Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:29])=[C:7]([C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:8]([I:20])=[C:9]([C:18]=1[I:19])[C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])(=[O:3])[CH3:2].[OH-].[Na+].[OH:32][CH:33]([CH2:36][O:37][CH3:38])[CH2:34]Cl>C(O)C(O)C>[OH:28][CH:25]([CH2:26][OH:27])[CH2:24][NH:23][C:21](=[O:22])[C:7]1[C:6]([I:29])=[C:5]([N:4]([CH2:34][CH:33]([OH:32])[CH2:36][O:37][CH3:38])[C:1](=[O:3])[CH3:2])[C:18]([I:19])=[C:9]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[C:8]=1[I:20]
Reactant: COCC(O)CCl
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Product: COCC(O)CN(C(C)=O)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I

Procedure:
To a suspension of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, prepared as in British Patent No. 1548594, (800 g, 1.07 mol) in propylene glycol (2.4 1) was added 16.5M sodium hydroxide (97.3 ml, 1.61 mol) and then the suspension was stirred at about 70° until the starting material was dissolved. Thereafter the solution was cooled to about 35° and 2-hydroxy-3-methoxypropyl chloride (199.8 g, 1.61 mol) was added. After about 16 h the reaction mixture was heated at about 50° for an additional 8 h. The reaction was quenched by adding hydrochloric acid and then the mixture evaporated in vacuo to dryness. The residue was suspended in methanol (2.3 1 and undissolved salts filtered off. The solution was diluted with water (575 ml) and treated with sufficient amounts of AmberliteRIR-120 cation exchange resin and DowexR 1×4 anion exchange resin to remove inorganic salts. After filtration the solution was treated with charcoal and evaporated to dryness in vacuo. The residue was dissolved in 2 -propanol (3.2 1) by heating and then the solution evaporated to dryness in vacuo. The residue was dissolved in hot 2-propanol (3.2 1) and the solution cooled to -40° whereby the product crystallized. The product was collected on a filter. Yield: 718 g. The crystals (700 g) was dissolved in boiling 2-propanol (2,8 1) and refluxed for 2 days. After some hours crystals insoluble in hot 2-propanol started to crystallize. The mixture was filtered while hot. Yield: 490 g. The crystals were dissolved in water and the solution evaporated to dryness in vacuo.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C=O.FC1C=CC=C(Cl)C=1C=O.FC1C=CC=C(Cl)C=1CO.[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH:34]=[O:35]>>[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH2:34][OH:35]
Reactant: O=Cc1c(F)cccc1F
Agent: O=Cc1c(Cl)cccc1Cl
Agent: O=Cc1c(F)cccc1Cl
Agent: OCc1c(F)cccc1Cl
Product: OCc1c(F)cccc1F

Procedure:
Particularly preferably, 2,6-dichlorobenzaldehyde is used in the process of the invention and 2-fluoro-6-chlorobenzaldehyde, 2-fluoro-6-chlorobenzyl alcohol, 2,6-difluorobenzaldehyde or 2,6-difluorobenzyl alcohol is obtained or 2,4-dichlorobenzaldehyde is used and 2,4-difluoro-benzaldehyde or 2,4-difluorobenzyl alcohol is obtained or 3,4-dichloro-benzaldehyde is used and 3-chloro-4-fluorobenzaldehyde or 3-chloro-4-fluorobenzyl alcohol is obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C:26]([O:28]CC)=O)[C:9](=[O:24])[C@H:10]([NH:16]C(OC(C)(C)C)=O)[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:32](F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:25][C:26](=[O:28])[NH:16][C@H:10]([CH2:11][C:12]([O:14][CH2:15][CH3:32])=[O:13])[C:9]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(=O)[C@@H](CC(=O)OC)NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of Example 255C (50.75 g, 120 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid. The reaction was stirred overnight and then concentrated. Ammonia was added (7 N, methanol, 250 mL) and the solution was warmed to 70° C. for 2 hours. The reaction was concentrated and dichloromethane was added (500 mL). The solution stirred for 10 minutes before the salt was removed by filtration. The solution was then concentrated and purification via flash chromatography (3% 2 N NH3 in methanol/dichloromethane) afforded the title compound.
Reaction SMILES: [Mg].II.[CH2:4](Br)[C:5]#[CH:6].[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Br-].C1(=O)CCCCC1.[Cl-].[NH4+]>CCOCC>[CH2:6]([C:8]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:5]#[CH:4]
Reactant: C#CCBr
Reactant: O=C1CCCCC1
Agent: II
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C#CCC1(O)CCCCC1

Procedure:
A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1--1 of anhydrous ether is treated with 0.6 g of mercuric chloride and about 100 mg of iodine. After several minutes, 3 ml of propargyl bromide is added and if no exotherm is noted, a small amount of reacting propargyl bromide and magnesium in ether is added. When the reaction begins, a mixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargyl bromide is added dropwise at a rate that produces vigorous refluxing of the solution. (The propargyl bromide must always be present in some excess otherwise the reaction will stop. If this happens, the addition of about 1 ml of propargyl bromide will restart the reaction.) After about half of the propargy bromide-cyclohexanone mixture has been added, another 500-750 ml of ether is used to dilute the reaction mixture. At the end of the addition, the reaction mixture is refluxed for at least 0.5 hour, cooled and poured into 4 liters of saturated ammonium chloride during good stirring. The ethereal layer is separated and the aqueous layer is washed with ether several times and the combined extract is washed twice with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether yields 583 g (630 g theory) of a dark oil which is distilled giving purified 1-propargyl-1-hydroxycyclohexane.
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH:3]([CH3:6])[CH2:4][CH3:5].[CH3:14][N:15](C=O)C>O.[C-]#N.[Zn+2].[C-]#N>[OH:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:14]#[N:15])=[CH:9][CH:8]=1)[CH:3]([CH3:6])[CH2:4][CH3:5]
Reactant: CCC(C)C(O)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCC(C)C(O)c1ccc(C#N)cc1
Temperature: 90 °C
Yield: 75 %

Procedure:
Add 4-(1-hydroxy-2-methyl-butyl)-1-bromo-benzene (1.9 g, 7.8 mmol), zinc cyanide (1.82 g, 15.6 mmol), and tetrakistriphenylphosphine palladium(0) (260 mg, 0.22 mmol) to anhydrous DMF (40 mL) under a nitrogen atmosphere. Heat the mixture at 90° C. for 12 h. Cool the mixture to room temperature, dilute with water and extract the aqueous phase twice with dichloromethane. Wash the combined organic extracts with water and brine. Dry the organic solution over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 20:1) to provide the desired intermediate (1.2 g, 75%). MS (APCI) m/z: 190 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[S:24][CH:25]=1.COC1C=C(C=C(OC)C=1)C(N)=S.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=3)[S:24][CH:25]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: COc1cc(OC)cc(-c2nc(CCl)cs2)c1
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: COc1cc(OC)cc(C(N)=S)c1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3cc(OC)cc(OC)c3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 14 b], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-thiazole (prepared from 3,5-dimethoxy-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in the presence of cesium carbonate and potassium iodide to yield [rac]-3-{4-[2-(3,5-dimethoxy-phenyl)-thiazol-4-ylmethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-3-{4-[2-(3,5-dimethoxy-phenyl)-thiazol-4-ylmethoxy]-3-fluoro-phenyl}-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH3:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:15])=[N:7]2.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH3:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:7]2
Reactant: O=Cc1ccccc1
Reactant: COc1c(Br)cc(Br)c2ccc(C)nc12
Solvent: CO
Product: COc1c(Br)cc(Br)c2ccc(C=Cc3ccccc3)nc12
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A mixture of 5,7-dibromo-2-methyl-8-methoxyquinoline (10.29 g) and benzaldehyde (15.84 g) is heated at reflux for 18 hrs. Upon cooling to room temperature, a precipitate forms. Methanol is added, and the reaction mixture is sonicated. The solid material is then collected by filtration. Crystallization from hot absolute ethanol yields 10.872 g of the title compound as a yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].[H-].[Na+].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:8][C:7]=1[F:14]
Reactant: Fc1ccccn1
Reactant: OCc1ccc(C2OCCO2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(COc2ccccn2)ccc1C1OCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To an N,N-dimethylformamide solution (20 mL) of (4-[1,3]dioxolan-2-yl-3-fluoro-phenyl)-methanol (2.44 g, 12.3 mmol) described in Manufacturing Example 204-1-3 was added sodium hydride (537 mg, 14.8 mmol, 60% in oil), which was cooled to 0° C., after which 2-fluoropyridine (1.27 mL, 14.8 mmol) was added to this suspension, which was stirred for 2 hours at 60° C. The mixture was cooled to room temperature and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (2.17 g, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C.Cl>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:13]=[CH:12]/[C:11]([OH:15])=[O:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(I)ccc1Br
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(/C=C/C(=O)O)ccc1Br
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-4-iodo-2-methoxybenzene (L. A. Hasvold et al, US 2004/0254159, EXAMPLE 57B) (33.45 g, 107 mmol) in MeCN (100 mL) was added acrylic acid (9.61 g, 133 mmol), triethylamine (37.2 mL, 267 mmol) and palladium acetate (719 mg, 3.2 mmol). The reaction mixture was heated to 90° C. for 40 min, cooled to RT and poured into 2.4 L 1M HCl. After stirring for 30 min, the solid was filtered, heated to reflux in EtOH (230 mL), allowed to cool to RT and stirred overnight. The solid was filtered and washed with 1:1 EtOH hexane (50 mL) to give desired product. LRMS ESI+ (M+H)+ 257.0.
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:34]([Cl:35])=[CH:33][C:10]3[N:11](COCC[Si](C)(C)C)[C:12]([O:14][CH:15]4[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=[O:21])[CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:34]([Cl:35])=[CH:33][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16]4)=[N:13][C:9]=3[CH:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)C1CCC(Oc2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)C1
Temperature: 80 °C

Procedure:
To a solution of ethyl 3-{[5-(biphenyl-4-yl)-6-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl]oxy}cyclopentanecarboxylate (80 mg, 0.135 mmol) in 2.7 mL of THF was added TBAF (0.700 mL, 0.700 mmol) dropwise via syringe. The reaction was heated at 80° C. for 1.5 h. After heating for 4 h, the reaction was concentrated and the residue was re-dissolved in 4 mL of MeOH and treated with 1 mL of 2.5 N NaOH. The reaction was maintained at ambient temperature overnight. Then the solvent was removed and the resulting residue was dissolved in H2O and acidified to pH 1 with 2 N HCl. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with 2 N HCl, H2O, and brine. The combined organic layers were then dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by reverse phase Gilson™ HPLC (30-100% MeCN/H2O) afforded a 1:1 cis/trans mixture of the title compound as a white solid. LCMS: calculated for C25H21ClN2O3 432.89, observed m/e 432.93 M+ (Rt 2.13/4 min). 1H NMR (500 MHz, CD3OD): δ7.7.72-7.63 (m, 8H), 7.58-7.55 (m, 2H), 7.49 (d, 4H), 7.47-7.42 (m, 4H), 7.42-7.38 (m, 2H), 7.37-7.32 (m, 2H), 5.54-5.47 (m, 1H), 5.46-5.40 (m, 1H), 3.16-3.05 (m, 1H), 3.05-2.95 (m, 1H), 2.54-2.43 (m, 1H), 2.42-2.31 (m, 3H), 2.31-1.95 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CN(C1C=CC=CN=1)C.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:29][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:19]([F:18])([F:30])[F:31])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCCCCC(O)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.23 g) in methylene chloride (10 ml) was added by little and little under ice-cooling a solution of optically active 1,1,1-trifluoro-2-decanol (0.96 g), dimethylaminopyridine (0.55 g) and triethylamine (0.48 g) in methylene chloride (20 ml). The mixture was left to stand overnight at room temperature in order to effect a reaction before the mixture obtained was poured in ice-water. Extraction was effected with methylene chloride and the extracted phase was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water in due order before it was dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain a crude product which was purified by toluene/silica from ethanol to obtain the titled compound (1.84 g).
Reaction SMILES: [CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:8]=3[S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33]C)=[O:32])=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1>>[CH:1]1([N:6]2[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][C:14]([O:16][CH2:18][C:19]4[CH:20]=[C:21]([C:25]5[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=5)[CH:22]=[CH:23][CH:24]=4)=[CH:15][C:8]=3[S:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=c1c2ccc(O)cc2sn1C1CCCC1
Reactant: COC(=O)c1ccc(-c2cccc(CBr)c2)cc1
Product: O=C(O)c1ccc(-c2cccc(COc3ccc4c(=O)n(C5CCCC5)sc4c3)c2)cc1
Yield: 35 %

Procedure:
2-Cyclopentyl-6-hydroxybenzo[d]isothiazol-3(2H)-one (0.094 g, 0.4 mmol) and methyl 3′-(bromomethyl)biphenyl-4-carboxylate (0.146 g, 0.48 mmol) were processed according to the general procedure described for Example 19 to afford 3′-((2-cyclopentyl-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yloxy)methyl)biphenyl-4-carboxylic acid as a colorless solid in 35% yield over 2 steps (0.053 g, after HPLC purification). 1H NMR (400 MHz, DMSO-d6): δ 7.99 (d, 2H, J=8.6 Hz), 7.83-7.79 (m, 5H), 7.70-7.69 (m, 1H), 7.51-7.42 (m, 2H), 7.45 (d, 1H, J=8.5 Hz), 5.34 (s, 2H), 4.49-4.47 (m, 1H), 1.86-1.76 (m, 2H), 1.75-1.57 (m, 6H). HRMS (ESI) calcd for C26H23NO4S [M+H]+: 446.1420. Found: 446.1420.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:15]1[C:14]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17]
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1ccc2c(c1)OC(CCO[Si](C)(C)C(C)(C)C)C(=O)N2
Product: Cc1ccc2c(c1)OC(CCO)C(=O)N2Cc1cccc(Cl)c1
Yield: 76 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-7-methyl-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-chlorobenzyl bromide, in 76% yield as a white solid after crystallization from ether/hexane, mp 72°-74° C.; IR (KBr) 3418, 1679, 1512, 1402, 1292, 1061, 763 cm-1 ; 1H NMR (CDCl3) δ2.20-2.36 (m, 3H), 2.27 (s, 3H), 3.92 (q, J=5.6 Hz, 2H), 4.83 (dd, J=7.6, 5.5 Hz, 1H), 5.10 (ABq, JAB =17.0 Hz, 2H), 6.68-6.75 (m, 2H), 6.84 (s, 1H), 7.10-7.14 (m, 1H), 7.22-7.29 (m, 3H); MH+ at m/z=332; Anal. Calc'd for C18 H18ClNO3.0.2H2O: C, 64.46; H, 5.53; N, 4.18. Found: C, 64.48; H, 5.51; N, 4.06.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:19])[N:3]=1.[CH3:20][C:21]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:22]=1[NH2:23]>C(O)CO>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:7]2[C:2]([NH:23][C:22]3[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:21]=3[CH3:20])=[N:3][C:4]([CH3:19])=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)nc2Cl)cc1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: OCCO
Product: COc1ccc(S(=O)(=O)c2ccc(C)nc2Nc2c(C)cc(C)cc2C)cc1
Yield: 65.5 %

Procedure:
2-chloro-3-(4-methoxybenzenesulfonyl)-6-methylpyridine (1.6 g, 5.39 mmol) and 2,4,6-trimethylaniline (4.4 g, 32.8 mmol) were heated at reflux in ethylene glycol (5.5 mL) for 20 h. After cooling, the reaction was partitioned between EtOAc (100 mL) and 0.5 N NaOH (20 mL) and the aqueous layer was extracted with EtOAc (100 mL) and the combined organic extracts were washed with water, brine, dried and stripped in vacuo. The residue was chromatographed on silica gel using 20% EtOAc/hexanes as eluent to give [3-(4-methoxybenzenesulfonyl)-6-methyl-pyridin-2-yl]-(2,4,6-trimethylphenyl)-amine as a solid (1.4 g), mp 165–167° C. mass spec. (AP+): m/z 397 (M+1).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:40]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:41])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)C4CCCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.62 g, 4.08 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.60 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, cyclohexanecarbonyl chloride (0.33 g, 2.22 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCL (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 6:4) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}cyclohexylcarboxamide (0.53 g; 72%) as a white solid: mp 142-144° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.36 (t, J=5.8 Hz, 1H), 7.86-7.77 (m, 2H), 7.64-7.61 (m, 1H), 5.18-5.11 (dd, J=5.3 and 12.5 Hz, 1H), 4.70 (d, J=5.8 Hz, 2H), 2.97-2.83 (m, 1H), 2.63-2.47 (m, 2H), 2.26-2.17 (m, 1H), 2.08-2.03 (m, 1H), 1.79-1.61 (m, 5H), 1.43-1.12 (m, 5H); 13C NMR (DMSO-d6) δ 175.58, 172.75, 169.82, 167.49, 166.96, 139.68, 134.75, 132.76, 131.49, 126.99, 121.73, 48.83, 43.90, 37.43, 30.92, 29.20, 25.43, 25.24, 21.96; Anal. Calcd. For C21H23N3O5: C, 63.47; H, 5.83; N, 10.57. Found: C, 63.12; H, 5.68; N, 10.41.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][C:8]([OH:10])=O)[C:3](=[O:5])[CH3:4].[CH:11]1([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:27]4[CH2:32][NH:31][CH2:30][C:28]=4[N:29]=3)=[CH:20][CH:19]=2)=[O:16])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:15](=[O:16])[NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:25]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[C:27]4[CH2:32][N:31]([C:8](=[O:10])[CH2:7][CH2:6][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[CH2:30][C:28]=4[N:29]=3)=[CH:22][CH:23]=2)[CH2:13][CH2:12]1
Reactant: CC(=O)N(C)CCC(=O)O
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CNC2
Product: CC(=O)N(C)CCC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 26 %

Procedure:
Method as example 127 using 3-(N-methylacetamido)propanoic acid and (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 3) as starting materials to yield a white solid (36.8 mg, 0.071 mmol, 26%).
Reaction SMILES: Br[CH:2]=[C:3]1[O:7][C:6](=[O:8])[CH:5]=[CH:4]1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.[F-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[C:15]([CH:14]=[CH:13][CH:12]=1)/[CH:2]=[C:3]1/[CH:4]=[CH:5][C:6](=[O:8])[O:7]/1
Reactant: O=C1C=CC(=CBr)O1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C/C(=C/c2cccc(C(F)(F)F)c2)O1

Procedure:
A mixture containing 5-bromomethylene-2(5H)furanone (0.175 g, 1 mmol), 3-trifluoromethylphenylboronic acid (0.228 g, 1.2 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.035 g, 0.05 mmol), tetrabutylammonium iodide (0.018 g, 0.05 mmol) and cesium fluoride (0.456 g, 3 mmol) in toluene (10 mL) and water (10 mL) were stirred at reflux for 24 hours under nitrogen. After cooling, brine (50 mL) was added and the product extracted with ethyl acetate (50 mL×3). The organic fractions were combined, washed with brine (50 mL×3), dried over anhydrous sodium sulfate and evaporated to dryness to give a brown solid. The resulting solid was chromatographed (silica gel: eluent 50:50 dichloromethane/light petroleum) giving the desired product 30 as a light brown powder. Yield 0.180 g (75%), m.p. 69-71° C., UV-Vis λmax (MeOH) 223 (15166), 323 (31738) nm.