Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([F:13])[C:3]=1[C:4]([OH:6])=O.CN(C=O)C.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:26]=[C:27]([C:29]3[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=3)[N:28]=2)[CH:25]=1.CCOC(C)=O.CCCCCC>S(Cl)(Cl)=O.N1C=CC=CC=1>[F:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]([F:1])[C:3]=1[C:4]([NH:33][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[N:28]=[C:23]3[CH:22]=[CH:21][C:20]([CH3:19])=[CH:25][N:24]3[CH:26]=2)=[CH:35][CH:34]=1)=[O:6]
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(F)c(C(=O)Nc2ccc(-c3cn4cc(C)ccc4n3)cc2)c(F)c1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
To a stirred solution of 2,6-difluoro-4-methoxybenzoic acid (0.25 g, 1.34 mmol) in thionyl chloride (7 ml) was added a drop of DMF and the reaction mixture was then heated under reflux for 3 h. On cooling to room temperature the excess reagent was removed under reduced pressure to give a crude residue. The amide was prepared as described in the Amide Coupling section using of the crude residue and 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.30 g, 1.34 mmol) in dry pyridine (15 ml) to give the title compound (0.24 g, 45%) as a pale yellow solid after work-up and flash chromatography (2:1 EtOAc/Hexane followed by EtOAc then MeOH).
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=3[O:27][CH3:28])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(N(C(C)C)CC)(C)C.[O:47]([CH2:54][CH2:55][CH2:56]Br)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(Cl)Cl.CCOC(C)=O.O>[CH3:28][O:27][C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[CH2:17][N:13]1[CH2:12][C:11]2([CH2:10][CH2:9][N:8]([CH2:56][CH2:55][CH2:54][O:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:30][CH2:29]2)[O:15][C:14]1=[O:16]
Reactant: COc1ccc([N+](=O)[O-])cc1CN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OC1=O
Reactant: BrCCCOc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1CN1CC2(CCN(CCCOc3ccccc3)CC2)OC1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound A8 (0.67 g, 1.59 mmol) was dissolved in DCM (3 mL) and combined with trifluoroacetic acid (3 mL). The reaction mixture was stirred for 5 min at RT and the solvent was then removed under a vacuum. The residue was combined repeatedly with toluene and the solvent was then removed again. The residue was then combined with sat. aq. NaHCO3 solution and repeatedly extracted with EtOAc. The combined organic phases were dried over Na2SO4 and the solvent was removed under a vacuum. The residue was redissolved in anhydrous THF (5 mL) and combined with diisopropylethylamine (333 μL, 1.91 mmol). The reaction mixture was combined with 3-phenoxypropyl bromide (277 μL, 1.75 mmol), stirred for 18 h at RT and combined with water and EtOAc. The organic phase was separated off and the aqueous phase repeatedly extracted with EtOAc. The combined organic phases were dried over Na2SO4 and the solvent was removed under a vacuum. The residue was purified by column chromatography (SiO2, DCM/MeOH 98:2). 433 mg (58% of theoretical) of the desired product 3-(2-methoxy-5-nitrobenzyl)-8-(3-phenoxypropyl)-1-oxa-3,8-diazaspiro[4.5]decan-2-one (432) were obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:13]1([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: Nc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Yield: 97 %

Procedure:
270 parts of β-naphthol, 175 parts of aniline and 5 parts of triphenyl phosphite are mixed and fused at 130° C. The reaction commences at an internal temperature of 190° C, with elimination of water. After 2 1/2 hours, internal temperature has reached 235° C and 34 parts of water have distilled off. 398 parts of N-phenyl-β-naphthylamine of melting point 100° - 102° are distilled, passing over at 230° C/15 mm Hg. This corresponds to a yield of 97% of theory.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[S:15]([F:25])(=[O:24])([C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[O:16]>CN(C)C(=O)C.O>[F:1][C:2]([F:10])([F:9])[C:3]([OH:7])([CH3:8])[C:4]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([S:15]([F:25])(=[O:24])=[O:16])=[CH:18][CH:19]=1)=[O:5]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)F)cc1)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a cooled (-20° C.) solution of α-trifluoromethyl lactic acid (2.0 g) in dry N,N-dimethylacetamide (15 ml) was added thionyl chloride (0.97 mL) dropwise over 10 minutes. The reaction mixture was stirred at -20° C. for 1 hour, warmed to 0° C. over 1 hour, then treated with sulfanilyl fluoride (2.22 g) in one portion and heated at 100° C. for 24 hours. After cooling to 22° C. the reaction mixture was diluted with water (150 ml) and extracted with ethyl acetate (3×35 ml). The combined organic extracts were washed with water, brine, dried and the solvent removed under reduced pressure. The crude product was purified by chromatography (13:1 CH2Cl2 :Et2 0) and recrystallised from methyl-t-butyl ether to give 3,3,3-trifluoro-N-[4-(fluorosulfonyl)phenyl]-2-hydroxy-2-methylpropanamide as colourless crystals, (1.7 g); mp 152°-154° C.; MS: m/z=316(M+1); NMR (CDCl3): 1.78 (s,3), 3.51 (broad s), 7.86-7.89 (m, 2), 7.99-8.03 (m,2), 8.79 (broad s,1). Analysis for C10H9 F4NO4S: Calculated: C, 38.10; H,2.88; N, 4.44; Found: C, 38.21; H, 2.97; N, 4.44.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1.[OH-].[Na+]>C(OCC)(=O)C>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:12]#[N:13])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)=[C:14]=[O:15]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(N=C=O)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-2-cyanobenzotrifluoride (1a) (2.0 g, 10.7 mmol) in ethyl acetate (6 mL) at 0° C. under argon, was added dropwise a 2.0 M solution of phosgene in toluene (6.5 mL, 12.9 mmol). The solution was stirred 30 min at 0° C. and allowed to return at room temperature. Toluene (3 mL) was then added to the ethyl acetate and the resulting solution was refluxed for 3 hrs using a Dean-Stark apparatus, equipped with an HCl trap (solid NaOH). The first 6 mL of distilled solvent was removed and replaced by toluene (6 mL). The solution was then filtrated and evaporated to give compound 8a (1.6 g) as an orange oil which was directly used for the next step. IR: 2268 (strong), 2232 (weak) cm−1.
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].N1C=CN=C1.C(O)(=O)C.[C:52]([O:56][C:57]([N:59]([CH2:67][CH2:68][S:69][S:70][C:71]([CH3:74])([CH3:73])[CH3:72])[CH2:60][C:61](OCC#N)=[O:62])=[O:58])([CH3:55])([CH3:54])[CH3:53]>O.[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1COCC1>[C:52]([O:56][C:57]([N:59]([CH2:67][CH2:68][S:69][S:70][C:71]([CH3:74])([CH3:73])[CH3:72])[CH2:60][C:61]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:62])=[O:58])([CH3:55])([CH3:54])[CH3:53]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CC(=O)OCC#N
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCSSC(C)(C)C)CC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h, 100 mg, 0.157 mmol) in water (1.0 ml) was added to a buffer (40 ml) in which imidazole (272.3 mg, 4.00 mmol) and N,N,N-trimethylhexadecan-1-aminium chloride (256.0 mg, 0.80 mmol) were dissolved and which was adjusted to pH 8 with acetic acid. A solution of cyanomethyl 2-((tert-butoxycarbonyl) (2-(tert-butyldisulfanyl)ethyl)amino)acetate (Compound 6g-A, 198 mg, 0.546 mmol) in THF (1.2 ml) was then added and the mixture was stirred at room temperature for 4 hours. The reaction solution was directly lyophilized, and the resulting residue was purified by column chromatography (0.05% aqueous TFA solution:0.05% TFA-acetonitrile solution=85:15).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12](S(C3C=CC=CC=3)(=O)=O)[CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO.O1CCCC1.[Cl-].[Na+].O>[F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:22]=[O:23])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccccc2)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=Cc1c[nH]c(-c2cccnc2F)c1
Reaction time: 1 h
Yield: 79.5 %

Procedure:
5-(2-Fluoropyridin-3-yl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (2.25 g) was dissolved in methanol (20 mL) and tetrahydrofuran (20 mL), a 8 mol/L aqueous sodium hydroxide solution (20 mL) was added dropwise at room temperature and the mixture was stirred for 1 hr. The reaction mixture was diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue and insoluble crystals were collected by filtration to give the title compound as pale-brown crystals (yield 1.03 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[F:12][C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15](N2C=CC(=O)NC2=O)[CH2:14]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:15]2[O:16][C@H:17]([CH2:18][OH:19])[C@@H:13]([F:12])[CH2:14]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Nc1nc(Cl)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 45 °C
Reaction time: 48 h
Yield: 23.7 %

Procedure:
2-Amino-6-chloro-9H-purine (0.48 g, 2.8 mmoles), (Aldrich Chemical Company, Milwaukee, Wis.) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added and the suspension was stirred at 45° C. After 2 days, the reaction mixture was filtered and solvent was removed in vacuo. The residue was flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:methanol:acetone (96:2:2). Solvent was removed and lyophilization yielded 0.15 g of 2-amino-6-chloro-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-purine (23%): mp 172° C.; [α]D20 -41.0 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 308 (7.7); at pH 13, 303 (7.6); 1H NMR (300 MHz, DMSO-d6) δ8.36 (s, 1H, H8), 7.01 (s, 2H, NH2), 6.27 (dd, 1H, H1', J=9.0 Hz, J=5.8 Hz), 5.42 (dd, 1H, H3', J=53.8 HZ, J=4.4 Hz), 5.14 (t, 1H, OH5', J=5.4 Hz), 4.20 (dt, 1H, H4', J=26.5 Hz, J=4.8 Hz), 3.57 (t, 2H, H5' and H5", J=5.3 Hz), 2.63-3.04 (m, 2H, H2' and H2"); MS (ci) 288 (M+1), 268 (M-F), 70 (MH2 --C5H8FO2).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:43]=[CH:42][C:32]([C:33]([NH:35][C@H:36]([CH3:41])[C:37]([F:40])([F:39])[F:38])=[O:34])=[C:31]([F:44])[CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:43]=[CH:42][C:32]([C:33](=[O:34])[NH:35][C@H:36]([CH3:41])[C:37]([F:39])([F:40])[F:38])=[C:31]([F:44])[CH:30]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C[C@@H](NC(=O)c1ccc(CN)cc1F)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: C[C@@H](NC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1F)C(F)(F)F
Yield: 62.4 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.561 g, 1.319 mmol) with (R)-4-aminomethyl-2-fluoro-N-(2,2,2-trifluoro-1-methyl-ethyl)-benzamide (0.698 g, 2.642 mmol) by using tris(dibenzylideneacetone)dipalladium(0) (0.241 g, 0.264 mmol), BINAP (0.33 g, 0.53 mmol) and cesium carbonate (1.51 g, 4.63 mmol) in anhydrous toluene (13 mL). Purify by chromatography on silica gel (40g RediSep® column) eluting with hexane/EtOAc (19:1 to 1:1 gradient over 30 min; 35 mL/min) and then by SCX chromatography to afford (R)-7-chloro-6-[3-fluoro-4-(2,2,2-trifluoro-1-methyl-ethylcarbamoyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (0.444g, 62%). MS (ES+) m/z: 540.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[NH:15][CH2:16][CH3:17].CN(C)C=O.CC(C)([O-])C.[K+].O>O1CCCC1.[H-].[Na+]>[CH2:16]([N:15]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1)[CH3:17]
Reactant: CCNc1ccc([N+](=O)[O-])cc1OCCCBr
Agent: CC(C)(C)[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCCOc2cc([N+](=O)[O-])ccc21
Reaction time: 2 h
Yield: 48 %

Procedure:
2-Ethylamino-5-nitro-phenol (2.50 g, 13.7 mmol) was azeotroped with toluene to ensure dryness, then dissolved in Tetrahydrofuran (300 mL). 3-Bromo-1-propanol (1.50 mL, 16.6 mmol), Tributylphosphine (5.5 mL, 22 mmol), and 40% w/w DEAD in Toluene (40:60, Diethyl Azodicarboxylate:Toluene, 9.6 g) were added, and the reaction was stirred under an atmosphere of Nitrogen overnight. Solvent was partially removed (300 mL removed) and the mixture was diluted with 300 mL EtOAc, then washed with satd. sodium bicarbonate (100 mL), water (2×100 mL) and brine (100 mL). The organics were dried over sodium sulfate and conc. onto 15 g SiO2 and chromatographed (ISCO, 120 g, 0-30% EtOAc:Hex) to afford [2-(3-Bromo-propoxy)-4-nitro-phenyl]-ethyl-amine as a yellow solid. [2-(3-Bromo-propoxy)-4-nitro-phenyl]-ethyl-amine was dissolved in Tetrahydrofuran (200 mL) and Sodium hydride, 60% disp. in mineral oil 0.55 g) was added. After 2 h, no reaction was observed, so N,N-Dimethylformamide (10 mL) was added. After overnight stirring, the reaction was near completion and was quenched with water, diluted with 500 mL ether then washed with water (50 mL), satd. sodium bicarbonate (2×50 mL) and brine (100 mL), dried over sodium sulfate and conc. in vacuo onto 8 g SiO2, then chromatographed (ISCO, 0-30% EtOAc:Hex, 120 g SiO2). The isolated product was ˜85% purity, with the alkyl bromide as the major impurity. The mixture was redissolved in DMF (20 mL). Potassium tert-Butoxide (0.23 g, 2.0 mmol) was added and the mixture stirred under nitrogen for 1 h, then water (100 mL) was added. The precipitate was cooled for 20 min, then collected by filtration, washing with water (2×50 mL) to give 9-Ethyl-3-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (1.99 g, 48%). 1H-NMR (CDCl3): 7.83 (dd, 1H, J=2.5, 8.4 Hz), 7.72 (d, 1H, J=2.5 Hz), 6.61 (d, 1H, J=8.4 Hz), 4.25 (t, 2H, J=6.4 Hz), 3.60 (t, 2H, J=5.4 Hz), 3.38 (q, 2H, J=7.2 Hz), 2.11 (m, 2H), 1.25 (t, 3H, J=7.2 Hz).
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(NCC)C.C(#N)C>C(Cl)(Cl)Cl>[NH2:1][C@H:2]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Solvent: CC#N
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The crude crystals (942 mg) of Fmoc-Leu-OBzl (2-MeO-4-OC12OC22) were dissolved in chloroform (9 mL), and diethylamine (1.99 mL, 19.2 mmol) was added dropwise under ice-cooling. The mixture was warmed to room temperature, acetonitrile (4.5 mL) was added, and the mixture was stirred for 3.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was precipitated with acetonitrile (10 mL) to give Leu-OBzl (2-MeO-4-OC12OC22) as wet crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.C([O-])(=O)C.[Na+]>CC1(C)N([O])C(C)(C)CCC1.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1O
Agent: CC(=O)[O-]
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CCOC(C)=O
Product: CC1(C)COC(=O)C1=O
Reaction time: 2 h
Yield: 89.4 %

Procedure:
2.5 g (19.2 mmol) of pantolactone were reacted with 1.8 g (7.7 mmol) of trichloroisocyanuric acid in the presence of 30 mg (0.12 mmol) of TEMPO derivative C and 1.65g (20.1 mmol) of sodium acetate analogously to Example 14. In contrast to Example 14, ethyl acetate (20 ml) was used as the solvent. The reaction had finished after 2 hours. After recrystallization of the crude product there were obtained 2.2 g (89%) of ketopantolactone, m.p. 68°-69° C., GC content: 100% (area percent).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=O)[CH3:24])=[CH:22][C:17]=2[N:16]=[CH:15]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].CO>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]([S@@:5]([NH:7][C@H:23]([C:21]1[CH:20]=[CH:19][C:18]2[N:14]([CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][O:8]3)[CH:15]=[N:16][C:17]=2[CH:22]=1)[CH3:24])=[O:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H](N[S@@](=O)C(C)(C)C)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 75 °C
Yield: 49.9 %

Procedure:
To a solution of (R)-2-methylpropane-2-sulfinamide (6.9 g, 57.31 mmol) and Ti(OEt)4 (26.1 g, 114.62 mmol) in THF (200 mL) at RT was added 82 (14 g, 57.31 mmol). The reaction mixture was heated to 75° C. overnight. After MS analysis indicated complete conversion of 122, the mixture was cooled to RT and then to −48.0° C. L-Selectride (172 mL, 1M solution in THF) was added dropwise. The reaction mixture was warmed. When the reduction was complete the reaction mixture was cooled to 0° C. and MeOH was added dropwise until gas evolution was no longer observed. The crude reaction mixture was poured into an equal volume of rapidly stirred brine. The resulting suspension was filtered through a plug of Celite® and the filter cake was washed with EtOAc. The filtrate was washed with brine, and the brine layer was extracted with EtOAc, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by SiO2 chromatography eluting with DCM/MeOH (20:1) to afford 10 g (50%) of (S)-2-methyl-N-((1S)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)ethyl)propane-2-sulfinamide (124) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7](OCC)(=[O:12])[CH2:8][C:9]([CH3:11])=O>C(O)(=O)C>[CH3:11][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][N:6]2[C:7](=[O:12])[CH:8]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nccs1
Solvent: CC(=O)O
Product: Cc1cc(=O)n2ccsc2n1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
To a stirred solution of 2-aminothiazole (5 g, 49.931 mmol) in acetic acid (40 ml) was added ethyl acetoacetate (9.48 ml, 74.843 mmol) at room temperature. The reaction mixture was heated to reflux for 12 h under nitrogen. The reaction mixture was cooled to room temperature. The residue obtained after concentration under reduced pressure was basified with saturated NaHCO3 solution and diluted with ethyl acetate (50 ml). The organic layer was washed with brine (100 ml), dried (Na2SO4) and concentrated to afford a crude product which was purified by silica gel column chromatography using 1% methanol in chloroform to give 3.3 g of the product as a white solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 6.15 (s, 1H), 6.95 (d, J=4.8 Hz, 1H), 7.94 (d, J=4.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1(O)[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19]Br)=[CH:14][CH:10]1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[C:11]([C:10]1[CH:14]=[C:15]([CH:16]=[CH:17][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:18]([OH:21])[CH2:19][NH:23][CH2:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1)(=[O:12])[NH2:13]
Reactant: NCCCn1nnc2ccccc21
Reactant: NC(=O)C1C=C(C(=O)CBr)C=CC1(O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(C(O)CNCCCn2nnc3ccccc32)ccc1OCc1ccccc1

Procedure:
A mixture of 17.5 gm of 2-benzyloxy-5-bromoacetyl salicylamide, 17.6 gm of 1-(3-aminopropyl)-1H-benzotriazole, 6 gm of sodium carbonate and 150 ml of ethyl acetate was refluxed for 1.5 hours. After separation of the inorganic constituents, the mother liquor was evaporated, the residue was dissolved in a 100 ml of acetonitrile, and the solution was acidified with 5 gm of oxalic acid. The precipitated 1-[3-(3-carbamoyl-4-benzyloxy-β-oxophenethylamino)-propyl]-1-H-benzotriazole oxalate was collected by suction of filtration converted with aqueous ammonia into the base (m.p. 186°-188° C.) and reduced in 100 ml of ethanol with sodium borohydride to form 1-[3-(3-carbamoyl-4-benzyloxy-β-hydroxyphenethylamino)propyl]-1-H-benzotriazole.