Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([Li])CCC.[CH2:11]([Sn:15]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])Cl)[CH2:12][CH2:13][CH3:14].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:21]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:17][CH2:18][CH2:19][CH3:20])[C:5]1[S:1][N:2]=[CH:3][CH:4]=1)[CH2:22][CH2:23][CH3:24]
Reactant: c1cnsc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccns1
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a cold (−78° C.) solution of isothiazole (100 mg, 1.175 mmol) in anhydrous THF (2.0 mL) was added n-butyllithium (0.808 mL, 1.292 mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78° C. A solution of tributylchlorostannane (0.380 mL, 1.410 mmol) in anhydrous THF (0.5 mL) was added, and the reaction mixture was stirred for 30 minutes at −78° C. The solution was allowed to warm to room temperature over a 1 hour period. Saturated aqueous sodium bicarbonate was added and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (19:1) to give the title compound as a pale yellow oil (139.3 mg, 32%). 1H NMR (500 MHz, CDCl3) δ ppm 0.90 (t, J=7.32 Hz, 9H), 1.14-1.20 (m, 6H), 1.28-1.39 (m, 6H), 1.51-1.62 (m, 6H), 7.27-7.32 (m, 1H), 8.66 (d, J=1.46 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3=[N:14][CH:15]=[C:16]([C:17]([NH:19][C@@H:20]([CH3:24])[C:21]([OH:23])=O)=[O:18])[N:12]3[C@@:11]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=4)=[CH:29][CH:28]=3)([CH3:25])[C:10]2=[O:40])[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O.[NH:48]1[C:52]([C@@H:53]2[CH2:58][CH2:57][CH2:56][NH:55][CH2:54]2)=[N:51][N:50]=[N:49]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:10](=[O:40])[C@:11]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)=[CH:31][CH:32]=3)([CH3:25])[N:12]3[C:16]([C:17]([NH:19][C@@H:20]([CH3:24])[C:21](=[O:23])[N:55]4[CH2:56][CH2:57][CH2:58][C@@H:53]([C:52]5[NH:51][N:50]=[N:49][N:48]=5)[CH2:54]4)=[O:18])=[CH:15][N:14]=[C:13]23)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: C1CNC[C@H](c2nnn[nH]2)C1
Reactant: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3ccc(F)cc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(-c3ccc(F)cc3)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N1CCC[C@@H](c2nnn[nH]2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.3 %

Procedure:
To a cold (0° C.) solution of (S)-2-{[(R)-7-(3,5-dichloro-phenyl)-5-(4′-fluoro-biphenyl-4-ylmethyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionic acid (0.12 g, 0.21 mmol) in DMF (1 mL) was added (R)-3-(1H-tetrazol-5-yl)-piperidine trifluoro-acetic acid salt (0.055 g, 0.21 mmol), HATU (0.093 mg, 0.25 mmol) and Et3N (0.059 mL, 0.41 mmol). The reaction was allowed to stir for 10 min and then HOAt (0.056 g, 0.41 mmol) was added. The mixture was allowed to warm to room temperature overnight. The crude reaction mixture was purified by reverse phase HPLC to give 35 mg of the title compound as a white solid, m/z 716.6 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C1([O:25][C:26]([C:28]2[N:29]([CH3:36])[C:30]([CH2:33][O:34][CH3:35])=[N:31][CH:32]=2)=O)C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:28]3[N:29]([CH3:36])[C:30]([CH2:33][O:34][CH3:35])=[N:31][CH:32]=3)=[O:25])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: COCc1ncc(C(=O)Oc2ccccc2)n1C
Product: COCc1ncc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)n1C

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 2-methoxymethyl-3-methyl-3H-imidazole-4-carboxylic acid phenyl ester, the title compound was obtained as white crystals 48% yield). MS: m/e=418(M+H+), mp 242-245° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[NH2:36])[C:26](F)=[N:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O>C1COCC1>[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[N:27][C:26]4[NH:36][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][C:30]=5[C:25]=4[CH:24]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1cnccc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
A 1N solution of bis(trimethylsilyl)amide in THF (2.78 mL, 2.80 mmol) was added dropwise to a solution of 5-(4-piperidin-1-ylmethyl-phenyl)-2-fluoro-[3,4]bipyridinyl-3′-ylamine (101 mg, 0.278 mmol) in THF (5.0 mL) at ambient temperature. The mixture was stirred for 1 h at ambient temperature and then treated with water. The resultant brown solution was partitioned between DCM and water, the layers separated, and the aqueous phase extracted into 20% methanol in DCM. The combined organic phase was concentrated in vacuo. The resultant residue was absorbed onto silica gel, and purified by flash chromatography (silica, 1-20% methanol in DCM) to provide a light orange-yellow solid (39.9 mg, 42%). 1H NMR. (DMSO-D6, 500 MHz): 12.24 (s, 1H), 8.99 (d, J=1.8 Hz, 1H), 8.93 (s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.77 (d, J=7.5 Hz, 2H), 7.45 (d, J=7.5 Hz, 2H), 3.49 (s, 2H), 2.36 (m, 4H), 1.52 (m 4H), 1.41 (m, 2H). LCMS (Method D): RT=4.64 min, M+H+=343.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](S(O)(=O)=O)=[CH:6][CH:7]=1.O.[CH2:13]([NH:20][C:21]1[C:22]([NH2:28])=[CH:23][CH:24]=[C:25]([Br:27])[CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC(OC)(OC)C1C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:28]1[C:22]2[CH:23]=[CH:24][C:25]([Br:27])=[CH:26][C:21]=2[N:20]=[C:13]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1ccc(Br)cc1NCc1ccccc1
Agent: COC(OC)(OC)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: Brc1ccc2c(c1)nc(-c1ccccc1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
p-TsOH.H2O (311.7 mg, 1.606 mmol) was added to a DCM (50 ml) solution of N′-benzyl-4-bromobenzene-1,2-diamine (4451 mg, 16.06 mmol) and trimethyl orthobenzoate (3096 μl, 17.66 mmol) and the resulting mixture was stirred at rt under an atmosphere of Nitrogen for 40 h. The reaction mixture was then concentrated in vacuo to give a yellow solid which was triturated with 40% MeOH/water (375 mL), filtered, washed with saturated NaHCO3 (20 ml)+H2O (80 ml) twice and 40% MeOH/H2O (2×50 ml), and dried to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm=5.44 (s, 2 H, 7.05-7.08 (m, 3 H), 7.30-7.36 (m, 4 H), 7.44-7.50 (m, 3 H), 7.66-7.68 (m, 2 H) and 7.99 (dd, 1 H, J=0.4 & 1.6 Hz). MS (ES+): m/z 363.20 and 365.26 [MH+].
Reaction SMILES: C([O:8][C:9]1[C:10]([O:38][CH3:39])=[CH:11][C:12]2[CH:13]3[CH:21]([CH2:22][CH2:23][C:24]=2[CH:25]=1)[CH:20]1[C:16]([CH3:37])([CH:17]([O:26][CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:18][CH2:19]1)[CH2:15][CH2:14]3)C1C=CC=CC=1>C1COCC1.[Pd]>[C:33]([Si:30]([CH3:32])([CH3:31])[O:29][CH2:28][CH2:27][O:26][CH:17]1[C:16]2([CH3:37])[CH:20]([CH:21]3[CH:13]([CH2:14][CH2:15]2)[C:12]2[CH:11]=[C:10]([O:38][CH3:39])[C:9]([OH:8])=[CH:25][C:24]=2[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: COc1cc2c(cc1OCc1ccccc1)CCC1C2CCC2(C)C(OCCO[Si](C)(C)C(C)(C)C)CCC12
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc2c(cc1O)CCC1C2CCC2(C)C(OCCO[Si](C)(C)C(C)(C)C)CCC12
Reaction time: 8 h

Procedure:
A stirred, degassed, solution of ether 46 (200 mg, 0.36 mmol) in THF (10 mL) was treated with 10% Pd/C (20 mg) and placed under an atmosphere of hydrogen overnight. The reaction was then filtered through celite and evaporated to give the desired phenol 47 as a clear colourless oil δH 6.80 (1H, s, ArH), 6.65 (1H, s, ArH), 5.55 (1H, s, OH), 3.87 (3H, s, OMe), 3.52-3.82 (4H, m, 2×OCH2), 3.42-3.48 (1H, m, 17-CH), 2.72-2.84 (2H, m, 6-CH2), 1.20-2.36 (13H, m), 0.94 (9H, s, tBu), 0.89 (3H, s, 18-Me) and 0.12 (6H, s, SiMe2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C3CCCC3)c3c(Cl)cccc23)c(C)c1
Yield: 50.8 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and cyclopentyl bromide (0.075 mL, 0.7 mmol) to give the title compound (0.090 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.C[Si]([N:36]=[C:37]=[O:38])(C)C>ClCCl.CN(C)C=O>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37]([NH2:36])=[O:38])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: C[Si](C)(C)N=C=O
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(N)=O)cc3)nc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
8-(4-Amino-benzyl)-3-butyl-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione (25 mg, 0.06 mmol) was dissolved in 95:5 dichloromethane/N,N-dimethylformamide (2 mL), and treated with trimethylsilyl isocyanate (Aldrich) (47 μl, 0.3 mmol). The reaction was stirred at room temperature for 18 h. The reaction was then concentrated under reduced pressure and the residue was purified by reverse phase HPLC to afford the desired product. LCMS, m/z(M+H)=464.98.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.C(OC(=O)[NH:30][CH:31]1[CH2:36][CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32]1)(C)(C)C.C(OC(=O)NC1CCCC(B2OC(C)(C)C(C)(C)O2)=C1)(C)(C)C>>[NH2:30][CH:31]1[CH2:32][C:33]([C:2]2[C:6]3[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]4[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=4[Cl:22])[CH3:13])[C:5]=3[O:4][CH:3]=2)=[CH:34][CH2:35][CH2:36]1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCC=C(B2OC(C)(C)C(C)(C)O2)C1
Agent: CC(C)(C)OC(=O)NC1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCCC(N)C3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to General procedure A with starting material 3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine and the mixture of [3-(4,4,5,5-Tetramethyl[1,3,2]dioxaborolan-2-yl)-cyclohex-3-enyl]-carbamic acid tert-butyl ester and [3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclohex-2-enyl]-carbamic acid tert-butyl ester. 1H-NMR (CD3OD, 400 MHz): δ=1.43-1.59 (m, 1H), 1.86 (d, J=6.8 Hz, 3H), 1.89-1.98 (m, 1H), 2.08-2.22 (m, 1H), 2.28-2.45 (m, 2H), 2.59 (dd, J=16.3, 4.93 Hz, 1H), 2.98-3.14 (m, 1H), 6.25 (br. s., 1H), 6.48 (q, J=6.7 Hz, 1H), 7.15-7.24 (m, 1H), 7.38 (dd, J=9.0, 4.9 Hz, 1H), 7.54 (s, 1H), 8.15 (s, 1H). MS (ES+): m/z 436.03 (MH+, 35Cl, 37Cl), 437.97 (MH+, 35Cl, 37Cl). HPLC: tR=2.20 min (polar—5 min, ZQ3).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9](Br)[CH:8]=[CH:7][C:6]=1[C@@H:12]1[C@@H:15]([CH2:16][CH2:17][C@H:18]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:14](=[O:34])[N:13]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:3])[CH3:2].[OH:41][C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:10]=[C:9]([C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([OH:41])[CH:47]=2)[CH:8]=[CH:7][C:6]=1[C@@H:12]1[C@@H:15]([CH2:16][CH2:17][C@H:18]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:14](=[O:34])[N:13]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccc(O)c1
Reactant: CC(=O)Oc1cc(Br)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
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: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)Oc1cc(-c2cccc(O)c2)ccc1[C@@H]1[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)C(=O)N1c1ccccc1
Temperature: 70 °C
Yield: 68.4 %

Procedure:
Using Suzuki coupling methodology, 5-Bromo-2-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}phenyl acetate (100 mg, 0.16 mmol) was combined with 3-hydroxyphenyl boronic acid (29 mg, 0.21 mmol) with deoxygenated toluene (3 mL) and deoxygenated ethanol (1 mL). 2.0 M aqueous potassium carbonate (0.31 mL, 0.31 mmol) was added and the vessel was purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.008 mmol) was added and the vessel purged again. The reaction was heated to 70° C. for 1.5 h, cooled, diluted with water and extracted with ethyl acetate (2×). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, concentrated and purified by chromatography (40 g silica gel, 20% to 90% ethyl acetate-hexane) to afford 4-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}-3′-hydroxybiphenyl-3-yl acetate (70 mg, 69% yield)); Rf 0.34 (1:2 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 10H), 7.06-6.90 (m, 5H), 6.79 (ddd, J=8.1, 2.5, 0.8 Hz, 1H), 6.03 (br s, 1H), 4.67 (d, J=2.3 Hz, 1H), 4.64 (t, J=5.6 Hz, 1H), 3.26 (ddd, J=4.8, 2.5, 2.4 Hz, 1H), 2.27 (s, 3H), 1.94-1.73 (m, 4H), 0.84 (s, 9H), −0.02 (s, 3H), −0.19 (s, 3H) ppm; MS [M−OSi(CH3)2C(CH3)3]+ 508.0.
Reaction SMILES: I[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.C([Sn](CCCC)(CCCC)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26])CCC.O1CCCC1>CN1CCCC1=O.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=2)=[C:18]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1[N+](=O)[O-]
Reactant: COc1ccc(C=CI)cc1
Agent: [Cu+]
Agent: O=C([O-])c1cccs1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1ccc(C=Cc2ccc(OC)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 72.8 %

Procedure:
By referring to the synthetic method of J. Org. Chem., 1997, 62, 199, to a solution of lithium acetate (280 mg) in water (3 ml) was added acetonitrile (90 ml), the solution was stirred at room temperature, then 4-methoxycinnamic acid (7.5 g), N-iodosuccinimide (10 g) were sequentially added thereto, the solution was stirred for 2 hours at room temperature, and then neutralized with a saturated aqueous solution of sodium bicarbonate. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide 1-(2-iodovinyl)-4-methoxybenzene (8.0 g). By referring to the synthetic method of J. Am. Chem. Soc., 1996, 118, 2748, to a solution of 1-(2-iodovinyl)-4-methoxybenzene (7.1 g) and tributyl(4-methoxy-2-nitrophenyl)tin (10 g) in 1-methyl-2-pyrrolidone (100 ml) was added copper(I) thiophene-2-carboxylate (6.6 g) on an ice bath under a nitrogen atmosphere, and the solution was stirred for 25 minutes at room temperature. Tetrahydrofuran was added thereto, the solution was stirred, then filtered through alumina, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (4.7 g).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[S:15][C:16]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:9][CH2:8]2)=[N:4][N:3]=1.C(N(CC)CC)C.Cl[S:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])(=[O:39])=[O:38]>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[S:15][C:16]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([S:37]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])(=[O:39])=[O:38])[CH2:27][CH:28]=5)[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:9][CH2:8]2)=[N:4][N:3]=1
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: Cc1nnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCS(=O)(=O)N1CC=C(c2ccc3nc(OC4CCN(c5nnc(C)s5)CC4)sc3c2)CC1
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
To a solution of 2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (95 mg, 0.230 mmol) and triethylamine (0.065 mL, 0.459 mmol) in CH2Cl2 (2 mL) at 0° C. was added methyl 3-(chlorosulfonyl)propanoate (64 mg, 0.345 mmol). The reaction mixture was stirred at this temperature for 15 min, then at rt for 2 h. The reaction mixture was quenched with sat. aq. NaHCO3 (2 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 70% EtOAc) to afford methyl 3-(4-(2-(1-(5-methyl-1,3,4-thiadiazol-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)propanoate (80 mg, 0.142 mmol, 62% yield) as a yellow solid. LCMS (m/z)=564 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@H:13]([OH:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[OH-:27].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:23]([O:22][C:20]([CH2:19][O:17][C@H:13]1[C@@H:14]([O:16][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:27])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(OCc1ccccc1)N1C[C@@H](O)[C@@H](O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1OCC(=O)OC(C)(C)C

Procedure:
237 mg of cis-N-benzyloxycarbonylpyrrolidine-3,4-diol, 1 ml of t-butyl bromoacetate and 100 mg of tetrabutylammonium hydrogen sulphate in 10 ml of toluene are stirred with 10 ml of 50% sodium hydroxide solution under phase transfer conditions. The organic phase is washed with water and evaporated. Chromatography of the evaporation residue on silica gel with ethyl acetate/hexane (1:3) gives 354 mg of benzyl cis-3,4-bis-t-butoxycarbonylmethoxy-pyrrolidine-1-carboxylate. MS: 354 (M-111).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>COCCOCCOC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[CH2:24][CH2:25]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccccn3)CC2)cc1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A mixture of 1-chloro-4-nitro-benzene (4.34 g, 27.6 mmol) and anhydrous potassium carbonate (5.08 g, 36.8 mmol) was added to a solution of 1-(2-pyridyl)piperazine (3.0 g, 18.4 mmol) in diglyme (10 mL) and heated at reflux for 24 h. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was concentrated in vacuo. The residue was diluted with chloroform and the organic layer was washed with water (5×40 mL), brine (3×30 mL), dried over anhydrous sodium sulphate and concentrated to yield a crude compound. This was purified by washing with hexane (5×5 mL) and then pentane (2×5 mL) to afford 1-(4-nitrophenyl)-4-(2-pyridyl)piperazine (4.0 g, 77%) as a yellow solid.
Reaction SMILES: [Na].[CH3:2][C@@:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4]1.[I-].[K+].Cl[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CO>[CH3:2][C@@:3]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:14][CH:15]=2)[C:7](=[O:8])[N:6]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:5](=[O:9])[NH:4]1
Reactant: C[C@]1(c2ccc(O[C@H]3CCCCO3)cc2)NC(=O)NC1=O
Reactant: COC(=O)CCl
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: CO
Product: COC(=O)CN1C(=O)N[C@](C)(c2ccc(O[C@H]3CCCCO3)cc2)C1=O
Reaction time: 2 h
Yield: 70.6 %

Procedure:
230 mg (10 mmol) of sodium were dissolved in 25 ml of anhydrous methanol under argon. 2.9 g (10 mmol) of 10.2 were added. The mixture was heated to reflux with stirring for 2 hours. 1.66 g (10 mmol) of potassium iodide were then added and a solution of 0.975 ml (10 mmol) of methyl chloroacetate in 1.1 ml of anhydrous methanol was added dropwise in the course of 15 minutes. The mixture was heated to reflux for 4 hours and then allowed to stand at room temperature overnight. A further 0.195 ml (2 mmol) of methyl chloroacetate in 0.22 ml of anhydrous methanol were added and the batch was stirred under reflux for 4 hours. The precipitate was filtered off with suction and the filtrate was concentrated. The residue was dissolved in methylene chloride, insoluble matter was filtered off and the filtrate was chromatographed on silica gel using methylene chloride/ethyl acetate (9:1). 2.56 g (71%) of 10.3 were obtained.