Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:27][CH:26]=[N:25][CH:24]=1)CCC.CCOC(C)=O.[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:23]3[S:27][CH:26]=[N:25][CH:24]=3)[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(-c3cncs3)c2)cn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
A solution of Example A1 (0.3 g, 1.192 mmol) in toluene (10 mL) was sparged with Ar, treated with 5-(tributylstannyl)thiazole (0.446 g, 1.192 mmol), Pd(PPh3)4 (0.138 g, 0.119 mmol) and heated at 110° C. for 16 h. The mixture was cooled to RT, treated with EtOAc and 10% aq. KF solution (30 mL) and stirred for 1 h. The solids were removed via filtration through diatomaceous earth, and the layers of the filtrate were separated. The aqueous layer was extracted with additional EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (180 mg, 50%) as a pale orange solid. 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.64-8.63 (m, 2H), 8.57 (d, J=5.7 Hz, 1H), 8.43 (d, J=8.9 Hz, 1H), 8.04 (dd, J=8.9, 2.8 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.15 (dd, J=5.7, 2.4 Hz, 1H); MS (ESI) m/z: 301.1 (M+H+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9](N3CCCCC3)=[CH:8]2)=[CH:2]1.[CH2:22]([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32][N:12]2[CH2:13][CH2:14][CH:15]([C:9]3[C:10]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[N:7]([CH2:6][C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[CH:8]=3)[CH2:10][CH2:11]2)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])[CH3:23]
Reactant: c1cnc2c(c1)c(N1CCCCC1)cn2Cc1ccoc1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: CCOC(=O)c1cc(CN2CCC(c3cn(Cc4ccoc4)c4ncccc34)CC2)ccc1OC
Yield: 182.4 %

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 0.62 g (2.2 mmol) of 1-furan-3-ylmethyl-3-piperidinyl-1H-pyrrolo[2,3-b]pyridine and 0.79 g (2.9 mmol) of 5-bromomethyl-2-methoxybenzoic acid ethyl ester. After standard work-up and purification, 0.95 g (91% of yield) of the expected ester were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[NH:16]([C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1)[NH2:17]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[N:17]=[C:10]([CH:11]([CH3:13])[CH3:12])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: NNc1nc2ccccc2s1
Reactant: CC(C)C(=O)CC(=O)c1ccc(F)cc1
Solvent: CC(=O)O
Product: CC(C)c1cc(-c2ccc(F)cc2)n(-c2nc3ccccc3s2)n1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of the 1,3-diketone (103 g, 495 mmol) (preparation described in Example 1, Step A) in glacial acetic acid (800 mL) was added 2-hydrazinobenzothiazole (85.8 g, 520 mmol). The resulting solution was refluxed for 2.5 hours and then cooled to room temperature overnight. The resulting precipitate was collected, washed with water and dried overnight to give 154 g (92%) of a cream colored solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:18])([F:17])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.[OH:19][C:20]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>CC(C)=O>[OH:19][C:20]1[CH:27]=[C:26]([O:28][CH2:13][C:12]2[CH:15]=[CH:16][C:9]([C:8]([F:18])([F:17])[F:7])=[CH:10][CH:11]=2)[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=Cc1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Potassium carbonate (16.51 g) and 4-trifluoromethylbenzylbromide (18.47 ml) were added to an acetone solution of 2,4-dihydroxybenzaldehyde (15 g). The mixture was stirred at room temperature for 15 hours and further stirred at 60° C. for 7 hours. After being cooled to room temperature, the mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford the title compound as a white powder (12.76 g).
Reaction SMILES: [C-:1]#[N:2].[K+].[I-].C[N+](C)(C)[CH2:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[NH:10][C:9]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CN(C)C=O>[C:17]1([C:9]2[NH:10][C:11]3=[N:12][CH:13]=[CH:14][N:15]=[C:16]3[C:8]=2[CH2:7][C:1]#[N:2])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[N+](C)(C)Cc1c(-c2ccccc2)[nH]c2nccnc12
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c(-c2ccccc2)[nH]c2nccnc12
Temperature: 75 °C

Procedure:
A solution of potassium cyanide (0.84 g) in water (20 mL) was added rapidly to a stirred solution of trimethyl(6-phenyl-5H-pyrrolo[2,3-b]pyrazin-7-ylmethyl)-ammonium iodide [1.1 g, Reference Example 33] in dimethylformamide (20 mL) and the mixture heated at 75° C. for 6 hours. The cooled solution was diluted with water (100 mL) and the precipitated solid filtered to give the title compound as a yellow solid, m.p. 247–248° C.
Reaction SMILES: [F:1][C:2]([F:22])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:23][C:24]([F:29])([F:28])[CH:25]1[O:27][CH2:26]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>C(#N)C>[F:1][C:2]([F:22])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:26][CH:25]([OH:27])[C:24]([F:29])([F:28])[F:23])[C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: FC(F)(F)C1CO1
Reactant: Oc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CC#N
Product: Oc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Yield: 54.1 %

Procedure:
A solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]phenol (11.0 g, 34.9 mmol), 3,3,3-trifluoro-1,2-epoxypropane (4.5 mL, 52.4 mmol) and ytterbium trifluoromethanesulfonate (2.2 g, 10 mol %) in 20 mL of acetonitrile was heated at 50° C. in a sealed glass tube for 16 h. The reaction mixture was cooled, water was added, and the reaction mixture was extracted with ether. The ether layer was washed with saturated aqueous sodium bicarbonate and brine and dried over MgSO4. The dried organic layer was evaporated to give 8.07 g (89%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2hydroxypropyl)amino]phenol product as a yellow oil. HRMS calcd. for C18H17F7NO3: 428.1097 [M+H]+, found: 428.1104. 1H NMR (CDCl3) δ3.58 (dd, 1H), 3.88 (dd, 1H), 4.39 (m, 1H), 4.68 (s, 2H), 5.91 (tt, 1H), 6.25-6.37 (m, 3H), 7.07-7.14 (m, 4H), 7.35 (t, 1H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:5]2[CH2:4]1)[CH3:2]>[Pd].CCO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: CCN1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CCN1CCn2nc(N)cc2C1
Reaction time: 8 h
Yield: 97 %

Procedure:
In a 250 mL round-bottomed flask, 5-ethyl-2-nitro-4,5,6,7-tetrahydro -pyrazolo[1,5-a]pyrazine (427 mg, 2.17 mmol, Eq: 1.00) was combined with EtOH (50 ml) to give a light yellow suspension. The reaction mixture was vacuum flushed three times with argon then 10% Pd/C (115 mg, 1.08 mmol, Eq: 0.5) was added and the reaction mixture was stirred under hydrogen balloon overnight. The reaction was filtered through a pad of celite. The celite pad was washed with ethanol. The combined filtrate and washes were concentrated in vacuo to afford the desired product (350 mg). (M+H)+=167 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 (t, J=7.18 Hz, 3 H) 2.59 (q, J=7.18 Hz, 2 H) 2.79-3.03 (m, 2 H) 3.57 (overlapping s, 4 H) 3.87-4.12 (m, 2 H) 5.35 (s, 1 H).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.[CH2:9]([N:16]1[CH2:21][C@@H:20]([CH3:22])[NH:19][CH2:18][C@@H:17]1[CH3:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH2:9]([N:16]1[C@@H:17]([CH3:23])[CH2:18][N:19]([CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[C@H:20]([CH3:22])[CH2:21]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C1CC2(CCO1)CO2
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1
Solvent: CO
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](C)CN1CC1(O)CCOCC1
Temperature: 150 °C

Procedure:
To a microwave vial was added 1,6-dioxaspiro[2.5]octane (259 mg, 2.3 mmol), (2S,5R)-1-benzyl-2,5-dimethylpiperazine (464 mg, 2.3 mmol) and 5 mL of MeOH. The vial was heated to 150° C. for 2 h in the microwave. The crude reaction was concentrated to provide intermediate H1(ii) (723 mg, 100%) 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.92 (d, J=6.22 Hz, 3H), 1.13 (d, J=5.84 Hz, 3H), 1.35-1.45 (m, 1H), 1.46-1.68 (m, 4H), 1.83 (dd, J=11.30, 9.80 Hz, 1H), 2.12 (d, J=13.94 Hz, 1H), 2.36-2.53 (m, 3H), 2.60-2.69 (m, 2H), 2.85 (d, J=9.04 Hz, 1H), 3.08 (d, J=13.38 Hz, 1H), 3.71-3.82 (m, 4H), 4.04 (d, J=13.38 Hz, 1H), 7.10-7.47 (m, 5H). Mass Spectrum: Calcd for C19H30N2O2 (M+H): 318. Found: 318.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]2)[CH2:26][O:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:23][C:24]1([CH3:36])[O:28][C@H:27]([CH2:29][N:30]2[CH:34]=[CH:33][C:32]([NH:35][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=4[Br:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:31]2)[CH2:26][O:25]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Br)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Br)=CC1=O
Temperature: 0 °C
Yield: 74.6 %

Procedure:
To a solution of (S)-2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.260 g, 0.71 mmol) in N,N-dimethylformamide (10 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.180 g, 0.91 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.663 g, 1.50 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.200 g, 1.55 mmol) was added. The mixture was stirred at room temperature for 5 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 20% to 100% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.290 g, 75%) as a yellow solid: HR-ES-MS m/z calculated for C25H31BrN4O5 [M+H]+ 547.1551, observed 547.1549, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.4 Hz, 3 H), 0.94 (d, J=6.4 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3H), 1.37-1.50 (m, 1H), 1.50-1.65 (m, 1H), 1.69-1.83 (m, 1H), 3.73 (dd, J=8.4, 5.8 Hz, 1H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.11 (t, J=5.8 Hz, 2H), 4.20 (d, J=18.4 Hz, 1H), 4.35 (quin, J=5.8 Hz, 1H), 4.61 (d, J=18.4 Hz, 1H), 4.77 (s, 1H), 4.90 (dd, J=10.6, 4.8 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.24-7.35 (m, 1H), 7.50 (m, 2H), 7.60 (d, J=2.1 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:4]([N:6]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1)[CH2:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)=[O:5].[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH3:26][C:21]1[CH:20]=[C:19]([N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[C:4](=[O:5])[C@@H:3]([NH:2][S:34]([CH3:33])(=[O:36])=[O:35])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:22]=1[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](N)c2ccccc2)cc1C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](NS(C)(=O)=O)c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
A solution of (S)-2-amino-N-(3,4-dimethyl-phenyl)-2-phenyl-N-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide hydrochloride (40 mg, 0.086 mmol, derived from example 1) in dry CH2Cl2 (1.5 mL) was treated with methanesulphonyl chloride (10 mg, 0.087 mmol) under Argon and the mixture stirred at ambient temperature for 30 min then quenched with aqueous Na2CO3 (2 M, 1 mL), concentrated, then redissolved in EtOAc (15 mL) and washed with aqueous Na2CO3 (2 M, 3×15 mL). The combined aqueous layers were extracted with EtOAc (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (42 mg, 96%) as a light yellow oil. MS m/e: 506.1 [M+H]+.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[OH:5].P([O-])([O-])([O-])=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[OH:2][CH:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[OH:5]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
A solution of 0.2 mg of bovine pancreatic insulin (Wako Pure Chemical Industries, Itd.) in 1 mL of a 2 mmol/L aqueous solution of hydrochloric acid, a solution of 320 mg of anhydrous β-lactose (Nacalai Tesque, Inc.) in 2 mL of distilled water, and 1 mL of a 200 mmol/L phosphate buffer (pH 8.4) were mixed in a test tube. The mixture was subjected to reaction at 40° C. for 24 hours. To 3 mL of the resulting solution was added 0.5 mL of a 100 mmol/L aqueous solution of citric acid to adjust the pH to 5.9, and the mixture was subjected to reaction at 40° C. The reaction mixture was intermittently analyzed for products obtained by the reaction of insulin with lactose by HPLC in a manner similar to that in Example 1. The results are shown in Table 4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]#[N:12])=[CH:5]2.[H-].[Na+].Cl[CH2:16][C@@H:17]([CH2:26][O:27][Si:28]([CH3:34])([CH3:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.O>[Si:19]([O:18][C@H:17]([CH2:26][O:27][Si:28]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:33])[CH3:34])[CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]#[N:12])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:25])[CH3:24]
Reactant: Cc1ccc2[nH]c(C#N)cc2c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CCl)O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)cc(C#N)n2C[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To a solution of 39 mg of 5-methyl-1H-indole-2-carbonitrile (0.25 mmol) in 0.5 mL of DMF 15 mg of NaH (60% in oil, 0.375 mmol) was added and mixture was stirred for 30 min. Then 170 mg of (R)-5-(chloromethyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (0.5 mmol) was added and stirring continued for 24 hs. The reaction mixture was diluted with 10 mL of water and extracted with DCM. Combined organic extracts dried over sodium sulfate, concentrated and purified using silica gel column eluting with hexane-ethyl acetate 50:1 to afford 56 mg of (S)-1-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-5-methyl-1H-indole-2-carbonitrile. 1H NMR (600 MHz, CDCl3): δ 8.09 (d, 1H, J=8.8 Hz), 7.35 (s, 1H), 7.24 (d, 1H, J=8.8 Hz), 7.18 (s, 1H), 4.04 (m, 1H), 3.82 (m, 1H), 3.77 (m, 2H), 3.68 (m, 1H), 2.43 (s, 3H), 1.08 (m, 18H), 0.26 (m, 12H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[C:14]2[C:10]=1[C:11]1[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:12]=1[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(S(C1C=C(C2C=C([C:46]([N:48]3[CH2:53]C[N:51](C)[CH2:50][CH2:49]3)=O)C=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:8][C:9]1[CH:17]=[C:16]([C:18]([NH:51][CH2:50][CH2:49][N:48]([CH3:53])[CH3:46])=[O:20])[CH:15]=[C:14]2[C:10]=1[C:11]1[CH:24]=[C:23]([CH3:25])[CH:22]=[N:21][C:12]=1[NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(=O)N3CCN(C)CC3)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: Cc1cnc2[nH]c3cc(C(=O)O)cc(SCc4ccccc4)c3c2c1
Product: Cc1cnc2[nH]c3cc(C(=O)NCCN(C)C)cc(SCc4ccccc4)c3c2c1

Procedure:
The title compound was synthesized from Compound 150 using an analogous procedure to that described in the preparation of Compound 140. 1H NMR (400 MHz, MeOD) δ ppm 2.53 (s, 3H) 3.02 (s, 6H) 3.43 (t, J=5.81 Hz, 2H) 3.82 (t, J=5.81 Hz, 2H) 4.42 (s, 2H) 7.16-7.26 (m, 3H) 7.31 (d, J=7.83 Hz, 2H) 7.82 (d, J=1.26 Hz, 1H) 7.96 (s, 1H) 8.30 (s, 1H) 8.80 (s, 1H) [M+H] calc'd for C24H26N4OS, 419; found, 419.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]1([C:14]2[N:15]=[C:16]([C:26](O)=[O:27])[N:17]([CH3:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH:1]1([NH:7][C:26]([C:16]2[N:17]([CH3:25])[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:15]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: Cn1c(C(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
Using essentially the same procedure as Example 4, Step B, but using cyclohexylamine (0.025 mL), 4,5-diphenyl-1-methylimidazole-2-carboxylic acid (30 mg, 0.10 mmol) from Example 4, Step A was converted to the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[C:8]([O:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])=[CH:4][CH:3]=1.[OH-].[Ca+2].[OH-].Cl[C:23]1[O:24][C:25]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=2[N:27]=1.O>CS(C)=O>[Cl:32][C:30]1[CH:29]=[CH:28][C:26]2[N:27]=[C:23]([O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:16])[C:8]([O:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])=[O:9])=[CH:17][CH:18]=3)[O:24][C:25]=2[CH:31]=1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OC[Si](C)(C)C
Reactant: Clc1ccc2nc(Cl)oc2c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3o2)cc1)C(=O)OC[Si](C)(C)C
Temperature: 40 °C

Procedure:
A mixture of 6.7 g (0.025 mole) of the R-enantiomer of trimethylsilyl-methyl 2-(4-hydroxy-phenoxy)-propionate, 0.9 g of calcium hydroxide and 10 ml of dimethylsulphoxide is heated at 40° C. A solution of 4.7 g (0.025 mole) of 2,6-dichlorobenzoxazole in 15 ml of dimethylsulphoxide is slowly added dropwise at this temperature, with stirring. The reaction mixture is subsequently stirred at 40° C. for 2 hours and at room temperature for 16 hours. Working up is then carried out by pouring the reaction mixture into water, extracting the resulting oily product with cyclohexane, washing the organic phase successively with dilute aqueous sodium hydroxide solution and water, rendering it weakly acidic with glacial acetic acid and then drying it and concentrating it under reduced pressure. 9.3 g (88.6% of theory) of the R-enantiomer of trimethylsilyl-methyl 2-{4-[(6-chloro-2-benzoxazolyl)-oxy]-phenoxy}-propionate are obtained in this manner in the form of crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.CS([Cl:16])(=O)=O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([Cl:16])[N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12
Reactant: [O-][n+]1ccc(Br)c2cc[nH]c21
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: Clc1cc(Br)c2cc[nH]c2n1
Temperature: 75 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a suspension of the 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (27 mmol) in N,N-dimethylformamide (57 mL) at 50° C. was added methanesulfonyl chloride (67.5 mmol) under nitrogen. Upon completion of the addition, the reaction was stirred at 75° C. for 1 hour. The reaction was cooled to room temperature and quenched with water (60 mL). Then, it was cooled to 5° C. and 6N sodium hydroxide solution was added to raise the pH to 7. The ice bath was removed and the resulting slurry was stirred at room temperature for 3 h. The precipitate was filtered, washed with water (50 mL), and dried under high vacuum to give the title product as a white solid (89%). ESMS [M+H]+: 231.0
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([C:17]([O:19]C)=[O:18])([CH3:16])[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([C:17]([OH:19])=[O:18])([CH3:16])[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)(C)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(C)(C)C(=O)O)C1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
1.045 g of (R)-3-(1-methoxycarbonyl-1-methyl-ethyl)-piperidine-1-carboxylic acid tert-butyl ester is taken up in 5 ml of methanol and the mixture is admixed with 5 ml of 3M NaOH. The mixture is then stirred at 60° C. for 20 hours. The methanol is removed in vacuo and the aqueous residue acidified with 2M HCl to pH 2-3. The mixture is extracted with ethyl acetate (3×) and the combined extracts are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil which can be used without further purification.