Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.C(Cl)Cl.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C(OCC)C.CO>[OH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:2]1
Reactant: CCC(=O)Cl
Reactant: O[C@H]1CCNC1
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CCC(=O)N1CC[C@H](O)C1
Temperature: -10 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
(S)-Pyrrolidin-3-ol (10.0 g, 81.0 mmol), triethylamine (23.6 mL, 170.0 mmol) and CH2Cl2 (150 mL) were combined in a pear-shaped flask to give a beige suspension. The mixture was cooled to −10° C. and propionyl chloride (7.06 mL, 81.0 mmol) was added dropwise over 15 min, maintaining the temperature between −10 to 0° C. The resulting beige suspension was stirred for 2 h at 0° C. MeOH (9.8 mL) was added and the mixture allowed to warm to room temperature then stirred for 1 h to give a brown solution. The mixture was evaporated in vacuo to give a beige residue which was stirred in diethylether (200 mL) and filtered. The filtrate was evaporated in vacuo to give 1-((S)-3-hydroxy-pyrrolidin-1-yl)-propan-1-one as a yellow oil (11.23 g, 95% yield). 1H-NMR (400 MHz, DMSO-d6, 298 K): δ ppm 0.92-1.02 m, 3H) 1.67-1.97 (m, 2H) 2.13-2.28 (m, 2H) 3.18-3.52 (m, 4H) 4.17-4.32 (m, 1H) 4.85-4.97 (m, 1H). LCMS: [M+H]+=144.0
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]=2[N:3]=1.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.[H-].[Na+].CN(C)CCCON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>>[N:31]1([CH2:30][CH2:29][O:14][N:13]=[C:8]2[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:5][C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]2=3)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Reactant: ClCCN1CCCC1
Agent: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Agent: Cl
Agent: [H-]
Product: Cc1nc(N)nc2c1C(=NOCCN1CCCC1)CC(c1ccccc1-c1ccccc1)C2

Procedure:
The title compound was prepared from 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 66, (30 mg, 0.087 mmol), N-(2-chloroethyl)-pyrrolidine hydrochloride (30 mg, 0.176 mmol) and sodium hydride (60% dispersion in oil) (18 mg, 0.470 mmol), following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:5]([NH2:6])=[C:4]([Cl:14])[CH:3]=1.C(N(CC)CC)C.[C:22]([CH2:26][C:27](Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:12])([F:11])[F:13])[C:5]([NH:6][C:27](=[O:28])[CH2:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:4]([Cl:14])[CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1c(Cl)cc(Br)cc1OC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1c(Cl)cc(Br)cc1OC(F)(F)F
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 4-bromo-2-chloro-6-trifluoromethoxy-aniline (2.9 g, 10 mmol) and triethylamine (1.5 g, 15 mmol) in anhydrous dichloromethane (50 mL) was added dropwise tert-butylacetyl chloride (1.6 g, 12 mmol) with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature, than the reaction mixture was diluted with dichloromethane and washed with water and dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by silica gel column (ISCO, hexane/EtOAc, 0-40%, 40 min) to give a white solid (3.6 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11][C:10]=1[CH2:17][CH2:18][CH3:19].[O:28]1[C:32]2[CH:33]=[CH:34][C:35](B(O)O)=[CH:36][C:31]=2[CH2:30][CH2:29]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([N:13]3[C:14](=[O:15])[C:9]([CH2:8][C:7]4[CH:6]=[CH:5][C:4]([C:20]5[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=5)=[CH:3][C:2]=4[F:1])=[C:10]([CH2:17][CH2:18][CH3:19])[N:11]=[C:12]3[CH3:16])=[CH:36][C:31]=2[CH2:30][CH2:29]1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 48 h

Procedure:
To a suspension of 3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (5.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (5.0 g), triethylamine (10.0 mL), pyridine (5.0 mL) and molecular sieves 4 A (10.0 g) in methylene chloride (100 mL) was added copper(II) acetate (5.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (5.41 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)=[CH:5][C:4]=1[NH:16][C:17]([NH2:19])=[S:18].BrBr>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]2[N:16]=[C:17]([NH2:19])[S:18][C:5]=2[C:6]([N:9]2[CH2:14][C@@H:13]3[CH2:15][C@H:10]2[CH2:11][O:12]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2C[C@@H]3C[C@H]2CO3)cc1NC(N)=S
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1ccc(N2C[C@@H]3C[C@H]2CO3)c2sc(N)nc12
Yield: 33 %

Procedure:
To a stirred solution of 279 mg (1.00 mmol) [2-methoxy-5-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-phenyl]-thiourea in 8 ml chloroform at room temperature was added dropwise 0.051 ml (1.00 mmol) bromine and the mixture heated at reflux for 24 h. The mixture was then concentrated in vacuo and the residue suspended in water. Sodium bicarbonate solution was added until the pH was 10, and the crystals were collected by filtration. Flash chromatography (5/95 methanol/dichloromethane) afforded 91.5 mg (33%) 4-methoxy-7-{(1S,4S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl)}-benzothiazol-2-ylamine as an off-white crystalline solid. ES-MS m/e (%): 278 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[NH2:24]OC(C1C=CC(OC)=CC=1)=O.COC1C=CC(C(ON)=O)=CC=1>CN1CCCC1=O.CCOC(C)=O>[NH2:24][N:10]1[C:8]2[N:9]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH:12]=[N:11]1
Reactant: COc1ccc(C(=O)ON)cc1
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2N
Reaction time: 0.33 h

Procedure:
Ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.865 mmol) was dissolved in N-Methyl-2-pyrrolidone (NMP) (8 mL), followed by addition of potassium tert-butoxide (116 mg, 1.038 mmol). After 20 minutes stirring, O-{[4-(methyloxy)phenyl]carbonyl}hydroxylamine 1-[(aminooxy)carbonyl]-4-(methyloxy)benzene (289 mg, 1.730 mmol) was added and the mixture stirred at room temperature for 16 h. The contents were diluted with EtOAc, and then washed with brine, and saturated NaHCO3. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography (eluent: 0 to 50% EtOAc). The final product as collected as 106 mg (50%). LCMS E-S (M+H)=274.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.14 (m, 4 H), 1.41 (t, J=7.07 Hz, 3 H), 2.34-2.47 (m, 1 H), 4.44 (q, J=7.07 Hz, 2 H), 6.39 (s, 2 H), 7.64 (s, 1 H), 8.09 (s, 1 H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:9]Cl)=[CH:5][CH:6]=[CH:7][CH:8]=1.C(=O)(OC)[O:12]C.O>CN(C)C=O>[CH2:2]1[O:12][CH2:9][C:4]2[C:3]1=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)OC
Reactant: ClCc1ccccc1CCl
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)COC2
Reaction time: 22 h
Yield: 37 %

Procedure:
The procedure described in Example 1 was followed in reacting 0.05 g mole of α,α'-dichloro-o-xylene with 0.06 g mole of dimethyl carbonate in 50 ml of N,N-dimethylformamide. After 22 hours, the reaction mixture was poured into 100 ml of water and the organic portion was extracted from the mixture with three 5050 ml portions of hexane. The combined extracts were dried over MgSO4 and the hexane was distilled off. The residue was distilled under reduced pressure to obtain 2.29 g (37 percent yield) of phthalan (1,3-dihydroisobenzofuran), b.p. 95° C./30 mm.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:1]1([N:7]2[CH2:8][C:9](=[O:11])[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]2=[S:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccccc1
Reactant: O=C(O)CNc1ccccc1
Product: O=C1CN(c2ccccc2)C(=S)N1c1ccccc1
Temperature: 150 °C
Yield: 37.3 %

Procedure:
A mixture of N-phenyl glycine (7.5 gram, 0.05 mole) and phenylisothiocyanate (8 grams, 0.06 mole) was heated at 150° C. for 3 hours with stirring. The reaction mixture solidified, was ground up, and crystallized from toluene, twice, to produce 5 grams (37% yield) of the above-identified product having a melting point of about 214° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([OH:16])[C:11](I)=[N:12][C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:26]([C:28]1[CH:42]=[CH:41][C:31]([CH2:32][N:33]2[CH2:36][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:34]2)=[CH:30][C:29]=1[F:43])#[CH:27].CN(C=O)C>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>[CH2:1]([C:8]1[CH:9]=[C:10]2[O:16][C:26]([C:28]3[CH:42]=[CH:41][C:31]([CH2:32][N:33]4[CH2:36][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:34]4)=[CH:30][C:29]=3[F:43])=[CH:27][C:11]2=[N:12][C:13]=1[Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cc(Cc2ccccc2)c(Cl)nc1I
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CN(Cc2ccc(-c3cc4nc(Cl)c(Cc5ccccc5)cc4o3)c(F)c2)C1
Reaction time: 16 h

Procedure:
In a sealed flask was combined 5-benzyl-6-chloro-2-iodopyridin-3-ol (1.50 g, 4.3 mmol), PdCl2(PPh3)2 (0.30 g, 0.43 mmol), copper(I) iodide (0.17 g, 0.87 mmol), N-ethyl-N-isopropylpropan-2-amine (6.1 mL, 35 mmol), methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (1.2 g, 4.8 mmol) and DMF (10 mL, 129 mmol). The flask was flushed with argon, sealed and placed in an oil bath for 16 h at 80° C. The reaction was concentrated to remove solvent, and the resulting black mixture was adsorbed onto silica. Flash chromatography (100% EtOAc) afforded a yellow oil that was further purified on a Varian HF Mega Bond Elut SCX column (eluted with 2M ammonia in MeOH). Trituration with of the resulting solids with ether afforded an off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.83-7.90 (1H, m), 7.49 (1H, s), 7.27-7.40 (5H, m), 7.22-7.24 (1H, m), 7.12-7.19 (2H, m), 4.20 (2H, s), 3.72 (3H, s), 3.65 (2H, s), 3.52-3.59 (2H, m), 3.32-3.38 (3H, m); MS (ESI) m/z: Calculated: 464.1; Observed: 465.1 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:27]1[CH2:26][CH2:25][C:20]2[N:21]([CH3:24])[C:22]3[CH:23]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:10][C:11]4=[O:29])[CH:16]=[CH:17][C:18]=3[C:19]=2[CH2:28]1)(=[O:39])[CH3:38]
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Yield: 33.8 %

Procedure:
To a solution of 4-(benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (0.2 g, 0.5 mmol) in CH2Cl2 (6 mL) was added triethylamine (0.20 mL, 1.4 mmol) followed by acetyl chloride (50 μL, 0.71 mmol). The reaction was stirred at room temperature until complete. After the solvent was removed under reduced pressure, the residue was purified by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) to give the title compound (72.2 mg, 36%) as a yellow solid and as a mixture of rotamers: mp 225-230° C.; 1H NMR (500 MHz, CDCl3) δ 7.53-7.36 (m, 6H), 7.32-7.30 (m, 2H), 7.06-7.00 (m, 1H), 6.09 (d, J=3.0 Hz, 1H), 6.07-6.04 (m, 1H), 5.06 (s, 2H), 4.82 (s, 1H), 4.67 (s, 1H), 4.03 (t, J=5.5 Hz, 1H), 3.84 (t, J=5.5 Hz, 1H), 3.64 (s, 3H), 2.90 (t, J=5.5 Hz, 1H), 2.84 (t, J=5.5 Hz, 1H), 2.24, 2.22 (2×s, 3H); ESI MS m/z 428 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=16.8 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=2)([CH3:16])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[C:28]([CH3:31])([CH3:30])[CH3:29].[CH3:32][N:33]1[C:38](C)([CH3:39])[CH2:37]C(O)[CH2:35][C:34]1([CH3:43])[CH3:42].[NH2-].[Li+].C(O)C>C1(C)C=C(C)C=C(C)C=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=2)([CH3:16])[CH2:9][CH2:10][C:11]([O:13][CH:14]2[CH2:35][C:34]([CH3:43])([CH3:42])[N:33]([CH3:32])[C:38]([CH3:39])([CH3:37])[CH2:15]2)=[O:12])=[CH:4][C:3]=1[C:28]([CH3:30])([CH3:29])[CH3:31]
Reactant: CCOC(=O)CCC(C)(c1ccc(O)c(C(C)(C)C)c1)c1ccc(O)c(C(C)(C)C)c1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: CCO
Solvent: Cc1cc(C)cc(C)c1
Product: CN1C(C)(C)CC(OC(=O)CCC(C)(c2ccc(O)c(C(C)(C)C)c2)c2ccc(O)c(C(C)(C)C)c2)CC1(C)C
Temperature: 160 °C

Procedure:
42.7 g of ethyl 4,4-di-(4-hydroxy-3-t-butyl-phenyl)-valerate and 17.1 g of 1,2,2,6,6-pentamethyl-4-hydroxy-piperidine in 120 ml of mesitylene, with the addition of 100 mg of lithium amide as the catalyst, are heated to 160° C. in a nitrogen atmosphere for 5 hours, whilst stirring. During this time, the ethanol formed distils off in the stream of nitrogen and can be measured in a cold trap. After cooling, 100 ml of toluene are added to the batch and the solution is washed with water, dried with calcium chloride and evaporated in vacuo. The crystalline residue is recrystallised from acetonitrile or chlorobenzene. In this way 1,2,2,6,6-pentamethyl-piperidin-4-yl 4,4-di-(4-hydroxy-3-t-butyl-phenyl)-valerate (stabiliser no. 2) is obtained as a white crystalline powder with a melting point of 203° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:6][CH:7]=1.[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])=[O:36].C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C(Cl)Cl.Cl[Pd]Cl>[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:3]=[C:4]([C:23]3[O:24][C:25]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:26][N:27]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:40][CH:39]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nnc(-c2ccccc2)o1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4)o3)c2)cc1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (250 mg, 0.4832 mmol), (4-methylsulfonylphenyl)boronic acid (116.0 mg, 0.5798 mmol), 4-ditert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium (3.421 mg, 0.004832 mmol) and K2CO3 (133.6 mg, 0.9664 mmol) in Toluene (2.250 mL) and water (250.0 μL) was heated to 100° C. for 48 hours. The mixture was allowed to cool to ambient temperature and diluted with DCM and water. The organic layer was separated, washed with 1M NaOH solution, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated with DCM to give the desired product as a peach solid (70 mg, 37% Yield). 1H NMR (400.0 MHz, DMSO) δ 3.27 (s, 3H), 7.64-7.69 (m, 5H), 8.01 (d, J=8.5 Hz, 2H), 8.07 (d, J=8.6 Hz, 2H), 8.25-8.27 (m, 2H), 8.66 (d, J=2.5 Hz, 1H) and 8.72 (d, J=2.5 Hz, 1H) ppm; MS (ES+) 392.9.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:8]2[CH:9]=[CH:10][CH2:11][CH:7]2[C:6]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][O:4]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:41](=O)(O)[O-:42].[Na+].CCCCCC.C(OC(=O)C)C>O1CCCC1>[OH:42][CH2:41][C:9]1[C@H:8]2[C@H:3]([O:2][CH3:1])[O:4][CH:5]=[C:6]([CH2:12][O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C@H:7]2[CH2:11][CH:10]=1
Reactant: COc1ccc(COCC2=COC(OC)C3C=CCC23)cc1
Reactant: O=C([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(COCC2=CO[C@@H](OC)[C@@H]3C(CO)=CC[C@H]23)cc1
Reaction time: 2 h
Yield: 70 %

Procedure:
1.578 g (3.53 mmol) of (1R,4aS,7aS)-7-t-butyldimethylsilyloxymethyl)-1-methoxy-4-(p-methoxybenzyloxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran was dissolved in 13 mg of tetrahydrofuran and then 3.8 ml (3.89 mmol) of tetrabutylammoniumfluoride (1M in THF) was added thereto. After stirring for 2 hours, the reaction was stopped by adding saturated aqueous sodium bicarbonate solution. The reaction solution was extracted with diethylether and saturated saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane/ethylacetate=3/1, v/v) to obtain 0.821 g (Yield 70%) of (1R,4aS,7aS)-7-hydroxymethyl-1-methoxy-4-(p-methoxybenzyloxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]1)=[O:15].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][CH2:10][NH:11][C:22]([CH:19]2[CH2:18][CH2:17][CH:16]([C:14]([O:13][CH3:12])=[O:15])[CH2:21][CH2:20]2)=[O:23])=[CH:6][CH:7]=1
Reactant: NCCSc1ccc(Cl)cc1
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCC(C(=O)NCCSc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[(4-chlorophenyl)sulfanyl]ethanamine (12.2 g, 542 mmol) in DMF (350 ml) was added sequentially 4-(methoxycarbonyl)cyclohexanecarboxylic acid (cis/trans mixture), EDC (11.4 g, 59.7 mmol) and HOAt (1.48 g, 10.9 mmol) at room temperature followed by Et3N (17.39 ml, 125 mmol). The reaction was stirred overnight at ambient temperature, diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and conc. The residue was purified by silica gel flash chromatography (0-70% EtOAc in heptane) to afford the product. LCMS: M+H=356.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:9](C)[CH2:10][Cl:11])([CH3:4])([CH3:3])[CH3:2].O.[CH3:22]N(C)C=O>>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:9][CH:10]([Cl:11])[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(CCl)N(CC(=O)OC(C)(C)C)Cc1ccccc1
Reactant: CN(C)C=O
Solvent: O
Product: CC(Cl)CN(CC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 80 °C
Reaction time: 2.33 h

Procedure:
An optically-active compound of [benzyl-(2-chloro-1-methylethyl)-amino]acetic acid tert-butyl ester (172.9 g) was dissolved in N,N-dimethylformamide (520 ml), and stirred at 80° C. for 140 minutes. The reaction mixture was cooled to 0° C. Then, thereto was added water (1200 ml), and the mixture was extracted with n-hexane/ethyl acetate (2/1, 1000 ml). The organic layer was sequentially washed with water (700 ml) and saturated aqueous sodium chloride solution (400 ml), and the separated aqueous layer was extracted with n-hexane/ethyl acetate (2/1, 600 ml) again. The combined organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=50/1 to 40/1) to give the titled compound (127.0 g).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([O:27][CH2:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31])[C:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:45]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:6]([O:27][CH2:28][O:29][CH:30]([Si:32]([CH3:35])([CH3:34])[CH3:33])[CH3:31])[C:7]([C:10](=[S:45])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCc1ncc(C(=O)c2ccc(OC)cc2OCC(=O)OCC)n1OCOC(C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCCCc1ncc(C(=S)c2ccc(OC)cc2OCC(=O)OCC)n1OCOC(C)[Si](C)(C)C

Procedure:
2-n-Butyl-5-(2-ethoxycarbonylmethoxy-4-methoxybenzoyl)-1-trimethylsilylethyloxymethoxy-1H-imidazole(475 mg, 0.97 mmol) dissolved in toluene (5 ml) was mixed with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (215 mg, 0.532 mmol) and the solution heated to 80° for 1 h under argon. The reaction was cooled and the toluene solution applied directly to a silica gel column. Elution with 25-30% EtOAc/hexanes afforded the title compound as a deep purple-blue oil. (316 mg, 64% ).
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1Br
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(O)c2ccccc2)c([N+](=O)[O-])cc1Br
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of aldehyde 13 (200 mg, 0.77 mmol) in THF (10 mL) at −78° C. was added slowly a solution of PhMgBr (2.7 mL, a 1.0 M solution in THF, 2.7 mmol). After the reaction mixture was stirred at this temperature for 30 min, the reaction was quenched with 1 M HCl (15 mL). The product was extracted with Et2O (2×20 mL). The organic layer was dried (Na2SO4), and concentrated, and the residue was purified by flash chromatography (hexane/EtOAc 3:1) to afford 14 (240 mg, 92%): Rf0.32 (hexane/EtOAc 3:1); 1H NMR (CDCl3) δ 2.96 (br s, 1H), 3.96 (s, 3H), 6.52 (s, 1H), 7.27 (m, 5H), 7.37 (s, 1H), 8.28 (s, 1H); 13C NMR (CDCl3) δ 57.0, 71.7, 110.5, 110.9, 127.1, 128.3, 128.7, 130.6, 140.6, 141.2, 160.0: ESI -HRMS [M+HCO2]− C15H1379BrNO6 calcd for m/z 381.9926, found 381.9931.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:20])[CH2:12][C:13]([O:15][C:16](C)(C)[CH3:17])=[O:14]>C(O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:20])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccccc1OCCO
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccccc1OCCO
Temperature: 25 °C

Procedure:
tert-Butyl 3-(2-(2-hydroxyethoxy)phenyl)-3-oxopropanoate (2.0 g, 7.14 mmol) in ethanol (20 mL) was heated in a microwave reactor at 120° C. for 90 min. The mixture was cooled to room temperature and the solvent was concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash chromatography (30-40% EtOAc: petroleum ether) to give the title compound as a yellow solid.