Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[N+](=C)=[N-].[OH:20][N:21]1[C:25](=[O:26])[C:24]([CH:28]([CH3:30])[CH3:29])([CH3:27])[N:23]=[C:22]1[C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34]>C(OCC)(=O)C.C(O)C.CCOCC>[OH:20][N:21]1[C:25](=[O:26])[C:24]([CH:28]([CH3:30])[CH3:29])([CH3:27])[N:23]=[C:22]1[C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([O:35][CH3:3])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC(C)C1(C)N=C(c2ccccc2C(=O)O)N(O)C1=O
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)c1ccccc1C1=NC(C)(C(C)C)C(=O)N1O
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A solution of potassium hydroxide (0.19 g, 0.00339 mol) and ethanol is added portionwise to a 0° C. mixture of Diazald® N-methyl-N-nitroso-p-toluenesulfonamide (0.73 g, 0.0034 mol) and ether. The mixture is kept in an ice-bath for 10 minutes then in an water bath for 10 minutes. The diazomethane is distilled into a mixture of o-(1-hydroxy-4-isopropyl-4-methyl-5-oxo-2-imi-dazolin-2-yl)benzoic acid (0.67 g, 0.00243 mol) and ethanol. After 45 minutes the reaction mixture is quenched with acetic acid and concentrated in vacuo to give an oil. The oil is dissolved into ethyl acetate, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield an off-white solid. The solid is chromatographed using silica gel and methylene chloride/ethyl acetate 3:1 as eluent to give the title compound as a white solid (0.18 g, 26%), mp 146°-150° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:26])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].O1CCCC1.C(C(CCCC)C([O-])=O)C.[Na+:48]>C(OCC)(=O)C>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([OH:26])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([O-:22])=[O:21])=[CH:14][CH:15]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[Na+:48]
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(OCc2ccc(C(O)c3cccc(C(=O)[O-])c3)cc2)ccc(C(C)=O)c1O
Reaction time: 8 h
Yield: 94 %

Procedure:
Compound 3-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoic acid (357 mg, 0.822 mmol) is stirred in a solution of ethyl acetate (4 mL) and tetrahydrofuran (4 mL) at room temperature. A solution of sodium 2-ethylhexanoate (150 mg, 0.904 mmol) in ethyl acetate (2 mL) is added and the reaction is stirred overnight. The reaction is concentrated and the resulting thick oil is diluted with ether (5 mL) and stirred vigorously. The resulting white precipitate is filtered, and dried under vacuum to give the title compound as a white solid (94%). 1H NMR (DMSO-d6) δ 12.85 (s, 1H), 7.86 (s, 1H), 7.81 (d, 1H), 7.69 (d, 1H), 7.38-7.39 (m, 4H), 7.33 (d, 1H), 7.19 (t, 1H), 6.72 (d, 1H), 5.84 (d, 1H), 5.70 (d, 1H), 5.22 (s, 2H), 2.57-2.62 (m, 5H), 1.46-1.53 (m, 2H), 0.88 (t, 3H). LCMS M−1 433 (parent acid).
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.I[CH3:12].[C:13](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C(#N)C.O>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH3:13])[N:10]=2)[N:5]=[CH:6][CH:7]=1.[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][N:10]([CH3:12])[C:3]=12
Reactant: O=C([O-])[O-]
Reactant: Ic1ccnc2c[nH]nc12
Reactant: CI
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc2nccc(I)c2n1
Product: Cn1ncc2nccc(I)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.19 %
Yield: 28.4 %

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (100 mg, 0.408 mmol), iodomethane (0.025 ml, 0.408 mmol) and cesium carbonate (266 mg, 0.816 mmol) were combined in DMF (5 mL). The mixture was stirred at room temperature for 1 hour then purified by preparative HPLC eluting with a gradient of 20-70% 10 mmol NH4HCO3 in 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column to give 7-iodo-2-methyl-2H-pyrazolo[4,3-b]pyridine (15 mg, 14.19% yield) and 7-iodo-1-methyl-1H-pyrazolo[4,3-b]pyridine (30 mg, 28.4% yield). MS [M+H] found 260.0. 7-Iodo-2-methyl-2H-pyrazolo[4,3-b]pyridine (15 mg, 0.058 mmol), Tris(dibenzylideneacetone)dipalladium(0) (1.326 mg, 1.448 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (8.38 mg, 0.014 mmol), 3′-fluoro-6′-methyl-2,2′-bipyridin-4-amine (11.77 mg, 0.058 mmol) and sodium 2-methylpropan-2-olate (16.69 mg, 0.174 mmol) were combined in dioxane (5 mL). The mixture was heated at 120° C. for 2 hours and then purified by preparative HPLC eluting with a gradient of 5-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to afford the title compound as a TFA salt.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[O:8][C:9]3[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([OH:21])[C:10]=3[C:11]=2[CH3:12])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:2]([O:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[O:8][C:9]3[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([O:21][C:7](=[O:8])[CH3:6])[C:10]=3[C:11]=2[CH3:12])=[CH:4][CH:3]=1)(=[O:1])[CH3:3]
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(O)cc3)c(C)c2c1O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OC(C)=O)cc3)c(C)c2c1OC(C)=O
Yield: 176.8 %

Procedure:
A solution of 2-(p-hydroxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (1 gm; 3 mmoles) in pyridine (15 mL) and acetic anhydride (3 mL) was stirred at 50° C. for 15 minutes. The volatiles were removed in vacuo leaving a residue that crystallised on cooling. It was slurried with hexane, filtered, washed with hexane, and air dried to yield 1.1 gm (87%) of 2-(p-acetoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran, mp. 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(Cl)(C)=O.[NH3:23]>C1(C)C=CC=CC=1.CO>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](=[NH:23])[NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: N#CCCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: N
Solvent: Cc1ccccc1
Solvent: CC(=O)Cl
Solvent: CO
Product: N=C(N)CCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
To a solution of 3-(4-(4-fluorophenoxyl)phenyl)propanenitrile (4.4 g, 18.24 mmol) in toluene (25 mL) and methanol (5.94 mL) was added dropwise AcCl (6.48 mL, 91 mmol) at 0° C. in 5 min. The mixture was stirred at room temperature for 2 h. The mixture was cooled to 0° C. in an ice bath, and ammonia (26.1 mL, 182 mmol) in methanol was added dropwise in 5 min. The mixture was stirred at room temperature overnight. The mixture was filtered to remove the solid, and the solid was washed with toluene (40 mL) and methanol (40 mL). The combined filtrate was concentrated in vacuo, the residue was triturated with diethyl ether, the resulting white solid was collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound (5.4 g, 16.12 mmol, 88% yield) as white solid. LCMS: rt=1.03 min, [M+H+]=259
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)C>[NH:10]([C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: Fc1cc(I)ccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1cc(I)ccn1
Temperature: 24.5 °C
Reaction time: 20 h

Procedure:
A solution of 2-fluoro-4-iodopyridine (prepared as described in Rocca, P. et al J. Org. Chem. 1993, 58, 7832-7838) (8.72 g, 39.1 mmol) in 80 mL of ethanol was treated with 20 mL of hydrazine hydrate and the mixture was stirred at room temperature (24-25° C.) for 20 hours. At the end of the reaction, the mixture was concentrated in vacuum and the resulting solid triturated with a mixture of hexanes/diethyl ether affording (8.52 g, 93%) the desired compound that was used in the following steps without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]Br.O>CO>[CH2:1]([N:8]([CH2:21][CH2:22][C:23](=[O:25])[CH2:24][Br:26])[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CC(=O)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CO
Product: O=C(CBr)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of N-benzyl-2-nitro-N-(3-oxobutyl)benzenesulfonamide (compound F, 30 g, 83 mmol) in methanol (300 ml) was added bromine (4.69 ml, 91 mmol) in one portion at 20-25° C. Stirred for 20 hours (no bromine colour), water (20 ml) added, heated to reflux for 30 min, diluted with MeOH (100 ml). The solution was cooled to 30° C. with stirring, seeded with compound G, stirred at 25-30° C. for 5 min (crystallisation occurred), cooled to 15° C., aged for 1 hour. Crystals collected, washed with 2×15 ml of MeOH (20-25° C.), dried on air to give N-benzyl-N-(4-bromo-3-oxobutyl)-2-nitrobenzenesulfonamide (19.4 g, 44.0 mmol, 53.1% yield).
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:45]([CH3:47])[CH3:46])[C:11]([N:13]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:14][C:15]([NH:17][C@H](C(C1OC=C(C2C(Cl)=CC=CC=2Cl)N=1)=O)CC(O)=O)=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C(N)[C@H](C(OCC=C)=O)C(C1OC=C(C2C(Cl)=CC=CC=2Cl)N=1)O)(C)(C)C.C([O:83][C:84](=[O:107])[CH:85](N)[C@H:86](C(OCC=C)=O)[CH:87]([C:89]1[O:90][C:91]2[CH:97]=[C:96]([Cl:98])[CH:95]=[C:94]([F:99])[C:92]=2[N:93]=1)[OH:88])(C)(C)C.C(OC(=O)C[C@H](NC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=CC=1)C(C1OC=C(C2C(Cl)=CC=CC=2Cl)N=1)O)(C)(C)C>>[C:1]([NH:9][C@@H:10]([CH:45]([CH3:47])[CH3:46])[C:11]([N:13]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:14][C:15]([NH:17][C@H:86]([C:87]([C:89]1[O:90][C:91]2[CH:97]=[C:96]([Cl:98])[CH:95]=[C:94]([F:99])[C:92]=2[N:93]=1)=[O:88])[CH2:85][C:84]([OH:83])=[O:107])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Reactant: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc2c(F)cc(Cl)cc2o1
Agent: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1
Agent: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc2c(F)cc(Cl)cc2o1)Cc1ccccc1

Procedure:
Compound 719 was prepared by a method similar to the method used to prepare compound 710, except compound 707 was replaced with compound 714 in the preparation of 708: 1H NMR (500 MHz, CD3OD) δ 8.70-8.54 (m), 8.48-8.35 (m), 8.34-8.08 (m), 7.98-7.87 (m), 7 .75-7.67 (m), 7.63 (m), 7.58 (m), 7.51-7.44 (m), 7.43-7.29 (m), 7.28-7.03 (m), 6.97 (m), 5.51 (m), 4.99-4.66 (m), 4.65-4.26 (m), 4.25-3.61 (m), 3.42 (m), 3.13-2.83 (m), 2.68-2.42 (m), 2.23-2.00 (m), 1.02-0.69 (m). ##STR98##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2].[Br:24]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC1C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Br:24])[C:10]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(C)cccc1OCCCC(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Solvent: O
Product: CCOC(=O)/C=C/c1c(CBr)cccc1OCCCC(=O)OCC
Temperature: 85 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a solution of 4-[2-((E)-2-ethoxycarbonyl-vinyl)-3-methyl-phenoxy]-butyric acid ethyl ester (8.0 g, 25.0 mmol) in chlorobenzene (190 mL) were added N-bromosuccinimide (6.67 g, 37.5 mmol) and 2,2′-azobisisobutyronitrile (AIBN) (591 mg, 3.6 mmol) at room temperature. Then, the solution was heated to 85° C. and stirred for 1 h. Then, the reaction mixture was cooled to room temperature and diluted with water (100 mL). Then, the organic compound was extracted into hexanes (3×100 mL). The combined organic extracts were washed with brine solution (150 mL) and the organic solution was dried over anhydrous magnesium sulfate. Filtration of the drying agent and the removal of the solvent gave a crude oil. The crude oil was purified by using a Biotage (40 L) column eluting with 15-25% ethyl acetate in hexanes to isolate 4-[3-bromomethyl-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (7.11 g, 71%) as a low melting solid: ES(+)-HRMS m/e calculated for C18H23BrO5 (M+Na)+ 421.0621, found 421.0621.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:25]=[CH:24][C:11]([O:12][CH2:13][C@H:14]([OH:23])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:10][CH:9]=1.O.[NH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.O>C(O)C.C1(C)C=CC=CC=1.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>[NH2:27][C:28]1[CH:33]=[C:32]([C:8]2[CH:25]=[CH:24][C:11]([O:12][CH2:13][C@H:14]([OH:23])[CH2:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:10][CH:9]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Reactant: Nc1cccc(B(O)O)c1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2ccc(OC[C@H](O)CCc3cccnc3)cc2)c1
Temperature: 25 °C
Yield: 82.9 %

Procedure:
Aqueous sodium carbonate solution (2 M, 1.55 ml) was added to a solution of (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.50 g), 3-aminobenzeneboronic acid monohydrate (0.26 g) and tetrakis(triphenylphosphine)palladium(0) (0.045 g) in ethanol (1.72 ml) and toluene (6.9 ml). The mixture was stirred at reflux under a nitrogen atmosphere for 3 hours and then, cooled to room temperature. The reaction mixture was poured into water and then extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (19:1) to give the title compound (0.43 g) as an which was recrystallised from isohexane:ethyl acetate to give a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH:15]([CH3:17])[CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].[H-].COCCO[Al+]OCCOC.[Na+].[H-].O1CCCC1>C1C=CC=CC=1>[CH3:1][C:2]1([CH:15]([CH3:17])[CH3:16])[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[CH:3]1[OH:14]
Reactant: CC(C)C1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C1(C)Cc2cc(O)c(Cl)c(Cl)c2C1O

Procedure:
2-Methyl-2-isopropyl-6,7-dichloro-1,5-indan-diol is prepared following substantially the same procedure described in Example 4, Step E, using the following substances: 2-methyl-2-isopropyl-5-hydroxy-6,7-dichloro-1-indanone (8.2 g., .03 mole); sodium bis-(2-methoxyethoxy)aluminum hydride (70% in benzene [10 ml.]; and tetrahydrofuran (100 ml.).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18](=[O:35])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])=[CH:21][C:20]=3[Cl:34])[CH:12]=2)[N:8]=[N:7]1)C.[Li+].[OH-].O.Cl>CO.CCOC(C)=O>[Cl:34][C:20]1[CH:21]=[C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[CH:23]=[CH:24][C:19]=1[C:18]([C:13]1[CH:12]=[C:11]([C:9]2[N:8]=[N:7][N:6]([CH2:5][C:4]([OH:36])=[O:3])[CH:10]=2)[CH:16]=[CH:15][C:14]=1[CH3:17])=[O:35]
Reactant: CCOC(=O)Cn1cc(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cn(CC(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reaction time: 2 h

Procedure:
A solution of compound 110 (236 mg, 0.46 mmol) in MeOH (3.0 mL) was added LiOH (55 mg, 2.31 mmol) and water (0.3 mL). The reaction mixture was stirred for 2 h under reflux. The reaction mixture was poured into a mixture of EtOAc/saturated NaCl. Aq. HCl (1 N, 0.5 mL) was added. The aqueous phase was washed with more EtOAc. The collected organic phases were washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography using a mixture of MeOH/DCM/acetic acid 400:2:1 as the eluent to afford the title compound as yellow foam. 13C NMR (DMSO-d6) δ 194.9, 168.4, 158.7 (dd), 155.7 (dd), 149.3, 145.3, 139.8, 136.0, 133.7, 133.7, 131.7, 128.1, 127.1, 126.5, 126.4 (dd), 125.0, 124.2 (dd), 122.8, 114.8, 112.0 (dd), 111.8, 105.0 (dd), 50.9, 19.4
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][C:16]1[CH:17]=[C:18]([C:22]2([O:30][CH3:31])[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:15][C:16]3[CH:17]=[C:18]([C:22]4([O:30][CH3:31])[CH2:27][CH2:26][O:25][C:24]([CH3:28])([CH3:29])[CH2:23]4)[CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: COC1(c2cccc(O)c2)CCOC(C)(C)C1
Product: COC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOC(C)(C)C1
Yield: 83 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with 4-(3-hydroxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran to give 4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-4-methoxy-2,2-dimethyltetrahydropyran in 83% yield.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:20][C:21]1([Cl:29])[C:24]([Cl:25])=[C:23]([Cl:26])[C:22]1([Cl:28])[Cl:27]>>[Cl:20][C:21]1([Cl:29])[C:24](=[O:6])[C:23]([Cl:26])=[C:22]1[Cl:27].[Cl:20][C:21]1([Cl:29])[C:24]([Cl:25])=[C:23]([Cl:26])[C:22]1([Cl:28])[Cl:27].[Cl:20][C:21]([Cl:29])=[C:24]([Cl:25])[C:23]([Cl:26])=[C:22]([Cl:28])[Cl:27]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: ClC1=C(Cl)C(Cl)(Cl)C1(Cl)Cl
Agent: O=S(=O)(O)O
Product: ClC(Cl)=C(Cl)C(Cl)=C(Cl)Cl
Product: O=C1C(Cl)=C(Cl)C1(Cl)Cl
Temperature: 100 °C

Procedure:
In a 1 liter flask, a mixture of 78 g of concentrated sulphuric acid and 78.5 g of phosphorus pentoxide was poured onto 100 g of 96% pure hexachlorocyclobutene [96 g (0.368 mole) of hexachlorocyclobutene; remainder hexachloro-1,3-butadiene], with stirring (molar ratio of hexachlorocyclobutene:sulphuric acid:phosphorus pentoxide=1:2:1). The mixture was heated at 100° C. for 3 hours. After cooling, the reaction mixture was poured onto ice, the organic phase was then separated immediately from the aqueous phase and the latter was extracted three times with petroleum ether. The petroleum ether solution and the organic phase were combined and dried with sodium sulphate, the petroleum ether was distilled under normal pressure and the residue was subjected to fractional distillation under 35 mbars. 43.6 g of tetrachlorocyclobutenone, 14.3 g of hexachlorocyclobutene and 3.6 g of hexachloro-1,3-butadiene were obtained. The selectivity of the reaction was 69.0% of theory with a conversion of 85% of theory.
Reaction SMILES: [C-:1]1(CC(Cl)=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.[C-:10]1(CC(Cl)=O)[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:19].CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(O)=O.C(N(CC)CC)C.[Na]>ClCCl>[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:19]
Reactant: O=C(Cl)C[c-]1cccc1
Agent: [Fe+2]
Agent: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1cc[cH-]c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
1,1'-ferrocenediacetyl chloride (2 g, 0.006 m) in dichloromethane (10 cm3) added dropwise to mixture of 6-aminopenicillanic acid (2.6 g, 0.012 m) and triethylamine (2.42 g, 0.024 m) in dichloromethane (30 cm3) at 0° C. Mixture stirred for 15 minutes at 0° C. and 1 hour at 15° C. Procedure as for previous penicillins. Yield of sodium salt of 1,1'-bis(6-acetamido-penicillanic acid)ferrocene was 2.63 g (59%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][S:12](Cl)(=[O:14])=[O:13]>ClCCl>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cccc(C)c1C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)c(C)c1C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94.3 %

Procedure:
2,3-Dimethylanisole (1 cm3, 7.23 mmol) was dissolved into dichloromethane (4 cm3) and cooled to 0° C. Chlorosulfonyl chloride (2 cm3, 30.0 mmol) was then added dropwise, over 10 min and once the addition was completed the mixture was allowed to warm to room temperature and stirred for a further 45 min. The reaction was then quenched by the slow addition of ice/water (50 cm3, CARE, exotherm) before further dichloromethane (30 cm3) and water (30 cm3) were added and the organic layer was collected. The aqueous layer was washed with dichloromethane (15 cm3) and then organic extracts were combined and washed with saturated aqueous sodium chloride solution (70 cm3) before being dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford title compound (1.6 g, 6.82 mmol, 94% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][N:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1)=[O:18]>>[CH:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][N:31]=[C:30]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[CH:29]=2)=[CH:25][CH:24]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1ccc(NC(=O)c2ccnc(Br)c2)cc1
Reactant: CSc1ncc2c(n1)CCNC2
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3ccc(C(C)C)cc3)ccn1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 2-bromo-N-(4-isopropyl-phenyl)-isonicotinamide were converted to the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([O:14][NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:34])[N:21]3[O:26]CC2C=CC=CC=2)=[O:17])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C@H:9]1[CH2:13][CH2:12][C@H:11]([O:14][NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:34])[N:21]3[OH:26])=[O:17])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)C1
Reaction time: 1 h
Yield: 111.5 %

Procedure:
A mixture of tert-butyl{trans-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]cyclopentyl}methylcarbamate 117 (0.90 mmol) and Pd/C (0.50 g) in methanol (20 mL) was hydrogenated at 30 psi at room temperature for 1 hour. The mixture was filtered through a Celite pad and concentrated to provide 118 (0.40 g) as a white foam.