Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:53][C@@H:54]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[S:69](=[O:71])(=[O:70])[NH:68][C:67](=[O:72])[CH:66]=2)=[CH:61][CH:60]=1)[C:55]([OH:57])=[O:56]>CN1CCCC1=O.CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([NH:53][C@@H:54]([CH2:58][C:59]1[CH:60]=[CH:61][C:62]([C:65]2[S:69](=[O:71])(=[O:70])[NH:68][C:67](=[O:72])[CH:66]=2)=[CH:63][CH:64]=1)[C:55]([OH:57])=[O:56])=[O:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-phenylalanine (98.5 mg, 0.371 mmol) in N-methylpyrrolidinone (2.2 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (128 mg, 0.337 mmol) and N,N-diisopropylethylamine (180 μL, 0.001 mol) and premixed for 5 minutes. To the solution was added (2S)-2-amino-3-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]propanoic acid (100 mg, 0.338 mmol) with several drops of DMSO to dissolve and the mixture was stirred overnight. The product was purified by preparative LCMS to afford the desired product (96 mg, 52%). 1H NMR (400 MHz, CD3OD): δ 7.81 (d, J=8.2, 2H), 7.42 (d, J=8.2, 2H), 7.18–7.36 (m, 5H), 6.98 (s, 1H), 4.70–4.73 (m, 1H), 4.26–4.30 (m, 1H), 3.02–3.13 (m, 3H), 2.71–2.76 (m, 1H), 1.33 (s, 9H); LCMS found for C26H9N3O8SNa (M+Na)+: m/z=566.0.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C[O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][N:9]=1)=O.[BH4-].[Na+]>CCOC(C)=O.CO.C1COCC1>[OH:5][CH2:6][C:8]1[N:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Calcium chloride (22.7 g, 204.9 mmol) was added to a suspension of dimethylpyridine-2,5-dicarboxylate (10.0 g, 51.2 mmol) in a mixture 1:2 THF: MeOH (300 mL). The mixture was cooled at 0 C, sodium borohydride (4.85 g, 128.1 mmol) was added portion wise. The reaction mixture warmed slowly to room temperature and stirred for 18 h. An additional 2.5 equivalent of sodium borohydride was added and the reaction mixture was stirred at room temperature for 2 days. Additional THF (100 mL) and MeOH (100 mL) was added and the mixture was stirred for ˜15 h. An additional 2.5 equivalent of sodium borohydride (newer batch) was added and the reaction mixture was stirred at room temperature for 15 h. The mixture was slowly poured onto ice-water and diluted with EtOAc (˜200 mL). The white solid was filtered and discarded. Phases from the filtrate were separated, the organic phase was washed with water (3×100 mL). The aqueous washes were combined and re-extracted with EtOAc (2×100 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound as an off white solid (5.8 g, 73%). Method B HPLC-MS: MH+ requires m/z=168 Found: m/z=168, Rt=0.91 min (100%).
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH3:20])[O:14]1.[CH:22]([C:24]([CH3:26])=[O:25])=[CH2:23].Cl>CCOCC>[CH3:12][C:13]1([CH3:21])[O:18][C:17](=[O:19])[CH:16]=[C:15]([CH2:20][CH2:23][CH2:22][C:24](=[O:25])[CH3:26])[O:14]1
Reactant: C=CC(C)=O
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(=O)CCCC1=CC(=O)OC(C)(C)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
In an argon gas stream, 20.6 ml of n-butyl lithium (1.6M solution in hexane) were added to 60 ml of an ether solution containing 3.53 g (0.033 mol) of diisopropylamine at -20° C. to form LDA. After stirring for 30 minutes, the solution was cooled to -78° C., and 10.4 ml (0.06 mol) of HMPA were added thereto, followed by stirring for 15 minutes. Afterward, a mixture of 4.26 g (0.03 mol) of 2,2-dimethyl-6-methyl-1,3-dioxin-4-one and 60 ml of ether as well as 60 ml of an ether solution containing 2.1 g (0.03 mol) of methyl vinyl ketone were added to the solution. After the temperature was gradually returned to room temperature, 10% hydrochloric acid was added thereto to neutralize the solution, and extraction was then carried out with ether. The resultant organic layer was dried over anhydrous magnesium sulfate. Next, the used solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 3.16 g of 2,2-dimethyl-6-(4-oxopentyl)-1,3-dioxin-4-one.
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]1[O:20][CH2:19]1>O1CCCC1>[C:6]1([S:12]([C:15]([CH3:17])([CH3:16])[CH2:19][CH2:18][OH:20])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CO1
Reactant: CC(C)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CCO)S(=O)(=O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of n-butyllithium in cyclohexanes (1.8M, 35.1 ml; 63.18 mmol) was added dropwise to a stirred solution of isopropyl phenyl sulphone (9.95 g, 54 mmol) in tetrahydrofuran (100 ml) keeping the temperature of the mixture below −60° C. The mixture was stirred for 30 min. and ethylene oxide was passed through the reaction mixture for 10 min. The mixture was warmed up to −40° C. for 30 min., then quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified on silica gel (i-hexane:ethyl acetate) to give the title compound (12.3 g, 99%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl-].[CH3:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]=[N+:19]([CH3:21])[CH3:20].COC1C(OC)=CC=CC=1C=O.CNC>>[CH3:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]([N:19]([CH3:21])[CH3:20])[C:3]1[C:4]2[CH2:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH2:8][C:9]=2[NH:1][CH:2]=1
Reactant: COc1cccc(C=[N+](C)C)c1OC
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CNC
Agent: COc1cccc(C=O)c1OC
Agent: [Cl-]
Product: COc1cccc(C(c2c[nH]c3c2CC=C(C(=O)O)C3)N(C)C)c1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1H-indole-6-carboxylic acid and (2,3-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2,3-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([Cl:13])=[C:8]([O:14][CH2:15][CH2:16][NH3+:17])[CH:7]=[CH:6]2.C([O-])([O-])=O.[K+].[K+].[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=O.[BH4-].[Na+]>CO>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([Cl:13])=[C:8]([O:14][CH2:15][CH2:16][NH:17][CH2:29][C:25]1[O:24][CH:28]=[CH:27][CH:26]=1)[CH:7]=[CH:6]2
Reactant: O=Cc1ccco1
Reactant: [NH3+]CCOc1ccc2cc(Br)ccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: Clc1c(OCCNCc2ccco2)ccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
To a solution of 2-[(6-bromo-1-chloronaphthalen-2-yl)oxy]ethanaminium chloride (91 mg, 0.27 mmol) in 10 mL of MeOH, K2CO3 (41 mg, 0.30 mmol) was added. After 10 min, 45 μL (0.54 mmol) of furan-2-carbaldehyde were added. The resulting solution was stirred for 1 h at room temperature, added with sodium borohydride (10 mg, 0.27 mmol) and then stirred for further 2 h at room temperature. The solvent was evaporated under vacuum and the crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH 95:5) to afford 2-[(6-bromo-1-chloronaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine as a brown solid (87 mg, 85% yield). 1H-NMR (DMSO-d6) δ: 8.35 (1H, d, J=2.05 Hz), 8.07 (1H, d, J=9.01 Hz), 8.00 (1H, d, J=9.01 Hz), 7.81 (1H, dd, J=1.05 Hz, J=2.08 Hz), 7.78 (1H, dd, J=2.05 Hz, J=8.98 Hz), 7.67 (1H, d, J=8.98 Hz), 6.70 (1H, dd, J=1.05 Hz, J=3.34 Hz), 6.34 (1H, dd, J=2.08 Hz, J=3.34 Hz), 4.55 (2H, d, J=5.44 Hz), 4.43 (2H, s), 3.43 (2H, d, J=5.44 Hz). HPLC-MS (ESI+): m/z 381.21 [M+H+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O.[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[Cl:15]>N1C=CC=CC=1>[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][C:9]=1[Cl:15]
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Br)c(Cl)c1
Reaction time: 1.5 h

Procedure:
In a 100 mL round bottomed flask 4-bromo-3-chloroaniline (A, 2.06 g, 10.0 mmol) was dissolve in pyridine (30 mL) at room temperature. Methanesulfonyl chloride (1.72 g, 15.0 mmol, 1.5 equiv) was added under an ice-water bath cooling. The ice bath was removed immediately after addition of the reagent. After stirring for 1.5 h, another methanesulfonyl chloride (0.57 g, 5.0 mmol, 0.5 equiv) was added at room temperature for the reaction to go to completion. After stirring for 0.5 h, the mixture was treated with H2O (50 mL) and extracted with EtOAc (50 mL×3). Combined organic layers were washed with brine (50 mL×2) and dried over Na2SO4. The solvent was removed in vacuo to give the crude material (very light brown solid, 5.32 g). The crude product was purified by a silica gel column chromatography (SiO2=80 g, EtOAc/hexane=1:1, Rf=0.3) to give the desired product as colorless crystals. The obtained crystals were recrystallized from EtOAc/hexane=1:2 (24 mL) to give the desired material [N-(4-bromo-3-chlorophenyl)methanesulfonamide (B)].
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([F:25])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].[CH3:26][S:27]([NH2:30])(=[O:29])=[O:28]>>[CH3:26][S:27]([NH:30][C:10](=[O:11])[C:9]1[CH:13]=[C:5]([O:4][C:3]2[C:17]([F:25])=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])[CH:6]=[CH:7][C:8]=1[N+:14]([O-:16])=[O:15])(=[O:29])=[O:28]
Reactant: CS(N)(=O)=O
Reactant: O=C(Cl)c1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CS(=O)(=O)NC(=O)c1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Reaction of 5-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitro benzoyl chloride with methanesulphonamide to give the required compound, i.e. N-methanesulphonyl-5-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2-nitro-benzamide.
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.C1[C:45]2NC=[C:48]([O:49][C@@H:50]3[O:55][C@H](CO)[C@H](O)[C@H](O)[C@H:51]3[OH:60])[C:44]=2[C:43](Cl)=C(Br)C=1.CC([C@H](O)C(O)=O)(CO)C>C(O)C(N)(CO)CO.Cl>[CH3:45][C:44]1([CH3:43])[C@H:51]([OH:60])[C:50](=[O:55])[O:49][CH2:48]1
Reactant: OC[C@H]1O[C@@H](Oc2c[nH]c3ccc(Br)c(Cl)c23)[C@H](O)[C@@H](O)[C@H]1O
Agent: CC(C)(CO)[C@H](O)C(=O)O
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Product: CC1(C)COC(=O)[C@H]1O
Reaction time: 1 h

Procedure:
A full inoculating loop of E. coli XL1Blue pKS+681 was grown (overnight, 37° C.) on an LB plate with ampicillin (100 μg/ml), IPTG (0.2 mM) and X-Gal (80 mg/l) and then resuspended (OD600=2.5) in 0.5 ml of Tris-HCl pH 7.0 and 50 mM D,L-pantolactone. A corresponding E. coli XL1Blue pBluescriptKS+-sample (OD600=2.5) was a useful comparison. After 1 h, the cells were centrifuged down and D,L-pantolactone, D,L-, D-, and L-pantoic acid were determined by HPLC analysis. Tab. 6a shows the activities and ee values for the various samples. The suspension had an activity of >90 U/L. However, no significant activity was evident in liquid culture batches (cf. Example 12).
Reaction SMILES: [OH:1][C:2]([C@@:5]1([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6]1)([CH3:4])[CH3:3].[ClH:36]>CCOCC.C1COCC1>[ClH:36].[ClH:36].[NH2:10][C@H:7]1[CH2:8][CH2:9][C@@:5]([C:2]([OH:1])([CH3:3])[CH3:4])([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CC[C@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)(C(C)(C)O)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
tert-Butyl [(3R)-3-(1-hydroxy-1-methylethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (75 mg, 0.15 mmol) was mixed with a 2.00 M solution of hydrogen chloride in ether (2 mL) and THF (1 mL). After being stirred for 1 h at room temperature, the reaction solution was concentrated to provide the desired product (70 mg, 98.7%). LCMS calculated for C17H28F3N4O2: (M+H) 473.2; found 473.2.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.[NH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([NH:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:17]=2)=[CH:12][CH:11]=1.C([O-])(=O)C.[Na+]>O.CN(C=O)C>[NH2:3][C:2]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([NH:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:17]=2)=[CH:14][CH:15]=1)=[O:1]
Reactant: N#C[O-]
Reactant: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(OCCN)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2nc(NC(=O)N(C)C)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A solution of potassium cyanate (64.9 mg) in H2O (0.5 ml) was added to a solution of N′-[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea hydrochloride (172.8 mg) and sodium acetate (65.6 mg) in a mixture of DMF (1.5 ml) and H2O (0.5 ml). The reaction mixture was stirred at ambient temperature overnight. The mixture was diluted with H2O, partitioned between AcOEt and H2O. The aqueous layer was reextracted with AcOEt. saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by 10% MeOH/CHCl3. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt-IPE to give N′-[5-(4-{2-[(aminocarbonyl) -amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (87.0 mg) as a powder.
Reaction SMILES: C(OC([N:11]1[CH2:14][CH:13]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[Si:16]([O:15][CH:13]1[CH2:12][NH:11][CH2:14]1)([C:29]([CH3:32])([CH3:30])[CH3:31])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)[Si](OC1CN(C(=O)OCc2ccccc2)C1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Yield: 95.6 %

Procedure:
A solution of 1-benzyloxycarbonyl-3-t-butyldiphenylsilyloxyazetidine (4.04 g, 9.07 mmol) in methanol (200 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (4.04 g) at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was filtered and the filtrate concentrated under reduced pressure, and the obtained residue was dried under reduced pressure to give 3-t-butyldiphenylsilyloxyazetidine (2.70 g, yield 96%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[O:11][C:12]2[CH:24]=[CH:23][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[CH:13]=2)[N:3]=1.Br[C:29]1[CH:34]=[C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:32]=[CH:31][N:30]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.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].CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C>[C:35]([C:33]1[CH:32]=[CH:31][N:30]=[C:29]([N:15]2[C:14]3[CH:13]=[C:12]([O:11][C:10]4[CH:25]=[CH:26][CH:27]=[C:8]([N:4]5[C:5]([CH3:7])=[CH:6][C:2]([CH3:1])=[N:3]5)[CH:9]=4)[CH:24]=[CH:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:34]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1cc(C)n(-c2cccc(Oc3ccc4c(c3)[nH]c3ccccc34)c2)n1
Reactant: CC(C)(C)c1ccnc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc(C)n(-c2cccc(Oc3ccc4c5ccccc5n(-c5cc(C(C)(C)C)ccn5)c4c3)c2)n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 93.8 %

Procedure:
A mixture of 2-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenoxy)-9H-carbazole 4 (530 mg, 1.5 mmol, 1.0 eq), 2-bromo-4-tert-butylpyridine (642 mg, 3.0 mmol, 2.0 eq), Pd2(dba)3 (55 mg, 0.06 mmol, 0.04 eq), JohnPhos (36 mg, 0.12 mmol, 0.08 eq) and tBuONa (231 mg, 2.4 mmol, 1.6 eq) in toluene (6 m) and dioxane (6 mL) was stirred at a temperature of 95-105° C. for 2 days under a nitrogen atmosphere. Then the mixture was cooled to ambient temperature. The solvent was removed under reduced pressure and the residue was purified through column chromatography on silica gel using hexane/ethyl acetate (10:1-5:1) as an eluent to obtain the desired product as a brown solid (685 mg in 94% yield). 1H NMR (DMSO-d6, 400 MHz): δ1.26 (s, 9H), 2.11 (s, 3H), 2.23 (s, 3H), 6.00 (s, 1H), 7.06-7.08 (m, 1H), 7.10 (dd, J=8.0, 2.4 Hz, 1H), 7.14 (t, J=2.4 Hz, 1H), 7.24-7.26 (m, 1H), 7.31 (t, J=7.2 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.41-7.48 (m, 3H), 7.61 (d, J=1.6, 1H), 7.74 (d, J=8.4 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.55 (d, J=4.8 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz): δ12.21, 13.22, 30.01, 34.81, 101.37, 107.50, 111.11, 113.01, 113.81, 115.78, 116.80, 118.49, 119.27, 119.72, 120.13, 121.11, 121.83, 123.20, 125.90, 130.45, 139.19, 139.43, 139.94, 141.01, 148.07, 149.37, 150.60, 155.32, 157.50, 163.03.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.Cl[C:13]([O:15][CH3:16])=[O:14].Cl>O>[Cl:11][C:6]1[CH:5]=[C:4]([NH:3][C:13](=[O:14])[O:15][CH3:16])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Nc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
5 ml of water and 2.5 ml of 10% aqueous sodium hydroxide solution were carefully added to 1.70 g of 4-amino-2-chlorophenol cooled in an ice-water bath and 2 ml of methyl chloroformate were added dropwise to the resulting mixture. The reaction mixture was then stirred for 3 hours at room temperature, at the end of which it was acidified with 4 ml of 2N hydrochloric acid, and the resulting mixture was extracted with methylene; chloride. The resulting extract was washed with water and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent to give 2.08 g (yield 87%) of the title compound as a pale brown crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:18])[NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH:5]=[CH:4][C:3]=1[S:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][CH:21]=1.Cl[C:35]1[C:44]2[C:39](=[CH:40][C:41]([CH:45]([CH3:47])[CH3:46])=[CH:42][CH:43]=2)[N:38]=[CH:37][N:36]=1>C(O)C>[CH:45]([C:41]1[CH:40]=[C:39]2[C:44]([C:35]([NH:1][C:2]3[CH:7]=[C:6]([C:8](=[O:18])[NH:9][C@H:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH3:11])[CH:5]=[CH:4][C:3]=3[S:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:25]=3)=[N:36][CH:37]=[N:38]2)=[CH:43][CH:42]=1)([CH3:47])[CH3:46]
Reactant: CC(C)c1ccc2c(Cl)ncnc2c1
Reactant: C[C@H](NC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1)c1ccccc1
Solvent: CCO
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2c1
Yield: 74.7 %

Procedure:
(S)-tert-butyl 4-(2-amino-4-(1-phenylethylcarbamoyl)phenylthio)-phenylcarbamate (50 mg, 0.1078 mmol) and the product of Example 91F (24.5 mg, 0.1186 mmol) were heated at reflux in anhydrous ethanol (2 mL) under a nitrogen atmosphere for one hour. The reaction was cooled and concentrated by rotary evaporation. The residue was purified by silica gel flash chromatography eluting with 3:97 methanol/methylene chloride to afford the title compound as an off-white solid (51 mg, 0.0805 mmol, 68%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31 (d, J=6.99 Hz, 6 H) 1.45 (d, J=7.35 Hz, 3 H) 1.47 (s, 9 H) 3.03-3.21 (m, 1 H) 5.01-5.29 (m, 1 H) 6.96 (d, J=8.46 Hz, 1 H) 7.16-7.25 (m, 1 H) 7.26-7.43 (m, 3 H) 7.32 (d, J=8.09 Hz, 2 H) 7.51 (d, J=8.82 Hz, 2 H) 7.55-7.63 (m, 2 H) 7.72 (dd, J=8.46, 1.47 Hz, 1 H) 7.94 (d, J=1.47 Hz, 1 H) 8.41 (d, J=8.82 Hz, 1 H) 8.44 (s, 1 H) 8.80 (d, J=8.09 Hz, 1 H) 9.58 (s, 1 H) 9.95 (s, 1 H); MS (ESI+) m/z 634 (M+H)+; MS (ESI−) m/z 632 (M−H)+.
Reaction SMILES: N.[Cl:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7](Cl)[N:6]=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1.C([N:24](C(C)C)CC)(C)C>C1COCC1>[Cl:2][C:3]1[N:4]=[C:5]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:7]([NH2:24])[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(Cl)nc(SCc2ccccc2)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: N
Solvent: C1CCOC1
Product: Nc1nc(SCc2ccccc2)nc(Cl)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 52 %

Procedure:
Ammonia solution (14 ml, 0.5 M in dioxane) was added dropwise to a solution of the product of example 2, step (c) (2.0 g) and diisopropylethylamine (3.31 ml) in THF (100 ml) over a 1 h period at RT. After stirring for a further 1 h the reaction was concentrated in vacuo onto silica and purified by column chromatography using 9:1 then 4:1 isohexane/ethyl acetate as eluent to yield the subtitled product as a yellow solid (980 mg, 52%).
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[C:7]([CH3:14])=[CH:8][CH:9]=[C:10](B(O)O)[C:4]=2[O:3]1.[OH:16]O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1([F:15])[O:6][C:5]2[C:7]([CH3:14])=[CH:8][CH:9]=[C:10]([OH:16])[C:4]=2[O:3]1
Reactant: OO
Reactant: Cc1ccc(B(O)O)c2c1OC(F)(F)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(O)c2c1OC(F)(F)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.1 %

Procedure:
(2,2-difluoro-7-methyl-1,3-benzodioxol-4-yl)boronic acid (Intermediate 196, 150 mg, 1.28 mmol) was dissolved in THF (1.5 mL) and a 30% w/w aqueous solution of H2O2 (2.56 mmol) and NaOH (51 mg, 1.28 mmol) were added and the reaction mixture stirred for 2 days at room temperature. The reaction was quenched with a 2N aqueous solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness, affording the title compound (140 mg) as yellow oil.