Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:24]([CH3:27])(=[O:26])=[O:25])([CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([CH3:22])[C:11]1=[O:23])[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+]>O1CCCC1.CO.O.Cl>[CH3:1][C:2]([S:24]([CH3:27])(=[O:25])=[O:26])([CH2:8][CH2:9][N:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([CH3:22])[C:11]1=[O:23])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(CCn1ccc(-c2ccccc2)c(C)c1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(-c2ccccc2)ccn(CCC(C)(C(=O)O)S(C)(=O)=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanoate (118.3 mg, 0.313 mmol) in tetrahydrofuran/methanol/water (4:1:1, 3.13 mL) was added lithium hydroxide monohydrate (26.3 mg, 0.626 mmol). The mixture was stirred at ambient temperature overnight. The mixture was diluted with aqueous HCl (1 N in water) and extracted with ethyl acetate 2×. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to dryness to afford 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanoic acid as a solid. 109.4 mg.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][CH3:19])[N:4]=1.[C:20]1([CH3:46])[CH:25]=[CH:24][C:23]([C:26]([O:28][C@@H:29]2[C@@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[O:37])[O:32][C@H:31](Cl)[CH2:30]2)=[O:27])=[CH:22][CH:21]=1.CO.C(Cl)Cl>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:31]2[O:32][C@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[O:37])[C@@H:29]([O:28][C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH3:46])=[CH:25][CH:24]=3)=[O:27])[CH2:30]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][CH3:19])[N:4]=1
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Reactant: CCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Agent: [Na]
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Yield: 84.5 %

Procedure:
The sodium salt of 2-chloro-6-(2-propylimidazol-1-yl)purine (0.13 g, 0.5 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.30 g, 0.8 mmol) in CH2Cl2 (10 mL) by general method 2. No α-nucleoside was detected by 1H NMR. Column chromatography was performed twice (25 g silica gel, MeOH/CH2Cl2, 1:30, and EtOAc/hexanes, 1:1) to give 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-propylimidazol-1-yl)purine (0.26 g, 83%), which was recrystallized (EtOAc) to give analytically pure material (0.17 g, 55%): mp 192-193° C.; UV (MeOH) max 220, 239, 287 nm (∈ 40 700, 38 300, 16 700), min 231, 265 nm (∈ 35 900, 10 300); 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H), 8.27 (s, 1H), 8.00 (d, J=7.8 Hz, 211), 7.86 (d, J=7.8 Hz, 2H), 7.32 (d, J=7.8 Hz, 2H), 7.28 (d, J=7.8 Hz, 2H), 7.20 (s, 1H), 6.61 (t, J=7.1 Hz, 1H), 5.82-5.83 (m, 1H), 4.84-4.68 (m, 3H), 3.29 (t, J=7.8 Hz, 2H), 2.98-3.01 (m, 2H), 2.47 (s, 3H), 2.38 (s, 3H), 1.86 (sext, J=7.5 Hz, 2H), 1.07 (t, J=7.3 Hz, 3H); NOE difference: H1′ was irradiated, and enhancement of H4′ (small), H8 and H2′,2″ signals was observed; 13C NMR (125 MHz, CDCl3) δ 166.29, 166.23, 154.38, 153.42, 151.47, 148.18, 144.97, 144.65, 142.40, 130.12, 129.78, 129.61, 129.56, 129.20, 126.63, 126.44, 122.95, 120.57, 85.46, 83.82, 75.19, 64.12, 38.88, 33.12, 22.03, 21.91, 21.60, 14.25; HRMS m/z 637.1940 (MNa+[C32H31ClN6O5Na=637.1942]). Anal. Calcd for C32H31ClN6O5: C, 62.49; H, 5.08; N, 13.66. Found: C, 62.44; H, 5.18; N, 13.72.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccccc1C(=C/C=C/C(=O)O)c1ccccc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccccc1C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1OC
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
As in Example 115, (E)-5,5-bis(2-methoxyphenyl)-2,4-pentadienoic acid (5 g) and 4-nitrophenol (2.7 g) in dichloromethane (35 mL) was treated with 1,3-dicyclohexylcarbodiimide (3.34 g). The mixture was stirred at 0°-5° C. for 30 minutes and then at room temperature for 18 hours. After the usual work up, the crude product was crystallized from 2-propanol to give 6.1 g of (E)-5,5-bis(2-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 141.5°-143° C. A portion from the 2-propanol to yield the analytical sample, mp 142°-143° C.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[C:24]([CH:26]([NH2:28])[CH3:27])[O:23][N:22]=2)=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]=[C:24]([CH:26]([NH:28][C:2]3[N:7]=[C:6]([N:8]4[CH2:12][CH2:11][O:10][C:9]4=[O:13])[CH:5]=[CH:4][N:3]=3)[CH3:27])[O:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: CC(N)c1nc(-c2ccc(Cl)cc2)no1
Reactant: O=C1OCCN1c1ccnc(F)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(N2CCOC2=O)n1)c1nc(-c2ccc(Cl)cc2)no1
Yield: 9.7 %

Procedure:
A solution of 3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (89.1 mg, 0.487 mmol), 1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethanamine (115.9 mg, 0.518 mmol, 1.06 equiv), and DIPEA (0.20 mL, 1.1 mmol, 2.4 equiv) in DMSO (1.5 mL) was heated at 110° C. for 100 min. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (MeOH in CH2Cl2 0 to 5%) provided 3-(2-(1-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one (18.2 mg, white solid) in 10.3% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:4][CH:3]=1.[N+:37]([C:40]1[CH:45]=[CH:44][C:43]([N:46]=[C:47]=[O:48])=[CH:42][CH:41]=1)([O-:39])=[O:38]>CN(C)C=O>[O:31]=[C:29]1[NH:28][C:27](=[O:32])[CH:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([O:20][CH2:19][C:17]3[N:16]([CH3:35])[C:15]4[CH:36]=[C:11]([O:10][CH2:9][CH2:8][C:5]5[CH:6]=[CH:7][C:2]([NH:1][C:47]([NH:46][C:43]6[CH:42]=[CH:41][C:40]([N+:37]([O-:39])=[O:38])=[CH:45][CH:44]=6)=[O:48])=[CH:3][CH:4]=5)[CH:12]=[CH:13][C:14]=4[N:18]=3)=[CH:22][CH:23]=2)[S:30]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(N)cc3)cc21
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(OCCc3ccc(NC(=O)Nc4ccc([N+](=O)[O-])cc4)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-[4-[6-[2-(4-aminophenyl)ethoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (4 g) and N,N-dimethylformamide (10 ml) was added 4-nitrophenyl isocyanate (0.16 g) and the mixture was stirred at room temperature for 1 hour and allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To the residue was added ethyl acetate. The precipitate was isolated by filtration and purified by preparative normal phase medium pressure liquid chromatography using ethyl acetate:tetrahydrofuran=4:1 as the eluant to give 1-[4-(2-[2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-1-methyl-1H-benzimidazol-6-yloxy]ethyl)phenyl]-3-(4-nitrophenyl)urea. To a solution of the product in a mixture of tetrahydrofuran and methanol (1:1, 10 ml) was added 4N hydrogen chloride in 1,4-dioxane (2 ml) and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated and the residue was recrystallized from a mixture of methanol and tetrahydrofuran to afford the title compound (0.16 g, mp 170° C.(dec)).
Reaction SMILES: [OH:1][C:2]([C:5]([OH:8])(C)[CH3:6])(C)C.[O-:9][CH2:10][CH2:11]CC.[O-][CH2:15]CCC.[O-]CCCC.[O-]CCCC.[Ti+4:29]>C(O)CCC>[CH3:6][CH:5]([O:8][C:10]([CH3:11])=[O:9])[CH2:2][O:1][CH3:15].[Ti:29]
Reactant: [Ti+4]
Reactant: CC(C)(O)C(C)(C)O
Reactant: CCCC[O-]
Solvent: CCCCO
Product: COCC(C)OC(C)=O
Product: [Ti]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pinacol (130 g) was added to BOH solution (500 g) of a commercially available titanium tetrabutoxide tetramer (243 g) and agitated at room temperature for 30 minutes. After the solution was concentrated under reduced pressure at 40° C., it was heated to 60° C. and heating was continued under reduced pressure to generate no distillate. Then, PGMEA (1,200 g) was added thereto and heated under reduced pressure at 50° C. until no BOH was distilled to obtain a PGMEA solution of a titanium-containing compound [A-IV] (1,000 g) (compound concentration: 22%). The molecular weight (Mw) of the compound measured in terms of polystyrene was 1,150.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:13][CH2:14][CH:15]=[CH2:16])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]([CH2:10][OH:11])([CH2:13][CH2:14][CH:15]=[CH2:16])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCCC(NC(=O)OC(C)(C)C)(C(=O)O)C(=O)OCC
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(CO)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
A solution of the 2-(tert-butoxycarbonylamino)-2-(ethoxycarbonyl)hex-5-enoic acid (7.5 g, 24.9 mmol) and triethylamine (3.01 g, 29.9 mmol, 4.15 mL) in THF (10 mL) was cooled to −40° C. and treated with ethyl chloroformate (2.97 g, 27.4 mmol, 2.65 mL). After stirring for 30 minutes, the precipitate (triethylamine hydrochloride) was removed by filtration and the filtrate was collected and cooled to −40° C. A solution of sodiumborohydride (950 mg, 24.9 mmol) in water (10 mL) was added and the resulting solution was stirred for 30 minutes. After quenching the reaction mixture with 3 N hydrochloric acid (5 mL), the mixture was diluted with ethyl acetate (150 mL), washed with water (1×50 mL) and extracted with ethyl acetate (1×150 mL). The combined organic layers were concentrated, dried over MgSO4, filtered and purified using a combiflash system (80 g silica gel column, eluting with 10-50% ethyl acetate in heptanes) to give ethyl 2-(tert-butoxycarbonylamino)-2-(hydroxymethyl)hex-5-enoate (5.6 g, 78%). 1H NMR (CDCl3) δ 5.71-5.62 (m, 1H), 5.52 (bs, 1H), 4.96-4.87 (m, 2H), 4.20-4.12 (m, 2H) 4.07-4.03 (m, 2H), 3.73 (d, J=12.0 Hz, 1H), 2.22-1.62 (m, 4H), 1.37 (m, 9H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.Br[Zn][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:23]([C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: CCCC[Zn]Br
Product: CCCCc1cc(O)cc2nc(-c3ccc(O)cc3)oc12

Procedure:
The title compound was prepared in substantially the same manner as described in Example 35, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole, and bromo(butyl)zinc. The desired product was obtained as a white solid, m.p. 125-127° C.; MS m/e 282 (M−H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11].O>[Cl-].[Zn+2].[Cl-].ClCCl>[C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)(=[O:12])[CH3:11]
Reactant: c1ccc2c(c1)CCO2
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCO2
Temperature: 100 °C
Yield: 24.1 %

Procedure:
A mixture of 44.4 g (0.37 moles) of 2,3-dihydrobenzofuran and 37.8 g (0.37 moles) of acetic anhydride were added with 5.0 g (37 mmoles) of anhydrous zinc chloride. The mixture was heated to 95-105° C. for 10 hrs; after cooling to room temperature the mixture is added with 50 ml of water and 50 ml of dichloromethane. The organic phase was separated and the aqueous phase was extracted twice with dichloromethane (2× 30 ml). The organic phases were collected together, and washed with 50 ml of a saturated aqueous solution of sodium carbonate. The organic phase was separated and evaporated u.v. (20° C./21 mbar). The residue was then distilled at 99-100° C./0.08 mbar obtaining 14.5 g (0.089 moles) of 5-acetyl-2,3-dihydrobenzofuran.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].[F:9][C:10]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:25][C:24]([C:30]4[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=4)([C:26]([F:29])([F:28])[F:27])[O:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:13][CH:12]([NH2:14])[CH2:11]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:9][C:10]1([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH2:25][C:24]([C:30]4[CH:35]=[C:34]([Cl:36])[C:33]([Cl:37])=[C:32]([Cl:38])[CH:31]=4)([C:26]([F:27])([F:28])[F:29])[O:23][N:22]=3)=[CH:19][CH:20]=2)[CH2:13][CH:12]([NH:14][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11]1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CC(=O)NC1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.2 %

Procedure:
2-(methylsulfonyl)acetic acid (22 mg, 0.16 mmol) was added to 3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl)cyclobutanamine (Preparation 16, 50.0 mg, 0.10 mmol) in DMF (1.5 mL) along with DIPEA (54 μL, 0.31 mmol) and HATU (61 mg, 0.16 mmol). The mixture is stirred for 3 days at room temperature. The reaction mixture is partitioned between brine (5 mL) and EtOAc (5 mL). The organics are separated, dried over MgSO4, filtered and evaporated to give a residue, which is purified on regular silica eluting from neat DCM to 15% MeOH/DCM to give the title compound (20 mg): 1H NMR (DMSO-d6) δ: 8.83 (1H, d), 7.85 (2H, s), 7.79 (2H, d), 7.58 (2H, d), 4.60-4.51 (1H, m), 4.42-4.30 (2H, m), 4.04 (2H, s), 3.12 (3H, s), 2.96-2.86 (2H, m), 2.65-2.54 (2H, m); m/z (Cl) 602.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([I:13])[CH:5]=1.C(N(C(C)C)CC)(C)C.[CH3:24][O:25][CH2:26]Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:24][O:25][CH3:26])=[C:6]([I:13])[CH:5]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(I)c(O)c(OC)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1c(I)cc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 4-hydroxy-3-iodo-5-methoxybenzoic acid methyl ester (4.6 g) in chloroform (30 mL) were successively added diisopropylethylamine (3.88 g) and chloromethyl methyl ether (1.88 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed successively with ethyl acetate, 1N hydrochloric acid, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with solvent (hexane:ethyl acetate=3:1, v/v) to give the title compound (2.70 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Br)nc2)cc1

Procedure:
To a round-bottomed flask was added 6-bromopyridin-3-ol (5.0 g), PMBCl (4.95 g), K2CO3 (7.93 g) and DMF (20 mL). The resultant mixture was stirred at r.t. overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers was washed with water (20 mL×2), brine (20 mL×2), and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the residue was recrystallized from ethyl acetate and petroleum ether to provide the subtitle compound. MS ESI+: m/z=294 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][OH:17])[C:9]=2[F:18])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH3:29][O:28][C:26](=[O:27])[O:17][CH2:16][C:10]1[C:9]([F:18])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(CO)c(F)c1-c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)OCc1ccc(OC)c(-c2cccc(Cl)c2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3′-Chloro-2-fluoro-6-methoxy-biphenyl-3-yl)-methanol (I-32, 3.00 g, 11.3 mmol) in pyridine (2.31 g, 29.3 mmol) and tetrahydrofuran (40 mL) was cooled to 0° C. in an ice water bath. The reaction vessel was purged with nitrogen and methyl chloroformate (2.34 g, 24.8 mmol) was added. The ice bath was removed and the reaction was stirred at room temperature overnight. The white suspension was adjusted to pH 2 by addition of 1 N aqueous hydrochloric acid (˜25 mL) and the yellow biphasic solution was diluted with dichloromethane (200 mL) and water (150 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The dichloromethane extracts were combined, washed with water (2×200 mL) and brine (200 mL), dried over sodium sulfate, filtered, and the solvent removed under vacuum to give I-145 (3.84 g, quantitative yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:25]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])(=[O:27])[NH2:26]>>[CH3:24][C:10]1[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:25]([NH2:26])(=[O:28])=[O:27])[CH:34]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.21) (0.200 g, 0.51 mmol) and 3-sulfamoyl-benzeneboronic acid (example F.2) (0.102 g, 0.51 mmol) according to the general procedure VI. Obtained as a white solid (0.120 g, 50%). MS (ISP) 467.1 [(M+H)+]; mp 196° C.
Reaction SMILES: [CH3:1][N:2]([S:6][N:7]([CH3:11])[C:8]([F:10])=[O:9])[C:3](F)=[O:4].[C:12]1([OH:22])[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:12]1([O:22][C:3](=[O:4])[N:2]([CH3:1])[S:6][N:7]([CH3:11])[C:8]([F:10])=[O:9])[C:21]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: CN(SN(C)C(=O)F)C(=O)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(SN(C)C(=O)Oc1cccc2c1CCCC2)C(=O)F

Procedure:
5,6,7,8-Tetrahydronaphthyl-N-methyl-N-(N'-methyl-N'-fluoroformylaminosulfenyl)carbamate was prepared by the procedure of Example IX by reacting 9.21 g of bis-(N-methyl-N-fluorocarbonylamino)sulfide with 7.41 g of 5,6,7,8-tetrahydro-1-naphthol in 300 ml of toluene with 5.05 g of triethylamine as acid acceptor to yield 9.5 g of an oil.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O>>[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([Br:16])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)N1CCNCC1
Reactant: O=Cc1cccc(Br)c1
Product: O=C(Nc1ccccc1)N1CCN(Cc2cccc(Br)c2)CC1

Procedure:
The title compound was prepared from piperazine-1-carboxylic acid phenylamide and 3-bromobenzaldehyde. 1H NMR (400 MHz, CDCl3): 7.50 (br s, 1H), 7.43-7.17 (m, 7H), 7.05-7.00 (m, 1H), 6.47 (br s, 1H), 3.52-3.45 (m, 6H), 2.48-2.42 (m, 4H).
Reaction SMILES: [Br:1]Br.[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=1.CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[BrH:1].[Br:1][C:7]1[O:3][C:4]([C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: Nc1ncccc1-c1ccco1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Br
Product: Nc1ncccc1-c1ccc(Br)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 187.4 %

Procedure:
A mixture of bromine (1425 mg) in acetic acid (30 mL) was added to a mixture of 3-furan-2-ylpyridin-2-amine (1500 mg) in acetic acid (30 mL) under ice-cooling, and the reaction mixture was stirred at room temperature overnight. To the reaction mixture was added a mixture of hexane and ethyl acetate. The resulting precipitate was collected by filtration and washed with ethyl acetate to give the title compound (2674 mg) as a brown solid.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[CH:23][N:22]([CH3:26])[C:21]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:19])[CH3:16]>ClCCCl>[CH3:26][N:22]1[C:23]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[O:8])=[C:24]([CH3:25])[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])=[C:21]1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2ccc(C)cc2)n1C

Procedure:
A solution of 30.8 g. p-toluoyl chloride and 26.6 g. (0.2 mole) of aluminum chloride in 250 ml. of 1,2-dichloroethane is added to a refluxing solution of 50.6 g. (0.2 mole) of ethyl 3-ethoxycarbonyl-1,4-dimethylpyrrole-2-acetate in 250 ml. of 1,2-dichloroethane over 30 minutes. The mixture is heated under reflux for 90 minutes, and poured into ice-diluted hydrochloric acid. The organic solution is separated, washed with brine, and dried over magnesium sulfate. The solvent is evaporated in vacuo, and the residue is recrystallized from methanol to give ethyl 1,4-dimethyl-3-ethoxycarbonyl-5-(p-toluoyl)-pyrrole-2-acetate as a white solid, m.p. 108-111° C.