Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]([I:9])=[CH:4][C:3]=1[OH:10].N1C=CC=CC=1.[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[S:18]([O:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]([I:9])=[CH:4][C:3]=1[O:10][S:18]([C:21]([F:22])([F:23])[F:24])(=[O:17])=[O:19])(=[O:19])=[O:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cc(I)c(I)cc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Oc1cc(I)c(I)cc1OS(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
To a flame-dried round-bottomed flask was added 1,2-dihydroxy-4,5-diiodobenzene (1 equiv., 7.85 mmol, 2.84 g), CH2Cl2 (55 mL), and pyridine (5 equiv., 39 mmol, 3.10 g, 3.16 mL). The solution was cooled to 0° C. and Tf2O (2.2 equiv., 17.3 mmol, 4.88 g, 2.91 mL) was added dropwise via syringe over 10 min. The reaction was stirred for 6 h while warming to ambient temperature, then cooled to 0° C. and quenched with H2O (30 mL). The separated aqueous layer was extracted with CH2Cl2 (2×30 mL). The combined organic layers were dried with MgSO4 and filtered through a tall pad of silica. The pad was washed carefully with CH2Cl2 to avoid the elution of impurities, and the filtrate was concentrated in vacuo to afford 4,5-diiodo-1,2-phenylene bis(trifluoromethanesulfonate) (4.90 g, 7.82 mmol, quantitative) as an off-white solid. The product is optionally purified by column chromatography (10% EtOAc/Hex). TLC Rf=0.60 (10% EtOAc/Hex); Melting point 46.5-47.7° C.; 1H NMR (400 MHz): δ 7.91 (s, 2H); 13C NMR (100 MHz): δ 139.6, 133.4, 118.5 (q, JC,F=321.0 Hz), 108.0. FTIR: 1429, 1335, 1215, 1125, 1105, 868, 788, 745, 689 cm−1. HRMS-ESI: calc. for C8H2F6I2NaO6S2 (M+Na)+: 648.7184. found: 648.7164.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:12]1[C:11]([O:10][CH3:9])=[CH:16][C:15]([O:17][CH3:18])=[CH:14][C:13]=1[P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOP(=O)(OCC)c1cc(OC)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1cc(OC)cc(OC)c1Br
Temperature: 0 °C
Reaction time: 6 h
Yield: 86.9 %

Procedure:
N-Bromosuccinimide (NBS) (8.9 g, 50 mmol) was added to the solution of diethyl 3,5-dimethoxyphenylphosphonate (12.5 g, 45.6 mmol) in CH2Cl2 (150 ml) at 0° C. The resulting suspension was stirred at 0° C. for 6 h. Na2CO3 (saturated, 60 ml) was added to quench the reactions. It was stirred at RT for 30 min, the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (80 ml×1). The combined organic layer was washed with brine and dried over MgSO4. It was filtered and the solvent was removed to give the crude product as a pale yellow oil (14 g, 87% yield). It was sufficiently pure enough for the next step. The pure sample was obtained by chromatography. 1H NMR (300 MHz, CD2Cl2) δ: 7.16 (dd, J1=3.0 Hz, J2=15.3 Hz, 1H), 6.67 (d, J=3.0 Hz, 1H), 4.20-4.06 (m, 4H), 3.89 (s, 3H), 3.85 (s, 3H), 1.34 (t, J=7.2 Hz, 6H). 31P NMR (121.5 MHz, CD2Cl2) δ: 15.59. 13C NMR (75.5 MHz, CD2Cl2) δ: 159.77 (d, Jc-p=20.0 Hz), 157.66 (d, Jc-p=19.0 Hz), 131.49 (d, Jc-p=189.2 Hz), 112.04 (d, Jc-p=8.7 Hz), 105.52 (d, Jc-p=4.5 Hz), 103.51 (d, Jc-p=2.9 Hz), 62.73, 62.66, 56.78, 55.96, 16.34, 16.26.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]2[C@@H:24]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:23][O:22][C:21]2=[O:32])[CH:6]=1.[OH-].[Li+]>>[CH2:25]([C@H:24]1[CH2:23][O:22][C:21](=[O:32])[N:20]1[CH2:19][C:13]1[CH:14]=[C:15]([Br:18])[CH:16]=[CH:17][C:12]=1[O:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:10]=[CH:9][CH:8]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)OC[C@@H]2Cc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)OC[C@@H]2Cc2ccccc2)c1
Yield: 47.3 %

Procedure:
Hydrolysis of {3-[2-((S)-4-benzyl-2-oxo-oxazolidin-3-ylmethyl)-4-bromo-phenoxy]-phenyl}-acetic acid methyl ester (0.49 mmol) with lithium hydroxide, followed by acidic work-up, yielded the desired product (0.115 g).
Reaction SMILES: [CH3:1][CH:2]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3][CH:4](NC(OCC)=O)[NH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[H][H]>[Ni].C(O)C>[CH3:1][CH:2]([NH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:3][CH2:4][NH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)NC(C)CC(NC(=O)OCC)NC(=O)OCC
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)NCCC(C)NC(=O)OCC

Procedure:
10 g of the 3-methyl-1,1,3-tri(ethoxycarbonylamino)propane prepared in Example 3a are hydrogenated at 165° C. and 200 bar of hydrogen in a stirred autoclave with 3 g of Raney nickel and 100 ml of ethanol in the course of 15 hours. Complete converion gives 1-methyl-1,3-di(ethoxycarbonylamino)propane with a selectivity of 96%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)C>[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCCCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 68.8 %

Procedure:
A mixture of methyl 4-hydroxybenzoate (3 g, 19.7 mmol), 4-phenylbutanol (3.04 ml, 19.7 mmol) and triphenylphosphine (7.74 g, 29.6 mmol) in anhydrous tetrahydrofuran (110 ml) was added with diethyl azodicarboxylate (4.65 ml, 29.6 mmol). The resulting mixture was left under stirring at room temperature for 36 h, then was added with ethyl ether (500 ml) and left to crystallize for 24 hours at 0° C. After that the solid was filtered and the filtrate was washed successively with 0.2M hydrochloric acid, 5% sodium bicarbonate and a sodium chloride saturated solution. After drying and removing the solvent under reduced pressure, a residue was obtained which was purified by chromatography through a silica gel column, eluting with petroleum ether:chloroform mixtures of increasing polarity, thereby recovering 3.856 g of the title compound (70% yield).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[N-:30]=[N+]=[N-].[Na+].CCOCC>CN(C)C=O>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)=[N:8][N:7]4[C:2]([NH2:30])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To a solution of 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (53 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was added sodium azide (85 mg, 1.3 mmol). The resultant mixture was heated to 100° C. for 18 hours. The reaction mixture was cooled to room temperature and ether was added. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (2:1 to 1:1 hexanes:ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-7-amine (30 mg, 60%) as an oil. 1H NMR (CDCl3) δ 7.97 (d, 1H), 7.77 (d, 1H), 7.60 (m, 2H), 7.22 (m, 1H), 7.10 (t, 2H), 6.26 (d, 1H), 6.14 (d, 1H), 5.26 (s, 2H), 5.09 (d, 1H), 4.29 (m, 1H), 2.06–1.99 (m, 2H), 1.75–1.45 (m, 6H); MS m/z 389 (M+1). This material was taken up in ether and treated with hydrochloric acid in ether to yield a yellow precipitate which was isolated by filtration as a hydrochloride salt.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].Br[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCCC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CCCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method D above, methyl 5-hexynoate (109 mg, 0.87 mmol) (see below) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (179 mg, 0.62 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (30 mg) and CuI (15 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 70° C. for 15 h to yield (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynoic acid methyl ester. (Yield 78 mg, 35%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:21]C(=O)C1C=CC=CC=1)=[N:9]2.S(=O)(=O)(O)O.[N+:35]([O-])([OH:37])=[O:36].[OH-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:35]([O-:37])=[O:36])=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH2:21])=[N:9]2
Reactant: O=[N+]([O-])O
Reactant: O=C(NC1=N[C@@]2(c3ccccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
N-((4aS,5S,7aS)-7a-(2-Fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (5.15 g) was dissolved in TFA (75 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 20 mL) was added, followed by fuming nitric acid (2 mL) dropwise over 20 mins. After stirring at 0° C. for 90 mins, the reaction mixture was poured onto ice (200 g) and basified to pH 12 with 6N NaOH (aq.). After allowing the ice to melt, the mixture was extracted with EtOAc (3×500 mL), and the combined organic portions dried over MgSO4 and evaporated to afford the title compound (22.1 g, purity approx. 71%) which was used in the subsequent step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 2.89 (d, J=3.8 Hz, 1H), 3.09 (br. s., 1H), 3.28-3.54 (m, 1H), 3.80-4.03 (m, 1H), 4.50-4.70 (m, 3H), 4.71-4.86 (m, 1H), 7.21-7.30 (m, 1H), 8.18-8.28 (m, 1H), 8.45 (dd, J=6.8, 2.8 Hz, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
4-Hydroxy-benzoic acid methyl ester (3.19 g, 21 mmol) was dissolved together with pyridine (1.97 g, 25 mmol) in dry THF (20 mL) and after cooling down to 0° C., methanesulfonyl chloride (2.29 g, 20 mmol) was added dropwise. The ice bath was removed and mixture was stirred at r.t. for 5 h. After diluting with DCM and extraction with water and aq. HCl (2N), the organic layer was dried (MgSO4) and evaporated to afford the crude but highly pure product as a solid which was used in the next step without further purification (4.38 g, 95.1%). 1H NMR (400 MHz, CDCl3): δ 8.07-8.09 (d, 2H), 7.32-7.34 (d, 2H), 3.90 (s, 3H), 3.16 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.[F-].[K+]>C1COCC1>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Cc1ccccc1B(O)O
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc([N+](=O)[O-])cc1
Yield: 98.4 %

Procedure:
4-Chloronitrobenzene (80 mg, 0.51 mmol) reacted with o-methylphenylboronic acid (85 mg, 0.63 mmol) using 0.5/1.0 mol % of Pd(OAc)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.55 mmol) in THF solvent at 50° C. for 22 h to give the title compound (107 mg, 98%): 1H-NMR (500 MHz, CDCl3): δ 8.30 (d, 2H, J=6.90 Hz, aryl coupling 1.8 Hz), 7.51 (d, 2H, J=6.92 Hz, aryl coupling 1.8 Hz), 7.35-7.23 (m, 4H), 2.29 (s, 3H, Ar—CH3). 13C{1H}-NMR (125 MHz, CDCl3): δ 148.80, 146.86, 139.60, 135.04, 130.70, 130.09, 129.39, 128.45, 126.11, 123.40, 20.31. GC/MS(EI): m/z 213 (M+), 165, 152.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:37])[CH:5]=[C:6]([Cl:36])[C:7]=1[CH2:8][C@@H:9]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[C:27]([OH:35])[CH:26]=1)[O:10][C:11](=[O:24])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH:55]2[CH2:59][CH2:58][O:57][CH2:56]2)(=O)=O)=CC=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:37])[CH:5]=[C:6]([Cl:36])[C:7]=1[CH2:8][C@@H:9]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[C:27]([O:35][CH:55]2[CH2:59][CH2:58][O:57][CH2:56]2)[CH:26]=1)[O:10][C:11](=[O:24])[CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OC2CCOC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-hydroxyphenyl)-2-(2-(1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (155 mg, 0.280 mmol) in DMF (3.8 ml), potassium carbonate (46.5 mg, 0.336 mmol) was added, and the mixture stirred at RT for 30 minutes. Tetrahydrofuran-3-yl 4-methylbenzenesulfonate (224 mg, 0.924 mmol) was added, and the mixture stirred at RT overnight. Water was added, and the aqueous phase extracted with AcOEt (2×). The organic phase was washed with brine, dried and evaporated under reduced pressure. The crude was purified through preparative HPLC (Method 2) to give 17 mg of title compound (yield 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45 (s, 2H), 7.92 (d, J=4.41 Hz, 4H), 7.18-7.27 (m, 1H), 7.05 (m, 2H), 6.98 (d, J=7.94 Hz, 1H), 6.02 (dd, J=8.38, 4.85 Hz, 1H), 5.12 (m, 1H), 4.30-4.58 (m, 2H), 3.62-4.06 (m, 4H), 3.14-3.43 (m, 2H), 2.20 (ddd, J=13.56, 6.73, 6.62 Hz, 1H), 1.86-2.05 (m, 1H). MS/ESI+ [M+H]+=622.7
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:29])([CH3:28])[C@@H:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])(=[O:7])=[O:6].[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O>[N:30]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:29])([CH3:28])[C@@H:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])(=[O:7])=[O:6])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 3-methylbutyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (29a) (0.32 g, 0.74 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.11 g (1.5 mmol) of sodium azide (NaN3). After work-up, the crude material (29b) was used in the next step without further purification. MS (ESI) m/z 478.18 (M+Na)+.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([C:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]=3[CH2:25][CH2:26][CH2:27][CH3:28])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:29].CO.Cl>O>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]([C:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]=3[CH2:25][CH2:26][CH2:27][CH3:28])[OH:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:29]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc2c(Br)c(O)ccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCc1oc2ccccc2c1C(O)c1ccc2c(Br)c(O)ccc2c1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Sodium borohydride (0.33 g, 8.98 mmol) was added into a mixture of 1-bromo-6-(2-butyl-benzofuran-3-carbonyl)-naphthalen-2-ol (1.9 g, 4.49 mmol) and methyl alcohol (10 mL). The reaction mixture was stirred for 1 hour poured into water, acidified with HCl (2 N) and extracted with ethyl ether. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on silica gel (hexanes/EtOAc 2:1) gave an off-white solid(1.65 g): MS m/e 424 (M+);
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[H-].[Na+].[O:14]1[CH2:16][CH:15]1[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:16][CH:15]([OH:14])[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1cncc(CCC2CO2)c1
Reactant: Oc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)COc1ccc2ccccc2c1
Yield: 17 %

Procedure:
Prepared according to the method described in Example 5 from 2-naphthol (0.150 g), sodium hydride (0.044 g; 60% dispersion in oil) and (±)-3-(2-oxiranylethyl)pyridine (0.150 g) in dimethylformamide at 100° C. for 30 minutes to give the title compound as a solid (0.050 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Cl)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 30.1 using 5,6-dichloronicotinic acid and 4-(trifluoromethoxy)aniline to afford an off-white solid. UPLC-MS (Condition 1) tR=3.05 min, m/z=350.9/352.9 [M+H]+, m/z=348.9/351.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.6 Hz, 2H) 7.86 (d, J=9.3 Hz, 2H) 8.63 (d, J=2.0 Hz, 1H) 8.90 (d, J=2.2 Hz, 1H) 10.70 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21].[H-].[Na+].[CH2:24](I)[CH3:25]>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH2:24][CH3:25])[C:16](=[O:20])[CH2:15]2)[C:3]=1[CH3:21]
Reactant: Cc1c(N2CCNC(=O)C2)nc2cc(F)cc(F)c2c1Br
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCN(c2nc3cc(F)cc(F)c3c(Br)c2C)CC1=O
Reaction time: 8 h

Procedure:
The 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperazin-2-one (70 mg, 0.20 mmol) was dissolved in THF (2.0 mL). To the solution was added sodium hydride (24.0 mg, 1.00 mmol) (60% dispersion) followed by addition of ethyl iodide (0.16 mL, 2.00 mmol). The reaction was stirred overnight. The reaction was quenched with water and the mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. The crude product was purified by medium pressure chromatography (silica gel, 0 to 100% EtOAc:hexanes) to give 4-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)-1-ethylpiperazin-2-one. Mass Spectrum (ESI) m/e=384.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@H:11]([C:19]([O:21]CCC)=[O:20])[N:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P([O-])([O-])([O-])=O>[CH2:1]([N:8]1[C@@H:12]([C:13]([O:15][CH2:16][CH2:17][CH3:18])=[O:14])[C@@H:11]([C:19]([OH:21])=[O:20])[N:10]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:9]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCOC(=O)[C@@H]1[C@H](C(=O)OCCC)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: CCCOC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Yield: 90.7 %

Procedure:
A suspension of di-n-propyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (200 mg) in 0.1M phosphate buffer (pH 8.0, 20 ml) was treated with Pig Liver Esterase (manufactured by Sigma Lab., 640 units, 4 mg) in a manner similar to that in Example 1 (1) to give (4S,5R)-1,3-dibenzyl-5-n-propoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (164 mg). M.P., 75°-90° C. [α]D20 =+2.1° (c=1, CHCl3).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.[F:24][C:25]([F:41])([F:40])[C:26]1[CH:30]=[CH:29][N:28]([C:31]2[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=2)[N:27]=1>ClCCl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:35]([C:34]3[CH:33]=[CH:32][C:31]([N:28]4[CH:29]=[CH:30][C:26]([C:25]([F:41])([F:24])[F:40])=[N:27]4)=[CH:39][CH:38]=3)=[O:36])[CH2:6][C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(-n2ccc(C(F)(F)F)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-n2ccc(C(F)(F)F)n2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (0.88 g) and diisopropylethylamine (0.66 g) in dichloromethane (50 ml) was added the 4-(3-trifluoromethylpyrazol-1-yl)benzoyl chloride (1.40 g). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (1.70 g), m.p. 166-167° C.; MS, m/z: 423.3 (M+H)+, 845.4 (2M+H)+.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:10]2[CH2:13][CH:12](O)[CH2:11]2)=[CH:5][CH:4]=1.[N:22]1[C:31]2[C:26](=[CH:27][C:28]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:10]2[CH2:13][CH:12]([N:32]([C:28]3[CH:27]=[C:26]4[C:31](=[CH:30][CH:29]=3)[N:22]=[CH:23][CH:24]=[CH:25]4)[S:33]([CH3:36])(=[O:34])=[O:35])[CH2:11]2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Nc1ccc2ncccc2c1
Reactant: OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)N(c1ccc2ncccc2c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1

Procedure:
reaction of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol hydrobromide with N-quinolin-6-ylmethanesulfonamide in the presence of DIAD and triphenylphosphine in toluene, to form N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-quinol-6-yl-methylsulfonamide (the reaction is preferably performed at a temperature of between 40 and 60° C.), and then