Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C1(C)C=CC(S(O[CH2:21][C@@H:22]2[O:24][CH2:23]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:21][C@@H:22]2[O:24][CH2:23]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)ccc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
A mixture of 5-bromo-2-hydroxybenzaldehyde (68.75 g), (R)-glycidyl 4-toluenesulphonate (65 g) and potassium carbonate (47.3 g) in dry dimethylformamide (1.5 L) was stirred and heated at 60° C. under nitrogen for 24 hours, then cooled and allowed to stand at ambient temperature for 24 hours. The mixture was poured into water (2 L) then extracted with ether (4×400 ml). The combined extracts were washed with brine (4×500 ml), dried over magnesium sulphate, and the solvent removed in vacuo to give an oil which was purified by flash chromatography over silica eluting with a 4:1 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate. Appropriate fractions were combined and the solvent removed in vacuo to give an oil, which on trituration with ether (150 ml) gave (R)-5-bromo-2-(2,3-epoxypropoxy)benzaldehyde as a colourless solid (43.3 g).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[Br:22][CH2:23][CH2:24]O>C(Cl)Cl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][CH2:24][CH2:23][Br:22])(=[O:11])=[O:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCCBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OCCBr)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
Anhydrous pyridine (8.5 mL, 105 mmol) and dry DCM (100 mL) were added to a 3-necked round-bottomed flask under a nitrogen atmosphere. The reaction flask was then cooled to about −20° C. with a dry ice/ethylene glycol bath. Trifluoromethanesulfonic anhydride (17 mL, 100 mmol) was added, whereupon a white/pink precipitate formed immediately. 2-Bromoethanol (7.1 mL, 100 mmol) was added after 5 minutes. The precipitate disappeared and then after a few minutes a new white precipitate formed. The reaction mixture was stirred for 20 minutes during which time it gradually warmed to r.t. The reaction mixture was then filtered through a phase separator and the residue was washed with 1:1 DCM/hexane (2×10 mL). The filtrate was run through a 4 cm silica plug with 1:1 DCM/hexane solution (300 mL). The solvent was removed in vacuo to give the title compound as a brown oil (21.2 g, 87%). δH (CDCl3) 4.76 (2H, t, J 6.4 Hz), 3.62 (2H, t, J 6.4 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[OH-].[K+].Br[CH2:18][CH2:19][O:20][CH3:21]>C(O)C>[CH3:21][O:20][CH2:19][CH2:18][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: COCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 50 °C
Reaction time: 16 h
Yield: 19.9 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 g, 51.5 mmol) in ethanol (50 mL) was treated with KOH (3.47 g, 61.8 mmol) and 1-bromo-2-(methyloxy)ethane (5.81 mL, 61.8 mmol) at room temperature and the resulting mixture was stirred at 50° C. under nitrogen for 16 h then cooled to room temperature. 1-Bromo-2-(methyloxy)ethane (2 mL, 21.3 mmol) was added and the resulting mixture was stirred at 50° C. for 60 h then cooled to room temperature. The mixture was filtered through celite and the insoluble were washed with ethanol. The combined filtrate and washings were concentrated in vacuo. Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 0 to 100% AcOEt in Hexanes) gave 1-[2-(methyloxy)ethyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.72 g, 10.25 mmol, 20%) as a yellow oil. LCMS (method G): Retention time 0.87 min, [M+H]+=252.9
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(OO)(=[O:25])C>CC(O)=O.O>[CH3:1][N:2]1[C@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([OH:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH:15]=[CH:16][C@:17]2([OH:25])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: CC(=O)OO
Solvent: CC(=O)O
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 200 mL flask, dried oripavine (10.00 g, 95% wt/wt %) was dissolved in HOAc/H2O (1:4, 100 mL) and cooled to 5° C. to 10° C. Peroxyacetic acid, CH3CO3H, (9.1 mL, 32% wt/wt %) was added over 3 minutes and the reaction mixture was stirred at 5° C. to 10° C. for 30 minutes. HPLC data showed that the reaction was completed. The reaction mixture was allowed to warm to 25° C. for 30 minutes. H2C2O4 (3.0 g) was added to the reaction mixture, and was stirred at room temperature for 30 minutes and then heated to 50° C. for 30 minutes. The solution was assayed by HPLC and >99% conversion was observed.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.[H-].[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=[C:20]([Cl:23])[C:21]=1Cl.Cl>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=[C:20]([Cl:23])[C:21]=1[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: Cc1ccc2ncc(O)cc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 3-Hydroxy-6-methylquinoline (92) (348 mg, 2.19 mmol) in DMF (3.5 mL), was added NaH (60% oil suspension, 90 mg, 2.25 mmol) in one portion at room temperature. After 5 min 3,4,5-trichloronitrobenzene (509 mg, 2.25 mmol) in DMF (2 mL) was added and the reaction mixture was heated at 50° C. with stirring for 2 h. After cooling to room temperature. Ice/water was added to the reaction mixture, which was then acidified with 2N HCl and extracted twice with AcOEt. Organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated. Crude residue was purified by column chromatography (hexane/AcOEt=4/1, 80 g of silica gel) to afford compound 93 (510 mg, 67%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C>[CH2:1]([O:8][C@@H:9]([C@H:12]([C@@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][O:11][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
A mixture of 239 (5.24 g, 12.4 mmol), imidazole (3.72 g, 54.6 mmol), and TBDMSCl (2.07 g, 13.6 mmol) in dry DMF (50 mL) was stirred at 0° C. under N2 for 30 min. The reaction was quenched with ice (20 mL), and the reaction mixture was partitioned between Et2O (200 mL) and H2O (100 mL). The separated organic phase was washed with H2O (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (hexanes:EtOAc, 3:1) to give a colorless oil 240 (6.164 g, 93%): [α]D −140.4° (c 0.87, CHCl3); 1H NMR (CDCl3) δ 7.35-7.25 (15H, m, Ar), 4.74 and 4.60 (2H, 2d, Ja,b=11.7 Hz, CH2Ph), 4.69 and 4.51 (2H, 2d, Ja,b=11.9 Hz, CH2Ph), 4.51 and 4.45 (2H, 2d, Ja,b=11.6 Hz, CH2Ph), 4.05 (1H, dddd, J3,4=2.3 Hz, J4,5a=J4,5b=5.9 H,J4,OH=5.9 Hz, H-4), 3.88 (1H, dd, J1a,1b=11.0 Hz, J1a,2=4.2 Hz, H-1a), 3.78 (1H, dd, J1b,2=4.9 Hz, H-1b), 3.77 (1H, dd, J2,3=4.1 Hz, H-3), 3.73 (1H, ddd, H-2), 3.54(1H, dd, H-5a), 3.49 (1H, dd, H-5b), 3.02 (1H, d, OH), 0.891 (9H, s, (CH3)3CSi), 0.05 (6H, s, (CH3)2Si); 13C NMR (CDCl3) δ 149.11, 145.62, 140.95 (3Cipso), 128.35-127.60 (15C, Ar), 80.25 (C-2), 77.25 (C-3), 73.65, 73.26, 72.84 (3CH2Ph), 71.16 (C-5), 69.75 (C-4), 62.04 (C-1), 25.88 (3C, (CH3)3CSi) 18.23 (1C, CSi), −5.40, −5.44 (2C, (CH3)2Si); MALDI-TOF MS: m/e 537.89 (M++H), 559.33 (M++Na). Anal. Calcd for C32H44O5Si: C, 71.60; H, 8.26. Found: C, 71.44; H, 8.34.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Yield: 97.7 %

Procedure:
5-chloro-1H-indole (2.15 g; 13.90 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (3.08 g; 15.29 mmol) and potassium hydroxide (3.67 g; 55.6 mmol) were added in MeOH (50 mL) and heated to reflux for 24 hours. The reaction mixture was cooled to room temperature and poured into ice water (70 mL). The reaction mixture was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulphate and concentrated to give 4.52 g (98%) of tert-butyl 4-(5-chloro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CO[C:39]1N=CC(N)=C[CH:40]=1>>[NH2:8][C:3]([C:4]1[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)[CH2:13][CH2:14]2)[CH:7]=[CH:39][CH:40]=1)=[O:2]
Reactant: COc1ccc(N)cn1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Product: NC(=O)c1cccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
N-(2-[((3R)-1-{1-[3-(aminocarbonyl)phenyl]piperidin-4-yl)pyrrolidin-3-yl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, substituting 3-aminobenzamide for 6-methoxypyridin-3-amine. The crude product was purified by preparative HPLC. MS m/z: 518 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1>[OH:1][C:2]1([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 3 h
Yield: 33.2 %

Procedure:
To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (4 g, 23 mmol) in THF (100 mL) at 0° C. was added (4-methoxyphenyl)magnesium bromide (0.5 M in ether) (47 mL, 23 mmol). The reaction mixture was stirred for 3 h, and then a satd. ammonium chloride solution (200 mL) was added. The mixture was extracted with ethyl acetate (200 mL), and the organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give a crude product. The product was purified by silica gel chromatography eluting with 25% ethyl acetate in hexane to give tert-butyl 3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate (2.2 g, 7.64 mmol, 32.7% yield). LCMS (Method 107): m/z 280.7 (M+H) RT=1.929 min; 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 6.21 (s, 1H), 4.00 (s, 3H), 3.75 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N:10]2CCCC2)=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.Cl.N[NH:20][C:21]([NH2:23])=[O:22]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]/[CH:9]=[N:10]/[NH:20][C:21]([NH2:23])=[O:22])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1/C=C/N1CCCC1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)N/N=C/Cc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-[(E)-2-(4-fluoro-2-nitrophenyl)ethenyl]pyrrolidine (77.25 g, 0.327 mol) in warm MeOH (500 mL) was added a solution of semicarbazide HCl (38.3 g, 0.343 mol) in warm water (200 mL). The reaction mixture was stirred at room temperature for 1 h and was then cooled in ice and filtered. The solid was washed with cold 1:1 MeOH/water (2×30 mL) and dried to give 71 g (90% over two steps) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[Br-].[S:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[Zn+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3[C:35]3[S:34][CH:38]=[CH:37][CH:36]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reactant: [Zn+]c1cccs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccs2)c1
Reaction time: 2 h
Yield: 83.6 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 24 mg, 0.046 mmol) was diluted with THF (1 mL) followed by the addition of bis(tri-t-butylphosphine)palladium (0) (2.4 mg, 0.0046 mmol) and 2-thienylzinc bromide (0.23 ml, 0.12 mmol). After stirring for 2 hours, the reaction was purified by silica gel chromatography, eluting with hexanes:ethyl acetate (3:1) to yield ethyl 2-(4-(4-((4-chlorophenethyl) carbamoyl)phenoxy)-3-(thiophen-2-yl)phenyl)acetate (20 mg, 83% yield) as a clear oil.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH2:10]1CCN2C(=NCCC2)C[CH2:11]1.C[Si](Cl)(C)C>ClC(Cl)C.CN(C=O)C>[CH3:4][C:3]1([CH3:5])[S:6][CH2:11][CH2:10][NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: CC1(C)SCCN[C@H]1C(=O)O

Procedure:
To a 0° suspension of 14.92 g (0.10 mmol) of D-penicillamine in 300 mL of dichloroethane and 2.0 mL of DMF was added 22.4 mL of DBU followed by 19.0 mL of trimethylsilyl chloride. The ice bath was removed and the reaction was stirred for 3h, after which an additional 29.9 mL of DBU was added. The reaction was stirred overnight at room temperature and then 10 mL of methanol was added and the reaction was stirred for 1h. The resulting white precipitate was filtered off, washed with 10 mL of methanol and dried in vacuo to provide 16 g of (3 S)-2,2-dimethyl-3-thiomorpholine carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=O)[CH:9]([S:14]([CH3:16])=O)[CH2:8]2.C[OH:18]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH:10]=[C:9]([S:14][CH3:16])[C:8]2=[O:18]
Reactant: CO
Reactant: COc1cccc2c1OC(=O)C(S(C)=O)C2
Agent: Cl
Product: COc1cccc2c(=O)c(SC)coc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
A mixture of 8-methoxy-3-(methylsulfinyl)chromanone (20 g), methanol (100 ml) and 1N hydrochloric acid (100 ml) is stirred at room temperature for 20 hrs. The methanol is removed at reduced pressure and the aqueous residue is extracted with chloroform. The chloroform extracts are combined, extracted with 1N sodium hydroxide solution, washed with water, dried over MgSO4 and evaporated to give an oil. The oil is heated at 100° C. in 5N hydrochloric acid (100 ml) for 5 hrs. The solution is cooled and the product which precipitated is filtered off. Recrystallization from ethanol gives 8-methoxy-3-(methylthio)chromone (2) as white crystals (12.1 g, 65%), mp 113°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.[I-:13].[Na+].ClC(OC(Cl)C)=O.C1(C)C=CC=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][I:13])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: COc1ccc(CCCO)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(CCCI)cc1
Reaction time: 4 h
Yield: 32.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 8.0 grams (0.048 mole) of 3-(4-methoxyphenyl)propanol and 7.9 grams (0.053 mole) of sodium iodide in 50 mL of acetone was stirred, and 5.7 mL (0.053 mole) of 1-chloroethyl chloroformate was slowly added. Upon completion of addition, the reaction mixture was heated to reflux where it was stirred for four hours. After this time the reaction mixture was cooled, and 50 mL of toluene was added. The acetone was removed by distillation after which the reaction mixture was heated for one hour at reflux in the toluene. The reaction mixture was then cooled and poured into 300 mL of water. The mixture was extracted with 200 mL of diethyl ether. The ether extract was washed with 100 mL of an aqueous 5% sodium thiosulfate solution and then with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil, and the oil was dissolved in methylene chloride and filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished with 40:1 petroleum ether and diethyl ether. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.3 grams of 3-(4-methoxyphenyl)propyl iodide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]([O:7][Si](C)(C)C)=[C:4]([CH3:6])[CH3:5].F[B-](F)(F)F.[C:17]1([N+:23]#[N:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C(OCC)C>[CH3:5][C:4]([N:24]=[N:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:6])[C:3]([O:2][CH3:1])=[O:7]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: N#[N+]c1ccccc1
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)C(C)(C)N=Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
1.0 mmol of (1-methoxy-2,2- dimethylethenyl)-oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The obtained mixture was stirred at 0° C. in a nitrogen atmosphere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5 N hydrochloric acid, water and a saturated aqueous solution of common salt successively. The obtained organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.90 mmol of methyl 2-methyl-2-phenylazopropionate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:10]([NH:22][C:23]2[N:28]=[C:27](SC#N)[C:26]([N+:32]([O-:34])=[O:33])=[CH:25][N:24]=2)[CH:9]=1.[OH:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH2:42])[CH2:38][CH2:37]1>C(#N)C.C(Cl)Cl>[F:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[C:10]([NH:22][C:23]2[N:28]=[C:27]([NH:42][C@H:39]3[CH2:40][CH2:41][C@H:36]([OH:35])[CH2:37][CH2:38]3)[C:26]([N+:32]([O-:34])=[O:33])=[CH:25][N:24]=2)[CH:9]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(SC#N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@H]2CC[C@H](O)CC2)n1
Reaction time: 16 h

Procedure:
Potassium carbonate (105 mg) was added to a stirred mixture of tert-butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenyl-carbamate (101 mg) in acetonitrile (5 ml) followed by the addition of trans-4-hydroxycyclohexylamine (44 mg). The reaction mixture was stirred for 16 hours, then diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 110 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)O)[C:10]([CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=1>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:10]([CH3:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(Cc2ccccc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: Cc1nn(Cc2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 1.6 %

Procedure:
Using (1-benzyl-3-methyl-1H-pyrazol-4-yl)(cyclohexyl)methanol (0.65 g) synthesized in Example 41(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.65 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (18.2 mg, 2%) was obtained as a white solid.
Reaction SMILES: [O:1]=[C:2](Cl)[O:3][C:4]([Cl:7])([Cl:6])[Cl:5].[CH2:9]([O:16][NH:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[CH2:9]([O:16][N:17]([C:2]([O:3][C:4]([Cl:7])([Cl:6])[Cl:5])=[O:1])[C@H:18]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[C@H:20]([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCOC(=O)[C@@H]1C[C@@H](NOCc2ccccc2)CN1C(=O)OC(C)(C)C
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H]1C[C@@H](N(OCc2ccccc2)C(=O)OC(Cl)(Cl)Cl)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Diphosgene (0.1 mL, 0.804 mmol) was added slowly to a solution of 2-allyl 1-tert-butyl (2S,4R)-4-[(benzyloxy)amino]pyrrolidine-1,2-dicarboxylate (261 mg, 0.745 mmol) and triethylamine (0.13 mL, 0.933 mmol) in dichloromethane (4 mL) at 0° C. The reaction mixture was stirred at 0° C. for 4 hours then allowed to stand at room temperature overnight. The reaction mixture was chromatographed on silica gel eluted first with hexane then with 4:1 hexane:ethyl acetate to afford the title compound as a clear gum.