Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C@@H:4]1[CH2:8][O:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[C:16]([OH:26])[CH:17]=[C:18]([O:20][C@@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[CH:19]=3)=[CH:11][CH:10]=2)=[N:5]1)[CH3:3].Cl[C:28]1[CH:33]=[N:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:24][O:23][CH2:22][C@@H:21]([O:20][C:18]1[CH:19]=[C:14]([C:12]2[NH:13][C:9]([C:6]3[O:7][CH2:8][C@@H:4]([C@@H:2]([OH:1])[CH3:3])[N:5]=3)=[CH:10][CH:11]=2)[CH:15]=[C:16]([O:26][C:28]2[CH:33]=[N:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][N:29]=2)[CH:17]=1)[CH3:25]
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
3-(5-{(4S)-4-[(1S)-1-Hydroxyethyl]-4,5-dihydro-1,3-oxazol-2-yl}-1H-pyrrol-2-yl)-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (880 mg, 2.44 mmol) synthesized in Example (112c) was dissolved in acetonitrile (20 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (630 mg, 3.27 mmol) synthesized in Example (97c) and potassium carbonate (1.20 g, 8.68 mmol) were added, followed by stirring at room temperature for 4 hours under nitrogen atmosphere. Water (50 mL) was added, and extraction was carried out with methylene chloride (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=1%-3%) to afford the desired compound (1.00 g, yield 79%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]NC(=O)CCC(N)=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]([Br:17])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: c1ccc(Cn2cnc3cncnc32)cc1
Solvent: ClC(Cl)Cl
Product: Brc1nc2cncnc2n1Cc1ccccc1

Procedure:
To a stirred solution of 12 (10.68 g, 50.7 mmol) in chloroform (500 mL) was added N-bromosuccinamide (45.20 g, 253.9 mmol) and the reaction mixture stirred under an atmosphere of nitrogen and at reflux temperature for 5 h. The reaction mixture was transferred to a separatory funnel and washed with saturated sodium sulfite solution (2×250 mL) followed by brine solution (2×250 mL). The chloroform fraction was dried over anhydrous sodium sulfate and concentrated and the reddish oil was purified by flash chromatography on silica gel using EtOAc/hexane (4:6) for elution. Yield 6.05 g. (41.2%). Mp 119-121° C.; 1H NMR (CDCl3): δ 5.53 (s, 2H, CH2), 7.35-7.39 (m, 5H, Ar—H), 9.03 (s, 1H, purine C8—H), 9.09 (s, 1H, purine C2—H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:20](O)[CH2:21][CH2:22][OH:23].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C(OCC)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:15]=[C:16]([CH3:18])[CH:17]=2)[O:19][CH2:20][CH2:21][CH2:22][OH:23])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(F)c2)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(F)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
A solution of 3-(3-fluorophenylsulfonyloxy)-5-methylphenol (930 mg, 3.3 mmol, as prepared in the preceding step), 1,3-propanediol (0.75 mL, 10 mmol), 1,1'-(azodicarbonyl)dipiperidine (1.76 g, 7.0 mmol), and anhydrous tetrahydrofuran (20 mL) was cooled to 0° C. under nitrogen. Tri-n-butylphosphine (1.7 mL, 7.0 mmol) was added dropwise over 8.5 minutes. The mixture was stirred at 0° C. for 5 minutes then at ambient temperature for 5.5 hours. Diethyl ether (100 mL) was added, and the mixture was stirred for 15 minutes. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography through silica gel (25% to 35% ethyl acetate in hexane) to give the title compound as a yellow oil (877 mg, 78%). 1H-NMR (300 MHz, CDCl3) δ 7.65-7.68 (m, 1H), 7.50-7.60 (m, 2H), 7.35-7.41 (m, 1H), 6.63 (br s, 1H), 6.41 (br s, 1H), 6.38 (br t, 1H, J=2.1 Hz), 4.01 (t, 2H, J=6.0 Hz), 3.82 (br t, 2H, J=6.0 Hz), 2.25 (s, 3H), 1.99 (pentet, 2H, J=6.0 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C16H17FO5S: 363.1 (M+Na), 379.0 (M+K). Found: 362.8, 378.9.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([CH3:33])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)cn1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)c(C)cn1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (133 mg, 0.75 mmol) and 3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K17) (244 mg, 0.75 mmol) in xylene (15 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light red solid (210 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10](OCC)OCC)[CH:3]=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:10]=[CH:9][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(COc1cccc(Br)c1)OCC
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc2ccoc2c1
Yield: 72.9 %

Procedure:
To a solution of 1-bromo-3-(2,2-diethoxyethoxy)benzene (2.3 g, 8.35 mmol) in toluene (28 mL), PPA (5.0 mL) was added, and the resultant mixture was stirred overnight while heated to reflux. The reaction solution was added with water at room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (hexane). 6-Bromobenzofuran (1.2 g, yield 68%, mixture with 7-bromobenzofuran) was obtained as a yellow oil.
Reaction SMILES: [CH:1]1([N:7]=[C:8]2[S:12][C:11]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:10][N:9]2[CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C([O-])([O-])=[O:23].[Na+].[Na+].OO>C(O)C.O>[CH:1]1([N:7]=[C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH2:18])=[O:23])=[CH:19][CH:20]=3)=[N:10][N:9]2[CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(-c2ccc(C#N)cc2)sc1=NC1CC=CCC1
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2ccc(C(N)=O)cc2)sc1=NC1CC=CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 4-[5-(cyclohex-3-enylimino)-4-methyl-4,5-dihydro-[1,3,4]thiadiazol-2-yl]-benzonitrile from protocol I76 (0.94 mmol, 280 mg) in ethanol (41 mL), a solution of Na2CO3 [3N] (12.3 mmol, 4.1 mL), and a solution of H2O2 at 30% in water (3.33 mL) were added. The mixture was stirred overnight at RT and concentrated under reduced pressure. The residue was stirred in water several hours, filtered, and dried under vacuum to afford the pure product. Yield: 64%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl[Sn]Cl.[OH-].[Na+]>Cl.CCO>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C#N)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(N)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
5-Methyl-2-nitrobenzonitrile (1.92 g, 11.84 mmol) was added in portions to a stirred solution of SnCl2 (11.22 g, 59.2 mmol) in conc. HCl (12 mL) and EtOH (12 mL). The reaction temperature was maintained at 20-30° C. using an ice bath. The reaction mixture was then stirred at room temperature for 1 h and poured into an ice cold aqueous solution of NaOH (6N, app. 30 mL) to neutralize to pH7. The product was extracted into EtOAc, washed with brine, dried over MgSO4 and concentrated to provide the title product (1.56 g, 99%) as a yellow-brown solid. 1H NMR (400 MHz, DMSO-d6) δ2.21 (s, 3H), 5.79 (bs, 2H), 6.68-6.71 (d, 1H), 7.10-7.13 (dd, 1H), 7.15 (s, 1H). 13C NMR (DMSO-d6) δ20.13, 93.99, 116.12, 118.94, 125.38, 132.32, 135.76, 150.21. MS 133 (MH+).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[N:3]=1.[OH:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.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>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:3]=[C:2]([C:36]3[CH:37]=[C:32]([OH:31])[CH:33]=[CH:34][CH:35]=3)[C:10]=12
Reactant: OB(O)c1cccc(O)c1
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1Cn1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1Cn1nc(-c2cccc(O)c2)c2c(N)ncnc21
Temperature: 100 °C

Procedure:
Prepared according to Procedure J. A mixture of 3-iodo-1-((8-methyl-2-o-tolylquinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (51 mg, 0.1 mmol), 3-hydroxyphenylboronic acid (15.2 mg, 1.1 eq), sodium carbonate (55 mg, 5 eq), tetrakis(triphenylphosphine)palladium (6 mg, 5% mmol) in DMF (1 mL) and water (0.3 mL) was heated to 100° C. under N2 for 4 h. The reaction mixture was cooled to room temperature, filtered and purified by reverse HPLC (MeCN/H2O/0.1% TFA) on C18 to give a white solid [PI3Kδ IC50=7 nM]. 1H-NMR (DMSO-d6) δ 8.37 (s, 1H), 8.35 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.65 (d, J=7.0 Hz, 1H), 7.53 (t, J=7.4 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.14-7.17 (m, 4H), 6.87-6.97 (m, 4H), 5.63 (s, br, 2H), 2.63 (s, 3H), 1.91 (s, 3H). Mass Spectrum (ESI) m/e=473 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[CH3:15][Sn](C)(C)C>ClCCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([CH3:15])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Cl)c(I)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1nc(Cl)c(C)c(N)c1Cl
Yield: 82.4 %

Procedure:
A mixture of methyl 4-amino-3,6-dichloro-5-iodopicolinate (8.1 g, 23.4 mmol), tetramethylstannane (8.35 g, 46.7 mmol), and bis(triphenylphosphine)palladium(II) chloride (2.5 g, 3.5 mmol) in 1,2-dichloroethane (40 mL) was irradiated in a Biotage Initiator microwave at 120° C. for 30 min, with external IR-sensor temperature monitoring from the side. The reaction mixture was loaded directly onto a silica gel cartridge and purified by flash chromatography (silica gel, 0-50% ethyl acetate/hexanes) to provide the title compound as an orange solid (4.53 g, 19.27 mmol, 83%): mp 133-136° C.; 1H NMR (400 MHz, CDCl3) δ 4.92 (s, 2H), 3.96 (s, 3H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.34, 150.24, 148.69, 143.94, 117.01, 114.60, 53.02, 14.40; ESIMS m/z 236 ([M+H]+), 234 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9]>C(N)CC.C(O)(C)C.O>[CH2:4]([NH:5][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9])[CH2:3][CH3:2]
Reactant: NS(=O)(=O)c1cnccc1Cl
Solvent: CCCN
Solvent: O
Solvent: CC(C)O
Product: CCCNc1ccncc1S(N)(=O)=O

Procedure:
2 g of 4-chloropyridine-3-sulfonamide are dissolved in 10 cm3 of n-propylamine and 10 cm3 of isopropanol. The mixture is brought to reflux for 2 hours, the solution is then cooled and the solvent is evaporated. The solid obtained is redispersed in water (20 cm3). The insoluble material is collected on the filter, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[N:11]1([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:13]([C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:14])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1nccnc1Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
To a solution of (3-chloropyrazin-2-yl)methanamine.HCl (9.57 g, 21.26 mmol, 40% wt) and Z-Pro-OH (5.3 g, 21.26 mmol) in dichloromethane (250 mL) was added triethylamine (11.85 mL, 85 mmol) and the reaction mixture was cooled to 0° C. After 15 min stirring at 0° C., HATU (8.49 g, 22.33 mmol) was added. The mixture was stirred for 1 hour at 0° C. and then overnight at room temperature. The mixture was washed with 0.1 M HCl-solution, 5% NaHCO3, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate=1/4 v/v %) to give 5 g of (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (62.7%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1ccc(N)c(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(C)C)cc1Br
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.8 %

Procedure:
A mixture of 2-bromo-4-isopropylaniline (5.05 g, 23.6 mmol), acetic anhydride (2.4 mL, 25 mmol), and triethylamine (3.5 mL, 25 mmol) in dichloromethane (25 mL) was stirred at ambient temperature for 4 days. The mixture was diluted with dichloromethane, washed sequentially with saturated aqueous Na2CO3 and 1M HCl, dried (MgSO4), filtered, and concentrated to provide the desired product (5.85 g). MS (DCI) m/e 256, 258 (M+H)+; 273, 275 (M+NH4)+.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][C@H:12]([OH:20])[CH2:13][CH2:14][CH2:15][C@@H:16]([CH3:19])[CH2:17][CH3:18])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(OCC)C>[C:1]1([CH3:21])[CH:2]=[CH:3][C:4]([S:7]([O:10][CH2:11][C@H:12]([O:20][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][O:22]2)[CH2:13][CH2:14][CH2:15][C@@H:16]([CH3:19])[CH2:17][CH3:18])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: CC[C@H](C)CCC[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC[C@H](C)CCC[C@H](COS(=O)(=O)c1ccc(C)cc1)OC1CCCCO1
Yield: 59 %

Procedure:
A mixture of 2.85 g of (2R,6S)-2-hydroxy-6-methyloctyl p-toluenesulfonate obtained in Step 5, 0.8 g of 3,4-dihydro-2H-pyran, 28 ml of diethyl ether, and 0.28 g of p-toluenesulfonic acid was allowed to react in a flask for 6 hours. The resulting solution was poured into 100 ml of a 1% sodium hydrogencarbonate aqueous solution, extracted with diethyl ether, washed with water, and concentrated to obtain 3.58 g of a crude product, which was then purified by HPLC to obtain 2.13 g (99%) of the titled compound.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:7][CH2:6][C@H:5]([C@:8]2([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]2)[CH2:4]1.[CH3:32][O:33][CH:34]1[C:39](=O)[CH2:38][CH2:37][O:36][CH2:35]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:32][O:33][CH:34]1[C@H:39]([NH:13][C@@H:10]2[CH2:11][CH2:12][C@:8]([C@H:5]3[CH2:6][CH2:7][O:3][CH2:4]3)([C:14]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=4)[CH2:20][CH2:21]3)=[O:15])[CH2:9]2)[CH2:38][CH2:37][O:36][CH2:35]1
Reactant: COC1COCCC1=O
Reactant: N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COCC[C@H]1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)([C@H]2CCOC2)C1
Temperature: 25 °C
Yield: 25 %

Procedure:
To a solution of (1R,3S)-3-[(3R)-tetrahydrofuran-3-yl]-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (73.8 mg, 0.152 mmol), 3-methoxytetrahydro-4H-pyran-4-one (59.4 mg, 0.456 mmol) and triethylamine (0.0848 mL, 0.608 mmol) in dry methylene chloride (4.1 mL) was added sodium triacetoxyborohydride (96.7 mg, 0.456 mmol). After being stirred at room temperature under N2, the reaction was quenched with aqueous NaHCO3 and diluted with CH2Cl2. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 three times. The organics were combined, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (Combi-Flash system, 0 to 40% MeOH in EtOAc, gradient, 12 gram column) to provide the desired product (20 mg, 41%). MS calculated for C26H37F3N4O4: (M+H) 527.3; found 527.3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5](N)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(O)(C)C.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:6]([CH:5]=[CH:4][CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cccc(Cl)c1
Yield: 89 %

Procedure:
172 parts of 5-chloroanthranilic acid are introduced into 550 parts of 45 percent strength by weight sulfuric acid and 600 parts of isopropanol. A solution of 100 parts of sodium nitrite in 140 parts of water is run in at 80° C. over 6 hours; nitrogen is evolved. The mixture is cooled, 1,500 parts of water are added and the product is filtered off. 140 parts (89% of theory) of 3-chlorobenzoic acid of melting point 151°-153° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.CS(O[CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][N:9]1[C:10]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[C:8]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CCC2
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1cc2c(n1CCCCOC)C(=O)CCC2
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A solution of ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indole-2-carboxylate (207 mg), 4-methoxybutyl methanesulfonate (273 mg) and cesium carbonate (652 mg) in N,N-dimethylacetamide (10 ml) was stirred at 60° C. for 15 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (10 ml×2). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-3:7) was concentrated under reduced pressure to give the object product (250 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:18]([OH:34])[C:19]([N:21]1[CH2:32][C@@H:31]([Cl:33])[CH2:30][C@H:22]1[C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=O)(C)(C)C.[CH2:42]([O:49][C:50]([NH:52][CH:53]([CH2:57][O:58][CH:59]1[CH2:63][CH2:62][CH2:61][O:60]1)[C:54]([OH:56])=O)=[O:51])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([O:49][C:50]([NH:52][C@@H:53]([CH2:57][O:58][CH:59]1[CH2:63][CH2:62][CH2:61][O:60]1)[C:54]([NH:8][C@H:9]([C:14]([NH:16][C@@H:17]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C@H:18]([OH:34])[C:19]([N:21]1[CH2:32][C@@H:31]([Cl:33])[CH2:30][C@H:22]1[C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:56])=[O:51])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Reactant: O=C(NC(COC1CCCO1)C(=O)O)OCc1ccccc1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC1CCCO1)NC(=O)OCc1ccccc1

Procedure:
Following a procedure similar to that described in Example 16, but using 100 mg (0.26 mmol) of (4S)-1-[2S,3S)-3-(N2 -t-butoxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide (prepared as described in Example 65) and 2-benzyloxycarbonylamino-3-(tetrahydrofuran-2-yloxy)propionic acid, 83 mg of the title compound were obtained as a colorless powder, melting at 64°-71° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:27])=[O:26])[N:21]=[C:20]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[N:19]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:18]1[CH:23]=[C:22]([CH2:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:26])=[O:27])[N:21]=[C:20]([C:34]2[CH:35]=[CH:36][C:37]([NH:38][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:39][CH:40]=2)[N:19]=1
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccn2)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)c2ccccn2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Phenyl chloroformate (0.390 mL, 3.10 mmol) was added to 4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(pyridin-2-ylsulfonylmethyl)pyrimidin-2-yl]aniline (1.1 g, 2.59 mmol) and sodium hydrogen carbonate (0.434 g, 5.17 mmol) in dioxane (25 mL) at RT. The resulting slurry was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash silica chromatography using gradient elution 0%-20% ethyl acetate in DCM, to give the desired material as a yellow foam (1.130 g).