Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[Cl:21].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O>[C:17]([O:16][C:14]([N:10]1[CH2:11][CH2:12][C:13]2[C:3]([CH2:2][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[C:4]([Cl:21])[CH:5]=[CH:6][C:7]=2[CH2:8][CH2:9]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CBr)c2CC1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(Cc3cccnc3)c2CC1
Temperature: 60 °C
Yield: 58.2 %

Procedure:
Combine 6-bromomethyl-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (700 mg, 1.89 mmol), pyridine-3-boronic acid (273 mg, 2.22 mmol), tetrakis(triphenylphospine)palladium(0) (1.1 g, 0.95 mmol), and sodium carbonate (600 mg, 5.66 mmol) in a mixture of toluene (14 mL), ethanol (3.5 mL) and water (0.7 mL). Heat the mixture to 60° C. for 12 h under nitrogen. Cool the reaction and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane and hexane/EtOAc (10:1, 5:1 and 1:1) to obtain 3-tert-butoxycarbonyl-7-chloro-6-pyridin-3-ylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an off-white solid (410 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:32](=[N:34][OH:35])[NH2:33])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:36](N1C=CN=C1)(N1C=CN=C1)=[O:37].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]4)[C:15]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][F:23])=[N:16][C:12]=3[CH:11]=[C:10]([C:32]3[NH:33][C:36](=[O:37])[O:35][N:34]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (408 mg, 0.82 mmol) and 1,1′-carbonyldiimidazole (146 mg, 0.90 mmol) dissolved in acetonitrile (8.2 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.488 mL, 3.26 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 3-{4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one. MS ESI calc'd. for C26H29ClFNγO2 [M+H]+ 526. found 526. 1H NMR (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.93 (s, 1H), 8.78 (s, 1H), 8.48 (s, 1H), 7.83 (s, 1H), 4.67-4.42 (m, 3H), 3.91-3.81 (m, 1H), 3.79-3.64 (m, 2H), 3.53-3.45 (m, 1H), 2.20-2.12 (broad, 1H), 2.06-1.98 (broad, 1H), 1.94-1.78 (m, 2H), 1.40-1.31 (broad, 2H), 1.17-1.07 (broad, 1H), 1.06-0.96 (broad, 1H), 0.89 (d, J=12.5, 1H), 0.67 (d, J=6.4, 3H), 0.63-0.36 (m, 5H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1.S(=O)(=O)(O)[OH:16]>[OH-].[Na+]>[OH:13][C:9]1[CH:10]=[CH:11][C:12]2[C:3]([CH2:4][C:5]([OH:14])=[O:16])=[CH:2][O:6][C:7]=2[CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: O=c1cc(CCl)c2ccc(O)cc2o1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1coc2cc(O)ccc12
Yield: 83 %

Procedure:
4-(Chloromethyl)-7-hydroxy-2H-chromen-2-one (10.9 g, 51.8 mmol) was dissolved in 1 M aqueous sodium hydroxide solution (500 mL), and the mixture was heated under reflux for 2 hr. The reaction mixture was allowed to cool, acidified with concentrated sulfuric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (8.27 g, yield 83%) as brown crystals.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>[Cu]I>[I:1][C:2]1[CH:10]=[CH:9][C:8]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1I
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Product: C[Si](C)(C)C#Cc1ccc(I)c(C(=O)O)c1
Reaction time: 16 h
Yield: 73 %

Procedure:
1.12 g of 2,5-diiodobenzoic acid (3 mmol, 1 eq.), 210 mg of dichlorobis-triphenylphosphinepalladium(II) (0.3 mmol, 0.1 eq.) and 200 mg of copper(I) iodide (1 mmol, 0.34 eq.) are dissolved in 60 ml of a THF/TEA mixture (3/1). After the addition of 425 μl of trimethylsilylacetylene (3 mmol, 1 eq.), stirring is continued at room temperature for 16 hours in the dark. The reaction medium is then evaporated to dryness and the residue obtained is purified by flash chromatography on silica 60H (hexane/EtOAc/AcOH: 70/30/1%) to give 754 mg of 2-iodo-5-trimethylsilylethynylbenzoic acid in the form of fine yellow needles after drying under vacuum (yield: 73%).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)([O:3]C)=[O:2].[OH-].[K+].Cl>C(O)C.CS(C)=O.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([CH3:21])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=3[CH:12]=2)=[CH:25][CH:26]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1ccc(CNc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(NCc3ccc(C(=O)O)cc3)ccc21
Yield: 57.3 %

Procedure:
2 g of this ester and 2.5 g of potassium hydroxide in 45 ml of 5:1:3 ethanol/dimethyl sulfoxide/water were refluxed for 1 hour. At room temperature, 20 ml of 2N hydrochloric acid were added to the solution. The precipitate was filtered off, recrystallized from methanol and yielded 1.1 g of the title compound of melting point 225°-231° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:34]1([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47]OS(C)(=O)=O)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.CN1CCNCC1>>[CH:34]1([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CCCC3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 61.4 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 61.4%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:16]([NH:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:27]C(OC(C)(C)C)=O)[C:24](O)=[O:25])(=[O:18])[CH3:17]>>[C:16]([NH:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH2:27])[C:24]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:25])(=[O:18])[CH3:17]
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(=O)NCCC[C@H](N)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 56 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)aniline and (S)-5-acetamido-2-(tert-butoxycarbonylamino)pentanoic acid, gave (S)-5-acetamido-2-amino-N-(4-(4-fluorophenoxy)phenyl)pentanamide (200 mg, 56%).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].C(=O)([O-])O.[Na+].[NH2:21][C:22]([NH2:24])=[S:23].N.Cl>O>[OH2:6].[NH2:24][C:22]1[S:23][CH:2]=[C:3]([C:4](=[N:8][O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6])[N:21]=1
Reactant: NC(N)=S
Reactant: COC(=O)CON=C(C(=O)O)C(=O)CCl
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: O
Product: COC(=O)CON=C(C(=O)O)c1csc(N)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 193 %

Procedure:
4-chloro-2-(methoxycarbonylmethoxyimino)-3-oxobutyric acid (200 g) was added to water (400 ml), and suspended and stirred at 5° C. The crystal was dissolved by using sodium hydrogencarbonate (71.2 g). Thiourea (70.5 g) was added, and reaction was performed for 60 minutes at 30° C. while keeping the pH at 5.5 by using aqueous ammonia. After the pH was adjusted to 2 by using dilute hydrochloric acid, the mixture was cooled to 5° C. and stirred for 30 minutes. The precipitated crystal was filtered and collected, and washed with cold water, and then dried under reduced pressure to obtain 2-(2-aminothiazole-4-yl)-2-methoxycarbonylmethoxy iminoacetic acid monohydrate (syn-isomer) (225.2 g) (96.5% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](I)[CH:4]=[N:3]1.[Br:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.BrC1C=C(C2C=NC=CC=2)C=CC=1>>[Br:8][C:9]1[CH:14]=[C:13]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cn1cc(I)cn1
Reactant: OB(O)c1cccc(Br)c1
Agent: Brc1cccc(-c2cccnc2)c1
Product: Cn1cc(-c2cccc(Br)c2)cn1

Procedure:
The reaction of 1-methyl-4-iodopyrazole (Liljefors, S., and Gronowitz S. Chemica Scripta, 15, 102-9 (1980)) (1.3 g, 6.2 mmol) with 3-bromophenyl boronic acid (1.24 g, 6.2 mmol) using the procedure for the preparation of 3-(3'-bromophenyl)pyridine gave crude 4-(m-bromophenyl)-1-methylpyrazole which was chromatographed on a column of Bakers Silica Gel (60-200 mesh) packed and eluted with CH2Cl2. The less polar fractions contained undesired, incorrectly coupled products while the later more polar fractions contained the desired product (0.82 g, 56% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[CH3:8].S(Cl)([Cl:16])=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([Cl:16])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(CCC(=O)O)cc1C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(CCC(=O)Cl)cc1C

Procedure:
A 1 L three-neck round bottom flask equipped with a condenser, magnetic stir bar, thermometer, and a nitrogen inlet was charged with 3-(3,4-dimethylphenyl) propionic acid (64.0 g, 0.359 mol), dichloromethane (500 mL), and thionyl chloride (110 mL, 1.5 mol). The reaction mixture was stirred at reflux for 7 hours. Dichloromethane and excess thionyl chloride were removed by rotary evaporation under reduced pressure to yield 3-(3,4-dimethylphenyl)propionyl chloride as an amber oil (70.6 g, 100% conversion by GC).
Reaction SMILES: [Pt+2:1].Cl[C:3]1([NH2:11])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1(Cl)[NH2:9]>P(OC[C@H]1O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)([O-])([O-])=O.[Ag+].[Ag+].O>[Pt+2:1].[NH2:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[NH2:11]
Reactant: NC1(Cl)CCCCC1(N)Cl
Agent: [Ag+]
Agent: [Pt+2]
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)([O-])[O-])O2)c(=O)[nH]c1=O
Solvent: O
Product: N[C@@H]1CCCC[C@H]1N
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of dichloro(1,2-diaminocyclohexane) platinum(II) (760 mg) and 1.08 g of disilver thymidine monophosphate was suspended in 30 ml. of water. The reaction mixture was stirred in the dark at room temperature for 36 hours and then evaporated to dryness. The title product obtained (698 mg) was a white material that is water-soluble but alcohol-insoluble. When tested in the TLC systems indicated below, the following Rf values were obtained:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[OH-].[Na+].Cl[CH:14]([F:16])[F:15]>O1CCOCC1.O>[F:15][CH:14]([F:16])[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: FC(F)Cl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1OC(F)F
Temperature: 70 °C

Procedure:
A mixture of 2-nitrophenol (6.01 g, 43.2 mmol) and sodium hydroxide (8.6 g, 216 mmol) in 50 mL of dioxane and 50 mL of water was heated to 70° C. and chlorodifluoromethane gas was introduced. The mixture was diluted with water and extracted with diethyl ether. The organic phase was washed with aqueous sodium hydroxide and then brine, dried (MgSO4) and concentrated to give 1-difluoromethoxy-2-nitrobenzene (8.21 g, 43.4 mmol) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[OH:26].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([F:19])[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc(O)c(F)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(O)c(F)c4)cc3CC[C@@H]12
Yield: 50.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-fluoro-4-hydroxyphenylboronic acid (122 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 111 mg (50%) of the title compound as a white solid. mp>240° C. FDMS: m/e=339. α[D]589 =+11.21 (c=1.07, chloroform).
Reaction SMILES: C[C:2]1[C:3]([CH3:16])=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:17](O)(=O)C1C=CC=CC=1>CC1C=CC(C)=CC=1>[CH3:16][C:3]1[CH:2]=[CH:15][C:14]([CH3:17])=[CH:13][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: O=C(O)c1ccccc1
Reactant: Cc1cccc(C(=O)c2ccccc2)c1C
Solvent: Cc1ccc(C)cc1
Product: Cc1ccc(C)c(C(=O)c2ccccc2)c1

Procedure:
The dimethylbenzophenone fraction is contaminated with a small amount (0.05-0.1 lb/lb dimethylbenzophenones) of benzoic acid that co-distills with it. The benzoic acid is removed from the final product as described in Example 1. The washed dimethylbenzophenone product may or may not be given a final distillation in a 10 trays Oldershaw column to improve product color and purity as described in Example 1. Synthesis of dimethylbenzophenone from an isomeric mixture of xylenes will produce a mixture of six dimethylbenzophenone isomers. Synthesis from pure p-xylene will produce only 2,5-dimethylbenzophenone; pure m-xylene will produce 2,4-, 2,5-, and 2,6-dimethylbenzophenone; and pure o-xylene will produce 2,3- and 3,4-dibenzophenone. One can therefore tailor the specific isomeric mixture produced by a provident choice of the composition of the initial xylene mixture.
Reaction SMILES: [N:1]1([S:7]([C:10]2[NH:11][C:12](=[O:16])[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:17](Cl)([CH3:20])(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl>[N:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:11]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cccc(S(=O)(=O)N2CCOCC2)[nH]1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cccc(S(=O)(=O)N2CCOCC2)n1
Reaction time: 0.08 h

Procedure:
A solution of the pyridone prepared in stage (v) (0.27 g) in dichoromethane (30 cm3) under nitrogen was cooled to 0° C. and a solution of mesyl chloride in chloroform was added (0.12 g in 5 cm3). The reaction mixture was stirred for 5 minutes then treated with triethylamine (0.1 g) in dichloromethane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[CH:7][C:6]=1[O:14][CH3:15].N1C=CN=C1.[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[O:1]([CH2:2][CH2:3][O:4][C:5]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([I:13])=[CH:9][C:10]=1[O:11][CH3:12])[Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(I)cc(OC)c1OCCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(I)cc(OC)c1OCCO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of 4-(2-hydroxyethoxy)-1-iodo-3,5-dimethoxybenzene (2.76 g, 8.52 mmol) synthesized by the process shown in Reference Example 5 in dimethylformamide (25 mL) were added imidazole (1.16 g, 17.0 mmol) and t-butylchlorodimethylsilane (1.61 g, 10.7 mmol), and the mixture was stirred at 50° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate-hexane (1:1). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 4-[2-(t-butyldimethylsiloxy)-ethoxy]-1-iodo-3,5-dimethoxybenzene as a colorless oil (3.56 g, yield: 95%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:8]([N+:20]([O-])=O)[CH:7]=1.[NH4+].[Cl-]>[Fe]>[NH2:20][C:8]1[CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:2]=2[F:1])[CH:11]=[CH:10][C:9]=1[S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cc(OCc2cc(F)ccc2F)ccc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Nc1cc(OCc2cc(F)ccc2F)ccc1Sc1ccc(O)cc1
Yield: 86.1 %

Procedure:
The product from Example 234c (1.70 g, 4.2 mmol) was reacted with Fe and NH4Cl as described in Example 10E to give the title compound (1.3 g, 84%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5](=O)[CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(O)=O.[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:5]1[CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:1])[CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CC(=O)CC1C
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C
Temperature: 0 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A round-bottom flask was charged with ethyl 2-methyl-4-oxocyclopentanecarboxylate (10.0 g, 58.8 mmol) and DCE (180 mL). The solution was cooled to about 0° C. and AcOH (5.7 mL, 100 mmol) and dibenzylamine (11.3 mL, 58.8 mmol) were added drop-wise, resulting in formation of a thick suspension. The reaction mixture was warmed to about 10° C. and sodium triacetoxyborohydride (21.2 g, 100 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for about 20 h. The reaction mixture was slowly poured into stirred saturated aqueous NaHCO3 (300 mL) for about 20 min. The layers were separated and the aqueous phase was extracted with DCM (3×100 mL). The combined organic extracts were washed with brine (2×100 mL), dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. The crude yellow oil was purified via flash column chromatography eluting with a gradient of 0-30% EtOAc in heptane. The solvent was removed under reduced pressure to give ethyl 4-(dibenzylamino)-2-methylcyclopentanecarboxylate (15.5 g, 75%) as colorless oil: 1H NMR (pyridine-d5) δ 7.53 (dd, J=0.9, 7.9 Hz, 4H), 7.43-7.35 (m, 4H), 7.33-7.25 (m, 2H), 4.22-4.06 (m, 2H), 3.79 (d, J=14.2 Hz, 2H), 3.70 (d, J=14.2 Hz, 2H), 3.34-3.22 (m, 1H), 2.76 (dd, J=7.9, 16.6 Hz, 1H), 2.25-2.13 (m, 1H), 2.09-1.94 (m, 2H), 1.88-1.79 (m, 1H), 1.52 (dd, J=10.5, 22.5 Hz, 1H), 1.16 (t, J=7.1 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1.CC(O)C.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:13]([O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7])([CH3:18])[CH3:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)ON1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a suspension of N-hydroxyphthalimide (2.52 g, 15.45 mmol) in THF (60 ml) was added triphenylphosphine (4.10 g, 15.63 mmol), 2-propanol (1.2 ml, 15.67 mmol) and diethyl azodicarboxylate (2.68 ml, 17.0 mmol) and the reaction stirred overnight. The mixture was concentrated and purified by column chromatography on silica gel (Hexanes/EtOAc, 4:1) to afford 2-isopropoxy-isoindole-1,3-dione (2.59 g, 82%) as a white solid. 1H NMR (CDCl3) δ 1.38 (d, 6H, J=6 Hz), 4.52-4.58 (m, 1H), 7.73-7.76 (m, 2H), 7.83-7.85 (m, 2H).
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:23](Cl)(Cl)=[O:24].C1(C)C=CC=CC=1>ClCCl>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]=[C:23]=[O:24])[CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=C=O)CC1
Reaction time: 0.25 h

Procedure:
To a solution of trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamine (500 mg, 2.20 mmol) (from Example 20a supra) and triethylamine (1.52 mL, 10.90 mmol) (Aldrich) in dichloromethane (15 mL) was added a 20% phosgene in toluene solution (3.2 mL, 6.50 mmol) (Fluka) at 0° C. The resulting mixture was stirred for 15 minutes, then filtered and the filtrate was concentrated to a residue that was distilled at 110° C. under high vacuum using a Kugelrohr apparatus to give trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl isocyanate (485 mg) as a colorless liquid.