Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:24].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1F)[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[Cl:19][C:18]1[C:13]([N:10]2[CH2:11][CH2:12][CH:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:33]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=4[F:25])[C:3]3=[O:24])[CH2:8][CH2:9]2)=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: N#Cc1ccc(F)c(F)c1
Reactant: N[C@H]1CCN(C2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@H]2CCN(C3CCN(c4ncc(C(F)(F)F)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 130 °C
Yield: 1.4 %

Procedure:
To a solution of (S)-3-amino-1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)pyrrolidin-2-one (Example 150, Step C, 0.30 g, 0.83 mmol) in DMSO (3 mL) was added 3,4-difluorobenzonitrile (0.35 g, 2.5 mmol) and potassium carbonate (0.34 g, 2.5 mmol) and the reaction was heated to 130° C. for 6 hours. The reaction was diluted with EtOAc (20 mL) and washed with water (20 mL), and brine (20 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified on silica using a gradient of 1:9 to 1:4 EtOAc:DCM as eluent to give a solid, which was further triturated with DCM to give (S)-4-(1-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-ylamino)-3-fluorobenzonitrile (0.006 g, 0.012 mmol, 2% yield). Mass spectrum (apci) m/z=482.0, 483.9 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH3:23])[C:13]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:12]=3[S:11]2)=[CH:6][CH:5]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(O)(=O)C>[ClH:29].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:30](=[O:32])[CH3:31])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH3:23])[C:13]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:12]=3[S:11]2)=[CH:8][CH:9]=1
Reactant: CCN(C)CCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CCN(C)CCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21

Procedure:
A mixture of 0.9 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 5 ml of acetic anhydride and 5 ml of acetic acid is treated in the same manner as described in Example 6. The crude product thus obtained is recrystallized from a mixture of chloroform, ethanol and ether. 0.9 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride is thereby obtained as needles.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH:19](C(O)=O)[C:20]([OH:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)=O>>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccc2c(CC(C(=O)O)C(=O)O)c[nH]c12
Agent: O=C=O
Product: O=C(O)CCc1c[nH]c2c(C(=O)c3ccccc3)cccc12
Yield: 100 %

Procedure:
A 2.4 g (0.07 mole) sample of 2-[(7-benzoyl-1H-indol-3-yl)methyl]propanedioic acid was heated at 190° C. under vacuum until carbon dioxide evolution ceased (1/2 hr). The syrup was cooled to give 2.1 g (100%) of a yellow solid, m.p. 166.5°-168.5° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9](Br)[CH:8]=[CH:7][CH:6]=2.[CH2:13]([CH:17]([Sn])C=C(CCCC)CCCC)[CH2:14]CC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:17]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([CH3:1])[N:3]=[CH:4]2)[CH:13]=[CH2:14]
Reactant: CCCCC(=CC([Sn])CCCC)CCCC
Reactant: Cc1cc2c(Br)cccc2cn1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1cccc2cnc(C)cc12

Procedure:
3-Methyl-5-bromoisoquinoline (1.0 g, 4.5 mmol), tributylallyltin (1.6 mL, 5.0 mmol), and dichlrobis(tri-o-tolylphosphine)palladium (II) were combined in toluene (100 mL) and refluxed for 14 hours. The mixture was cooled, diluted with ethyl acetate, and washed twice with aqueous NH4Cl. The organic phase was separated, concentrated, and the residue was purified by chromatography (ethyl acetate:hexanes, 30:70) to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 9.21 (s, 1H), 8.00 (d, 1H), 7.63 (m, 2H), 7.58 (m, 1H), 4.18 (s, 2H), 3.62 (s, 3H), 2.62 (s, 3H). MS (DCI/NH3) m/e 216 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)CC>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:12][CH:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]([OH:11])=[O:10])[CH2:23][CH2:22]1
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCCO
Product: COc1ccccc1N1CCN(CC(Cc2ccccc2)C(=O)O)CC1
Temperature: 25 °C
Yield: 18.3 %

Procedure:
2-(Phenylmethyl)propenoic acid (Mannich et al., Chem. Ber., 1922, 55, 3486) (2.00 g, 12.35 mmol) and 1-(2-methoxyphenyl)piperazine (2.37 g, 12.35 mmol) in propanol (25 mL) were boiled under reflux for 18 hours, cooled to room temperature, and evaporated in vacuo. The residue was triturated with acetone and diethyl ether to give 2-[[4-(2-methoxyphenyl)piperazinyl]methyl]-3-phenyl propanoic acid (0.80 g) as a colorless powder, mp. 155°-158° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Si](C)(C)[CH3:16].CCCCCCC>CO>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: CO
Solvent: CCCCCCC
Product: COC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid 10-1 (5.22 g, 28.2 mmol) in methanol (30 mL) was added chlorotrimethylsilane 10-2 (6.00 g, 1.96 eq.). The reaction mixture was stirred under reflux during 16 h, then cooled down to room temperature, concentrated and the resulting precipitate was filtered off, washed with a small quantity of methanol, then heptane, to provide 4.36 g (78% yield) of 2-fluoro-5-nitro-benzoic acid methyl ester 10-3 as a white powder; m/z=200 (M+H)+.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1COCC1.Cl>[N:13]1([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:14][CH2:15][C:16]([C:32]([O:34][CH2:35][CH3:36])=[O:33])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of iPr2NH (4.72 g, 46.6 mmol) at −20° C. in THF (70 mL) was added n-butyllithium (13.99 mL, 35.0 mml, 2.5 M in hexanes). After 15 minutes at −20° C., the solution was cooled to −78° C., and 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (6.00 g, 23.3 mmol) was added. After stirring at −78° C. for 1 h, ethyl chloroformate (7.59 g, 70.0 mmol) was added dropwise. The reaction was then allowed to warm to room temperature over 4 h. The solution was diluted with 1 N HCl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated. Flash chromatography of the crude (0-25% EtOAc/hexanes) yielded the desired product as a yellow oil. 1H NMR (CDCl3, 600 MHz) δ 4.18 (q, J=7.1 Hz, 4H), 3.43-3.38 (m, 4H), 2.05-2.00 (m, 4H), 1.42 (s, 9H), 1.23 (t, J=7.0 Hz, 6H). MS: cal'd 352 (MNa+), exp 352 (MNa+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].CN(C)[CH:21]=[O:22]>O1CCCC1>[Cl:1][C:2]1[C:3]([CH:21]=[O:22])=[C:4]([F:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Cl)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C=O)c1F
Temperature: -55 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A solution of 4-chloro-2-fluoro-1-methoxy-benzene (Aldrich; 10.2 g, 63.5 mmol) in dry tetrahydrofuran (500 mL) was cooled to −78° C. under a nitrogen atmosphere. A solution of lithium diisopropylamide (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 39.9 mL, 70.2 mmol) was added dropwise by syringe. The reaction mixture was warmed to −55° C. and held at this temperature for 1 h. The mixture was then cooled again to −78° C., and dry N,N-dimethylformamide (10.7 mL, 139 mmol) was added by syringe. The cooling bath was removed and the reaction was allowed to warm to −10° C. and quenched by the addition of ice flakes (˜200 mL) and a solution of saturated ammonium chloride (200 mL). Ethyl acetate (200 mL) was added, the layers were separated and the aqueous later was extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, evaporated, and purified by silica gel chromatography, eluting with 0-30% ethyl acetate/hexanes to give 6-chloro-2-fluoro-3-methoxy-benzaldehyde (5.6 g, 47% yield) as an oil that solidified upon standing.
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([CH:27]=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](Cl)(=O)C.[Sn](Cl)(Cl)(Cl)Cl.O>ClCCl>[CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](=[O:28])[CH3:31])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
10-(4-Cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbaldehyde of Step A (3.7 g) dissolved in dichloromethane (75 mL) was treated with acetyl chloride (1.9 g) and tin (IV) chloride in dichloromethane (12.5 mL, 1N). After stirring overnight at room temperature, water was added. The organic solution was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and filtered through a short column of Magnesol® to provide the desired title compound as a pale yellow amorphous solid (1.3 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH2:25]([CH2:27][NH2:28])[OH:26]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:28][CH2:27][CH2:25][OH:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: NCCO
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(CNCCO)ccc1-2

Procedure:
Following the procedure for 212, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde and ethanolamine were reacted to give 285 isolated as a pale yellow solid (131 mg, 47%). LCMS: RT=6.85 min, [M+H]+=386. 1H NMR δ (ppm) (CDCl3): 8.31 (1H, d, J=8.11 Hz), 7.89 (1H, s), 7.12 (1H, d, J=8.19 Hz), 7.02 (1H, s), 5.93-5.82 (1H, m), 4.37 (2H, t, J=5.06 Hz), 3.81 (2H, s), 3.66 (2H, t, J=5.12 Hz), 3.38 (2H, t, J=5.06 Hz), 2.81 (2H, t, J=5.11 Hz), 1.60 (6H, d, J=6.63 Hz). 2 Exchangeable protons not seen.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: c1ccsc1
Reactant: O=C(Cl)CCCCCBr
Product: O=C(CCCCCBr)c1cccs1

Procedure:
Using thiophene (5 ml) and 6-bromohexanoyl chloride (10.5 ml) according to the same method as that of Reference Example 1, the title compound (12.8 g) was obtained as a pale red solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[C:15](F)[CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[C:17]([CH:18]=1)[O:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
Methyl 2-hydroxybenzoate (2.75 mL, 21.3 mmol) and 4-chloro-2-fluoro-1-nitrobenzene (1.85 g, 10.6 mmol) were dissolved in acetonitrile (25.0 mL). The cesium carbonate (6.94 g, 21.3 mmol) was added and the reaction mixture was stirred at 80° C. for 24 hours. The mixture was cooled down to room temperature then poor into ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (10-30% ethyl acetate in hexanes) to afford title compound 419 (2.55 g, 78%). MS (m/z): 308.2 (M+H). 1H NMR (DMSO-d6) δ (ppm): 8.14 (d, J=8.8 Hz, 1H), 7.98 (dd, J=7.8, 1.6 Hz, 1H), 7.74 (ddd, J=8.1, 7.4, 1.8 Hz, 1H), 7.47 (td, J=7.6, 1.2 Hz, 1H), 7.39 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (dd, J=8.3, 1.1 Hz, 1H), 6.88 (d, J=2.0 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: N1CCCC1.[CH3:6][CH2:7][C:8](=O)[CH2:9][CH3:10].[OH:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:22])[CH3:21]>CO>[CH2:7]([C:8]1([CH2:9][CH3:10])[CH2:21][C:20](=[O:22])[C:14]2[C:13](=[CH:18][C:17]([OH:19])=[CH:16][CH:15]=2)[O:12]1)[CH3:6]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCC(=O)CC
Solvent: CO
Solvent: C1CCNC1
Product: CCC1(CC)CC(=O)c2ccc(O)cc2O1
Reaction time: 24 h
Yield: 39.5 %

Procedure:
Pyrrolidine (9.3 g) and pentan-3-one (11.3 g) were added to a solution of 1-(2,4-dihydroxyphenyl)ethanone (14 g) in methanol (150 mL) and the solution was stirred for 24 hours and then heated under reflux for 10 hours. The reaction mixture was concentrated in vacuo, and to the residue was added water (10 mL). To the mixture was added 1N hydrochloric acid solution to adjust its pH to 5 to 6, and extracted with ethyl acetate (25 mL×3). The combined organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The resultant crude product was purified by column chromatography on silica gel (Solvent; petroleum ether/ethyl acetate=10/1) to give the titled compound (8 g) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH2:14][C:15]#[CH:16])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[O:26]1[C:2]([CH3:17])([CH3:1])[CH:3]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][O:13][CH2:14][C:15]#[CH:16])=[CH:10][CH:11]=1
Reactant: C#CCOCc1ccc(OCC=C(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C#CCOCc1ccc(OCC2OC2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.15 g of p-[(3-methyl-2-butenyl)oxy]-α-propargyloxy-toluene is dissolved in 40 ml of methylene chloride and cooled to 0°C. (ice-bath cooling). 1.5 g of 80% by weight m-chloroperbenzoic acid is added portionwise to this mixture and the solution is thereafter stirred at 0°C. for 2 hours. The mixture is worked up as follows: diluted with 350 ml of methylene chloride; washed with ice-cold 1-N caustic soda; washed with saturated aqueous sodium chloride solution; dried over sodium sulfate; and evaporated. By chromatography on Kieselgel, there is obtained p-[(2,3-epoxy-3-methylbutyl)oxy]-α-propargyloxy-toluene; B.P. 120°-123°C/0.1 mmHg.
Reaction SMILES: [N+:1](=[C:3]([C:10](=[O:13])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2].C(N(CC)CC)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[Br:33]Br>C(Cl)Cl>[N+:1](=[C:3]([C:10](=[O:13])[CH:11]([Br:33])[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-:2]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)CC
Reactant: BrBr
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)C(=[N+]=[N-])C(=O)C(C)Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To an ice-cooled solution of allyl 2-diazo-3-ketopentanoate (9.1 g, 0.05 mole) in 100 mL of CH2CL2, was added 8.35 mL of triethylamine, followed by dropwise addition of 11.6 mL trimethylsilyl triflate (13.34 g, 0.06 mole) over twenty minutes. The resulting solution (orange) was stirred at 0° C. for one hour. A solution of bromine (8.0 g, 0.05 mole) in 30 mL CH2Cl2 was added over twenty minutes at 0° C. The mixture was stirred at 0° C. for one hour. The reaction mixture was then washed with water three times, dried over magnesium sulphate and concentrated to give the title compound as an oil (12.74 G, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[N:13][OH:14])=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].ClN1C(=O)CCC1=O.[CH2:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:28]=[CH2:29].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:11]([C:12]2[CH2:29][CH:28]([CH2:27][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:14][N:13]=2)=[C:10]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=NO)c1Cl
Reactant: C=CCc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C2=NOC(Cc3ccccc3)C2)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.80 g (2.7 mmol) of methyl 2-chloro-3-hydroximinomethyl-4-methylsulfonylbenzoate are dissolved in 20 ml of dimethylformamide with 0.38 g (2.9 mmol) of N-chlorosuccinimide. After stirring at room temperature for 4 hours, 0.49 g (2.9 mmol) of allylbenzene and then 0.29 g (2.9 mmol) of triethylamine are added dropwise at 0° C. After stirring at room temperature for 16 hours, the reaction mixture is concentrated in a rotary evaporator, the residue is dissolved in dichloromethane and the solution is washed with sodium bicarbonate solution and with water. After drying over magnesium sulfate and evaporating the solvent, 1.1 g (100% of theory) of methyl 2-chloro-3-(5-benzylisoxazolin-3-yl)-4-methylsulfonylbenzoate are obtained as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[N:13]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>CO.O1CCCC1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][O:16][CH2:15][CH2:14][C:12]3[N:13]=[C:9]([S:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:31])=[O:3])[S:10][CH:11]=3)=[CH:23][CH:22]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(-c3ccc(F)cc3)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Sc1nc(CCOCc2ccc(-c3ccc(F)cc3)cc2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.2 %

Procedure:
2-[(4-{2-[(4′-Fluorobiphenyl-4-yl)methoxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid ethyl ester (400 mg) synthesized in Example 155-3 was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL), aqueous sodium hydroxide solution (1 mol/L, 2 mL) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, aqueous 10% citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 1:1) to give the title compound (245 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([S:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Nc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cccc(SCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cold (0° C.), stirred slurry of 1.7 g of sodium hydride oil dispersion (60%) in 100 mL of dry THF, under argon, is added via cannula 4.95 g of 3-aminothiophenol in 5 mL of THF. After 5 min, 4.6 mL of benzyl chloride is added. The mixture is allowed to warm to room temperature and stirred for 18 h, then cooled to 0° C. and partitioned between water and diethyl ether. The organic phase is washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residual oil on silica using 30% ethyl acetate in heptane provides 7.57 g of the title compound as a beige crystalline solid, which may be recrystallized from ether-hexane.
Reaction SMILES: BrBr.Br[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:24]=[C:23]2[C:14]([O:15][C:16]3[C:17]([F:28])=[CH:18][C:19]([O:26][CH3:27])=[CH:20][C:21]=3[C:22]2=[O:25])=[CH:13][CH:12]=1.C1COCC1>C(OCC)C.[Zn]>[Br:10][C:11]1[CH:24]=[C:23]2[C:14]([O:15][C:16]3[C:17]([F:28])=[CH:18][C:19]([O:26][CH3:27])=[CH:20][C:21]=3[C:22]2([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:25])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Agent: BrBr
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC1(O)c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Bromine (0.797 ml, 15.47 mmol) was added to a suspension of zinc dust (8.09 g, 124 mmol in diethyl ether (150 ml) at RT. After 5 minutes, ethyl 2-bromoacetate (6.86 ml, 61.9 mmol) was added drop wise over a time period of 20 minutes and the reaction mixture was heated to reflux for 2 hours. 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (10 g, 30.9 mmol) was added in one portion, followed by THF (100 ml) and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was quenched with aqueous saturated NH4Cl solution (100 mL) and EtOAc (100 mL) and stirred 2 hours at RT. The solution was filtered and the organic phase was separated. The solvent was removed under educed pressure to afford ethyl 2-(7-bromo-4-fluoro-9-hydroxy-2-methoxy-9H-xanthen-9-yl)acetate (12.7 g, 30.9 mmol, 100% yield).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:10]([CH3:18])=[N:11][C:12]([CH3:17])=[C:13]([Br:16])[C:14]=1O.P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Br:8][C:9]1[C:10]([CH3:18])=[N:11][C:12]([CH3:17])=[C:13]([Br:16])[C:14]=1[Cl:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(C)c(Br)c(O)c1Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1nc(C)c(Br)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Triethylamine (28.8 mL, 206 mmol) was added to a nitrogen purged solution of 3,5-dibromo-2,6-dimethylpyridin-4-ol (58 g, 206 mmol) and phosphorous oxychloride (57.7 mL, 619 mmol) in chloroform (450 mL) and stirred for 1 h at rt, then 3 h at 80° C. The reaction was removed from heating and immediately concentrated under house vaccum; then under high vacuum. The appearance was a cream colored solid, which was azeotroped with toluene (2×100 mL); treated with ice (200 g) for 10 min and carefully neutralized with NaHCO3 (powder), and 1N NaOH solution, and extracted with DCM (2×400 mL). The combined organic layers were dried (MgSO4), concentrated, and a beige solid was obtained that was washed with hexanes and dried under high vacuum to give 3,5-dibromo-4-chloro-2,6-dimethyl-pyridine 52.74 g (85.1%). Concentration of the hexanes gave 3.5 g of less pure product.