Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:15][NH:16][CH3:17].C(N(C(C)C)C)(C)C>ClCCl>[CH3:15][N:16]([CH3:17])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)N(C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.43 g (20 mmol) of 4-nitrobenzenesulphonic acid chloride are added dropwise at 0° C. to a solution of 2.45 g (30 mmol) of dimethylamine-hydrochloride and 6.46 g (50 mmol) of N,N-diisopropyl-N-methylamine in 30 ml of dichloromethane. The mixture is stirred for 18 hours at ambient temperature. Then the reaction solution is washed with water and dilute hydrochloric acid, dried over magnesium sulphate and evaporated to dryness.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][O:7][CH3:8].Br[C:10]1[CH:15]=[C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])[C:13]([Cl:21])=[CH:12][N:11]=1.CCOC(C)=O>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:13]1[C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=[CH:15][C:10]([CH2:4][CH2:5][CH2:6][O:7][CH3:8])=[N:11][CH:12]=1
Reactant: COC(OC)c1cc(Br)ncc1Cl
Reactant: COCCCBr
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: II
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCCc1cc(C(OC)OC)c(Cl)cn1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a suspension of Mg (911 mg, 37.5 mmol) and of iodine (one crystal) in dry THF (30 mL) was added dropwise 5% of the total amount of 1-bromo-3-methoxypropane (4.59 g, 30.0 mmol). The mixture was heated to reflux with the help of a heat gun until the Grignard formation had started. The rest of the 1-bromo-3-methoxypropane was added slowly, while an exothermic reaction proceeded. After the end of the addition, the reaction mixture was stirred under reflux for 20 min, and was allowed to cool to rt. This Grignard sol. (1M in THF, 23.5 mL, 23.5 mmol) was added dropwise to a mixture of 2-bromo-5-chloro-4-dimethoxymethyl-pyridine (2.50 g, 9.38 mmol) and Ni(dppp)Cl2 (495 mg, 0.938 mmol) in THF (50 mL) at 0° C. The reaction mixture was stirred at rt for 30 min, and was then heated to reflux for 2 h. The mixture was allowed to cool to rt, and was dissolved with EtOAc. This mixture was washed with aq. sat. NaHCO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane→EtOAc/heptane 1:1) yielded the title compound (1.51 g, 62%). LC-MS: tR=0.80 min; ES+: 260.15.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Br:11].CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CONC>CN(C)C=O.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]([O:19][CH3:15])[CH3:21])=[O:7])=[CH:4][C:3]=1[Br:11]
Reactant: Nc1ccc(C(=O)O)cc1Br
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-L round-bottom flask, was placed a solution of 4-amino-3-bromobenzoic acid (50 g, 231.45 mmol, 1.00 equip) in N,N-dimethylformamide (500 mL), TEA (128 mL, 4.00 equip), HATU (106 g, 278.78 mmol, 1.20 equip), and methoxy(methyl)amine hydrochloride (45 g, 461.33 mmol, 2.00 equip). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with water (1 L). The resulting solution was extracted with ethyl acetate (1 L) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to yield 4-amino-3-bromo-N-methoxy-N-methylbenzamide as a yellow solid. LCMS (ES, m/z) 259 [M+H]+
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[C:18]([O:20][CH3:21])=[O:19].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42](O)=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=2[C:18]([O:20][CH3:21])=[O:19])=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)c(C(=O)OC)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 115 %

Procedure:
To a stirred solution of dimethyl (S)-4-(2-pyrrolidinylmethoxy)isophthalate (616 mg, 2.10 mmol) in DMF (13 mL) was added pentafluoro ester of 3-methoxy4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.00 g, 2.08 mmol) and Et3 N (425 μl, 3.12 mmol), and the resulting mixture was stirred for 3.5 hr at room temp. The resulting mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over Na2SO4. After removal of the solvent, the residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 1.41 g(q.y.) dimethyl (S)-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]isophthalate as a yellow oil. 1H-NMR (CDCl3) δ 1.86–2.29 (m, 4 H), 2.30 (s, 3 H), 3.47–3.57 (m, 2 H), 3.58 (s, 3 H), 3.59 (s, 2 H), 3.83 (s, 3 H), 3.91 (s, 3 H), 4.22–4.37 (m, 2 H), 4.42–4.47 (m, 1 H), 6.44–8.46 (series of m, 12 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNc2ccccc2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.20 mmol) and aniline (26 μL, 0.28 mmol) in 1,2-dichloroethane (5 mL) is stirred 25 min, before the addition of NaBH(OAc)3 (60 mg, 0.28 mmol) follows. The solution is stirred overnight at RT, then diluted with CH2Cl2 and washed with an aqueous saturated solution of NaHCO3. The combined organic extracts are dried over Na2SO4 and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 97:3) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.25. MS (LC-MS): 570.0 [M+H]+; tR (HPLC, nucleosil C18 column, 10-100% CH3CN/H2O/ 5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.31 min.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:2]([O:9][C:10]([CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCCN1
Reaction time: 18 h
Yield: 55.2 %

Procedure:
L-Proline benzyl ester hydrochloride (96 mg, 2.0 eq) in DMF was put into a flask and K2CO3 (132 mg, 2.0 eq) was added, stirred for a while, and 3-(2-chloro-6-trifluoromethyl-4-yl-pyridin-3-yl)-acrylic acid (50 mg) was added at room temperature. The reaction mixture was stirred for 18 hrs. After the reaction was completed through the TLC checking, the mixture was diluted with EtOAc, washed with 1N HCl solution. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a crude 6-trifluoromethyl-pyridin-2-yl}-pyrrolidin-2-yl carboxylic acid benzyl ester (45 mg). N-(4-Aminomethyl-5-ethynyl-2-fluoro-phenyl)-methanesulfonamide, HCl salt (30 mg, 0.11 mmol) was reacted with 6-trifluoromethyl-pyridin-2-yl}-pyrrolidin-2-yl-carboxylic acid benzyl ester (45 mg) to give 1-{3-[2-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzylcarbamoyl)-vinyl]-6-trifluoromethyl-pyridin-2-yl}-pyrrolidin-2-yl-carboxylic acid benzyl ester (3.2 mg, 4.5%) after purification by column chromatography (EtOAc/MeOH=10/1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:45][C:46]1[O:47][C:48]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][C:49]=2[CH:50]=1.BrCC1OC(C(F)(F)F)=CC=1>>[F:55][C:54]1[C:48]2[O:47][C:46]([CH2:45][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([CH2:13][O:12][C:11]5[CH:14]=[C:15]6[C:19](=[CH:20][C:10]4=5)[CH2:18][CH2:17][O:16]6)[C:2]3=[O:21])=[CH:50][C:49]=2[CH:51]=[CH:52][CH:53]=1
Reactant: Fc1cccc2cc(CBr)oc12
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cc3cccc(F)c3o2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and 2-(bromomethyl)-7-fluorobenzofuran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[(7-fluoro-1-benzofuran-2-yl)methyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (83%) as a colorless solid: mp 192-193° C.; 1H NMR (300 MHz, CDCl3) δ7.31-7.24 (m, 2H), 7.22-6.96 (m, 5H), 6.77-6.74 (m, 1H), 6.56 (s, 1H), 6.43 (s, 1H), 5.31-5.23 (m, 1H), 5.03-4.95 (m, 2H), 4.75-4.68 (m, 1H), 4.59-4.49 (m, 2H), 3.10-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.6, 161.8, 161.2, 152.8, 147.8 (d, JC-F=249.7 Hz), 141.9 (d, JC-F=11.3 Hz), 141.4, 132.7, 131.6 (d, JC-F=3.2 Hz), 128.8, 123.9, 123.7, 123.6, 120.1 (d, JC-F=5.2 Hz), 119.0, 116.6 (d, JC-F=3.9 Hz), 110.8 (d, JC-F=16.1 Hz), 109.0, 105.6 (d, JC-F=2.1 Hz), 93.2, 80.4, 72.4, 57.7, 37.5, 29.0; MS (ES+) m/z 428.3 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].Br[CH:19]([CH3:29])[C:20]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21]>O1CCCC1>[C:10]([CH:12]([CH:19]([CH3:29])[C:20]([C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: CCOC(=O)CC#N
Reactant: CC(Br)C(=O)c1cccnc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C(C)C(=O)c1cccnc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 70 %

Procedure:
To a solution of diisopropylethylamine (45 mL) and ethyl cyanoacetate (11.5 g) in tetrahydrofuran (50 mL) was added dropwise a solution of 2-bromo-1-(2-fluoropyridin-3-yl)propan-1-one (29.6 g) in tetrahydrofuran (50 mL), and the mixture was stirred at room temperature for 14 hr. Insoluble materials were filtered off, and filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a brown oil (yield 18.8 g, 85%).
Reaction SMILES: [C:1]1([N:7]2[N:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC([N:22]1[CH2:27][CH2:26][NH:25][C:24]([CH3:29])([CH3:28])[CH2:23]1)=O)(C)(C)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].CC1(C)CNCCN1C(C1N=CN(C2C=CC=CC=2)N=1)=O>>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH3:28][C:24]1([CH3:29])[CH2:23][NH:22][CH2:27][CH2:26][N:25]1[C:12]([C:9]1[N:10]=[N:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)=[O:14]
Reactant: CC1(C)CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(O)c1nnn(-c2ccccc2)n1
Agent: CC1(C)CNCCN1C(=O)c1ncn(-c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1C(=O)c1nnn(-c2ccccc2)n1

Procedure:
This intermediate was prepared from 2-phenyl-2H-tetrazole-5-carboxylic acid and 3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in two steps according to the preparation of (2,2-dimethyl-piperazin-1-yl)-(1-phenyl-1-H-[1,2,4]-triazol-3-yl)-methanone trifluoroacetate.
Reaction SMILES: COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.[H-].[Na+].Cl[CH2:32][C:33]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:34]>CN(C=O)C>[CH2:36]([N:35]([CH2:38][CH3:39])[C:33](=[O:34])[CH2:32][N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9](=[O:10])(=[O:11])[NH:8][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)[CH:13]=[CH:14][C:15]1=2)[CH3:37]
Reactant: CCN(CC)C(=O)CCl
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CN1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 26.7 %

Procedure:
To a flask charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIate M) (0.104 g, 0.25 mmol) was added DMF (0.7 ml), and cooled in an ice water bath prior to the addition of NaH (60% in mineral oil) (10 mg, 0.25 mmol). The mixture was stirred for 45 min at 0° C., then 30 min at room temperature. To a separate vial charged with 2-chloro-N,N-diethylacetamide (37 mg, 0.25 mmol) was added DMF (0.3 ml), then the solution of deprotonated amine. The resulting mixture was sealed and shaken at rt overnight. The mixture was quenched with the addition of MeOH, then dried under reduced pressure and purified with NH4OH modified RP-HPLC affording N,N-diethyl-2-(7-(N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3 H)-yl)acetamide (27.4 mg, 27%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01 (t, J=7.05 Hz, 3 H) 1.18 (t, J=7.10 Hz, 3 H) 3.21-3.27 (m, 2 H) 3.36 (br. s., 2 H) 3.39-3.45 (m, 2 H) 4.18 (t, J=4.35 Hz, 2 H) 4.26 (s, 2 H) 6.49 (d, J=8.71 Hz, 1 H) 6.75 (d, J=4.35 Hz, 1 H) 7.00 (d, J=2.06 Hz, 1 H) 7.13 (dd, J=8.59, 2.06 Hz, 1 H) 7.19 (d, J=4.58 Hz, 1 H) 12.47 (br. s., 1 H). m/z (ESI) 411.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH2:23][CH2:24]O)[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1.N1C=CC=CC=1.P(Br)(Br)[Br:41]>C(Cl)Cl>[Br:41][CH2:24][CH2:23][C@@:20]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:19][C:18](=[O:33])[N:17]([C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)[CH3:16])[CH2:22][CH2:21]1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCBr)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 41.8 %

Procedure:
To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (250 mg, 0.55 mmol) in methylene chloride (10 mL) was added pyridine (0.5 mL) and PBr3 (75 mg). The formed mixture was stirred for 2 h. The mixture was washed with water. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-6-(2-bromoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (60 mg, 23%). 1H NMR: (400 MHz, CDCl3): δ=1.45 (d, 3H), 2.12-2.38 (d, 4H), 2.43 (m, 1H), 2.94 (m, 2H), 3.49 (m, 1H), 5.22 (m, 1H), 6.83 (m, 2H), 6.95 (m, 4H), 7.19 (m, 1H), 7.22 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:31])([C:14]2[S:15][C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[F:31][C:11]1([C:14]2[S:15][C:16]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[CH:17][N:18]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(COc3ccc(S(C)(=O)=O)cc3)s2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)c1ccc(OCc2cnc(C3(F)CCNCC3)s2)cc1
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 89, 1.30 g, 2.76 mmol) in methanol (5 mL) was added 4 N HCl in dioxane (10 mL). The resulting solution was stirred overnight. The mixture was then evaporated to dryness in vacuo to afford the desired product as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([CH2:41][C:42]([O:44][CH3:45])=[O:43])[OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46]O>C(OC)(OC)OC>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@:10]1([CH2:41][C:42]([O:44][CH3:45])=[O:43])[O:40][CH3:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@]1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CO
Solvent: COC(OC)OC
Product: COC(=O)C[C@]1(OC)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 60 °C

Procedure:
Methyl 2-((2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-hydroxytetrahydro-2H-pyran-2-yl)acetate (6) (1.4 g, 2.28 mmol) was dissolved in a solution of MeOH (6 mL) and trimethyl orthoformate (4 mL). PL-SO3H resin (Polymer Laboratories, 0.25 g, 3.75 mmol/g loading) was added and the reaction mixture was heated to 60° C. for 4.75 h. The mixture was filtered through cotton, rinsing with MeOH and CH2Cl2, then concentrated to a syrup (1.4 g, 99%). LC/MS tR=3.27 min, calcd for C38H42O8: 626.29, found 649.6 (M+Na)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.[CH3:10][N:11](C=O)C>CO.O.[C-]#N.[C-]#N.[Zn+2].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>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([C:10]#[N:11])=[N:7][C:6]=1[CH3:8]
Reactant: Cc1nc(Br)ccc1N
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CO
Solvent: O
Product: Cc1nc(C#N)ccc1N
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-2-methylpyridin-3-amine (compound 1, 500 mg, 2.69 mmol) in DMF (10 mL) was added Zn(CN)2 (943 mg, 8.06 mmol) and Pd(PPh3)4 (288 mg, 0.3 mmol) at room temperature. The reaction was stirred at 110° C. in microwave reactor for 1 h. After it was cooled to room temperature, the mixture was filtered and purified by reverse phase chromatography (X bridge Prep C18OBD, 40-60% MeOH in water with 10 mmol NH4HCO3 modifier) to afford the compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:63]1([CH2:69][CH:70]2[CH2:75][CH2:74][CH2:73][CH2:72][NH:71]2)[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH2:75][CH:70]1[CH2:69][N:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: C1CCN(CC2CCCCN2)CC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN3CCCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(piperidin-1-ylmethyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2>>[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[C@@H:12]([C@@:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:11][O:10]1)[CH3:13]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnc2c(Cl)ncnc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 47.9 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (607 mg) and 6-chloropurine (422 mg), (2S)-2-[(1R)-1-[6-chloro-9(9H)-purinyl]ethyl]-2-(2,4-difluorophenyl)oxirane (440 mg) was obtained as a white powder by the same way as in Reference Example 2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.N#N.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([NH:36][C@H:37]([C:45](Cl)=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:44])[NH2:43])(=[O:35])=[O:34])[CH:27]=[CH:26]2>C(Cl)(Cl)Cl>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([S:33]([NH:36][C@H:37]([C:45]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:46])[CH2:38][CH2:39][CH2:40][NH:41][C:42](=[NH:43])[NH2:44])(=[O:35])=[O:34])[CH:27]=[CH:26]2
Reactant: COc1ccc2cc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)ccc2c1
Reactant: CCOC(=O)C1CCCCN1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCCCN1C(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2.2 g of ethyl 2-piperidinecarboxylate and 4.1 ml of triethylamine in 50 ml of chloroform, which was cooled in an ice-salt bath, was added in portions N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl chloride obtained above. The reaction mixture was stirred overnight at room temperature. At the end of this period, 500 ml of chloroform was added and the chloroform solution was washed twice with 50 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue was washed with ethyl ether to give 2.9 g of powdery ethyl 1-[N2 -(6-methoxy-2-naphthylsulfonyl)-L-arginyl]-2-piperidinecarboxylate. For analysis of the product, a portion of the product was converted to the flavinanate, M.P. 192°-3° C. I.R. (KBr): 3,210, 1,747, 1638 cm-1