitioned between ethyl acetate and aqueous saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated under vacuum to give a pink solid which was chromatographed on flash silica gel eluting with a gradient of ethyl acetate to MeOH in ethyl acetate (10%) to give the title compound of 14A (348 mg, 52% yield).
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:9][C:7]([NH2:10])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[C:1]([O:4][C:5]12[CH2:9][C:7]([NH:10][CH3:11])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC12CC(N)(C1)C2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC12CC(OC(C)=O)(C1)C2

Procedure:
To an anhydrous DMF (5 mL) solution of 3-aminobicyclo[1.1.1]pentan-1-yl acetate (1 mmol; prepared as described in Example 1, Step 2) is potassium carbonate (3 mmol) followed by the addition of methyl iodide (1 mmol) by syringe at room temperature. The reaction is monitored by LCMS and TLC. After consumption of starting material, the reaction mixture is quenched by adding water (3 mL) and extracted with ethyl acetate (3×). The organic layers are combined, dried (magnesium sulfate), filtered, and concentrated. The crude residue is subjected to flash chromatography (silica gel, EtOAc/hexanes) to afford 3-(methylamino)bicyclo[1.1.1]pentan-1-yl acetate.