Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1)[C:12]#[N:13].C(N(CC)CC)C.[CH3:45][O:46][CH2:47][C:48](Cl)=[O:49]>C(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][N:31]([C:48](=[O:49])[CH2:47][O:46][CH3:45])[CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]1)[C:12]#[N:13].[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: COCC(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC(=O)N1CCc2nc(NC(C)C)c(N3CCC(Oc4ccc(C#N)cc4F)CC3)nc2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-fluoro-4-((1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)benzonitrile 2,2,2-trifluoroacetate (98.6 mg, 0.094 mmol) and triethylamine (0.039 mL, 0.283 mmol) in DCM (1.0 mL) was added methoxyacetyl chloride (0.017 mL, 0.188 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min and then concentrated via rotary evaporation. The crude material was diluted with DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B, with the exception that a Waters XSelect® CSH C18, 5 μm, ID 4.6×50 mm was used, using an ACN gradient of 30% to 70% to give the title compound as a TFA salt (2.9 mg, 5.2%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.18 (d, J=6.6 Hz, 6H), 1.87-1.97 (m, 2H), 2.08-2.16 (m, 2H), 2.62 (t, J=5.8 Hz, 0.9H), 2.72 (t, J=6.1 Hz, 1.1H), 2.89-2.97 (m, 2H), 3.22-3.28 (m, 1H), 3.29 (br s, 1.3H), 3.30 (s, 1.7H), 3.64-3.67 (m, 1.1H), 3.72-3.75 (m, 0.9H), 4.10-4.16 (m, 1H), 4.17 (br s, 0.9H), 4.19 (s, 1.1H), 4.36 (br s, 0.9H), 4.41 (s, 1.1H), 4.80-4.86 (m, 1H), 5.58-5.63 (m, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.66-7.70 (m, 1H), 7.87 (dd, J=11.2, 1.9 Hz, 1H); ESI-MS m/z [M+H]+ 483.5.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:8][CH2:7][CH:6]([OH:9])[CH2:5][O:4]1.[H-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl>>[Cl:1][CH2:2][CH:3]1[O:8][CH2:7][CH:6]([O:9][CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[F:12])[CH2:5][O:4]1
Reactant: OC1COC(CCl)OC1
Reactant: Fc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Product: Fc1ccccc1COC1COC(CCl)OC1

Procedure:
By the method of Example 43, 2-chloromethyl-5-hydroxy-1,3-dioxane was reacted with sodium hydride and o-fluorobenzyl chloride to yield 2-chloromethyl-5-(2-fluorobenzyloxy)-1,3-dioxane. This mixture of isomers was distilled using a short path distillation apparatus at 0.1 mm to obtain three fractions. Fraction 1, b.p. 95°-100°/0.1 mm was found by VPC analysis to be 3.8% cis-2-chloromethyl-5-(2-fluorobenzyloxy)-1,3-dioxane (the remainder in each case being the trans isomer). Fraction 2, b.p. 98°-102°/0.1 mm was 13.8% cis isomer. Fraction 3, b.p. 165°-170°/0.1 mm was 99% cis and solidified on standing; the solid was sublimed to a solid, m.p. 60°-62°, which was found by nmr analysis to 94% cis isomer and 6% trans isomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:23]/[OH:24])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][Si:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:34][Si:35]([NH:38][C:39]([O:24]/[N:23]=[C:19]1/[CH2:20][CH2:21][CH2:22][C:15]2[C:14]([S:11]([N:10]([CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:26])[CH3:25])(=[O:13])=[O:12])=[CH:18][S:17][C:16]/1=2)=[O:40])([CH3:37])[CH3:36]
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Reactant: C[Si](C)(C)N=C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/OC(=O)N[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound (1.0 g) of Example 1 in toluene (10 mL) was added triethylamine (1.75 mL) and trimethylsilyl isocyanate. After stirring at room temperature for 2 hours, the solution was dilutied with ethyl acetate, and the resulting insoluble matter was extracted, the crude product that were obtained by removing the solvent by evaporation was purified by NH-silica gel column chromatography (ethyl acetate/hexane), and a pale yellow oily substance (1.0 g) was obtained.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C1C=CC=CN=1)C.O.C(OCC)(=O)C>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([NH:29][C:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:5]=[CH:6][CH:7]=[CH:8]3)=[O:17])[CH:30]=[CH:31][CH:32]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: Nc1cccc(OCc2ccccc2)c1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(OCc2ccccc2)c1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
Thionyl chloride (2 mL) was added to 6-quinolinecarboxylic acid (100 mg, 0.577 mmol), and the solution was stirred for 2 hours under reflux. Then, the solution was allowed to cool to room temperature, and excess thionyl chloride was evaporated in vacuo. The obtained residue was dissolved in N,N-dimethylformamide (2 mL), 3-benzyloxyaniline (115 mg, 0.577 mmol), triethylamine (0.12 mL, 0.866 mmol) and dimethylaminopyridine (1 mg) were added, and the solution was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (53 mg, 26%) was obtained as a white solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14]([O:23]CC)(=[O:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:14]([CH2:15][C:16](=[CH:1][C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])([OH:23])=[O:22]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1cc(OC)c(O)c(OC)c1)CC(=O)O
Temperature: 0 °C
Yield: 48 %

Procedure:
A 3.6 g of syringaldehyde and 5 ml of diethyl succinate were dissolved in 60 ml of tetrahydrofuran. To the solution was added 4.9 g of potassium t-butoxide, and the mixture was heated under reflux for 24 hours. The mixture was poured into ice water. The aqueous solution was acidified with 6N hydrochloric acid and extracted with 100 ml of ethyl acetate. An organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give 3 g (yield 48%) of ethyl α-carboxymethyl-3,5-dimethoxy-4-hydroxycinnamate. The product was dissolved in 20 ml of N,N-dimethylformamide. To the solution was added 2.1 g of N,N'-dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added methanol to filter off an insoluble material, which was washed with methanol and dried to give 2 g (yield 80%) of the corresponding acid anhydride compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:23][OH:24])[CH:16]=[CH:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][CH2:29]Cl.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:23][O:24][CH2:27][O:28][CH3:29])[CH:16]=[CH:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc3cccc(CO)c32)CC1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCOCc1cccc2ccn(C3CCN(C(=O)OC(C)(C)C)CC3)c12
Reaction time: 0.67 h
Yield: 80.8 %

Procedure:
Dissolve 4-(7-hydroxymethylindol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.76 mmol) in 5 mL of tetrahydrofuran and add sodium hydride (36 mg, 1.5 mmol) at room temperature. After 40 minutes, add methoxymethyl chloride (0.11 mL, 1.5 mmol) and stir the mixture for 4 hours. Concentrate the reaction and subject it to flash chromatography using 5:1 hexanes:ethyl acetate to give 0.23 g product. FAB MS 374.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].Cl>CCOC(C)=O.C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=2)[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:10]=1
Reactant: CCCCc1ccc(CBr)cc1
Reactant: COC(=O)Cc1ccc(CCNS(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCc1ccc(CN(CCc2ccc(CC(=O)OC)cc2)S(C)(=O)=O)cc1

Procedure:
A mixture of [4-[2-methanesulfonylamino-ethyl]-phenyl]-acetic Acid methyl ester (38 mg, 0.14 mmol), 1-bromomethyl-4-butylbenzene (35 mg, 0.15 mmol), K2CO3 (25 mg, 0.182 mmol) and acetonitrile was heated at reflux for 1 h. Aqueous HCl (2 mL, 1N) and EtOAc (30 mL) were added to the reaction. The organic solution was dried with MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.28-7.05 (m, 8H), 4.37 (s, 2H), 3.65 (s, 3H), 3.58 (s, 2H), 3.26 (t, 2H), 2.77 (t, 2H), 2.69 (s, 3H), 2.60 (t, 2H), 1.59 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([OH:21])(=O)[C:17]#[C:18][CH3:19].[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=1>O1CCCC1>[F:44][C:42]([F:43])([F:45])[C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:16](=[O:21])[C:17]#[C:18][CH3:19])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][CH:39]=1
Reactant: CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(C(F)(F)F)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
Isobutyl chloroformate (1.56 g, 11.4 mmol) and N-methylmorpholine (1.15 g, 11.4 mmol) were added to an ice cold solution of 0.961 g (11.4 mmol) of 2-butynoic acid in 40 mL of tetrahydrofuran under N2. After stirring for 10 min, a solution of 1.50 g (4.57 mmol) of 6-amino-4-[(3-trifluoromethylphenyl)amino]-3-quinolinecarbonitrile in 12 mL of tetrahydrofuran was added dropwise. After stirring at 25° C. overnight, volatile material was removed and the residue was slurried in water and filtered. The crude product was washed 3 times with small portions of hot ethyl acetate and then dried in vacuo (45° C.) to give 0.831 g of yellow solid: mass spectrum (electrospray, m/e): M+H 395.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[NH:8][C:9](=[O:11])[O:10][C@H:6]2[CH2:5][C@H:4]([CH2:12][OH:13])[C@H:3]1[OH:14].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.O>[Si:24]([O:13][CH2:12][C@@H:4]1[C@@H:3]([OH:14])[C@H:2]([OH:1])[C@H:7]2[NH:8][C:9](=[O:11])[O:10][C@H:6]2[CH2:5]1)([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: O=C1N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)C[C@@H]2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](O)[C@@H]1O
Reaction time: 2.5 h
Yield: 73.6 %

Procedure:
To a solution of (3aR,4R,5R,6R,7aS)-4,5-dihydroxy-6-(hydroxymethyl)hexahydrobenzo[d]oxazol-2(3H)-one (2.23 g, 11.0 mmol) in DMF (15 mL) at room temperature was added imidazole (2.24 g, 33.0 mmol) followed by TBDMSCl (1.98 g, 13.2 mmol). The mixture was stirred at this temperature for 2.5 h. The mixture was diluted with water (150 mL) and extracted with EtOAc (5×50 mL). The extracts were dried with MgSO4 and the solvents were evaporated. The crude product was purified by silica gel column chromatography, eluted with 5% MeOH in DCM to give the product (3aR,4R,5R,6R,7aS)-6-(((tert-butyldimethylsilyl)oxy)methyl)-4,5-dihydroxyhexahydrobenzo[d]oxazol-2(3H)-one (2.57 g, 74%) as a white solid. 1H NMR (400 MHz, MeOD) δ 4.68-4.71 (m, 1H), 3.85 (dd, J=8.0 Hz, 3.2 Hz, 1H), 3.63 (dd, J=8.0 Hz, 5.2 Hz, 1H), 3.47-3.55 (m, 2H), 3.37 (t, J=7.8 Hz, 1H), 2.14 (dt, J=12.5 Hz, 2.3 Hz, 1H), 1.86-1.94 (m, 1H), 1.52-1.58 (m, 1H), 0.89 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:5][NH:6][C:7]1[C:8]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15][C:9]=2[N:10]=[C:11]([CH2:13]Cl)[N:12]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].CCOCC.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CN(C=O)C.O.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:5][NH:6][C:7]1[C:8]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15][C:9]=2[N:10]=[C:11]([CH2:13][NH:27][CH2:28][CH2:29][CH2:30][OH:31])[N:12]=1
Reactant: COc1ccc(CNc2nc(CCl)nc3sc4c(c23)CCCC4)cc1Cl
Reactant: NCCCO
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(CNCCCO)nc3sc4c(c23)CCCC4)cc1Cl

Procedure:
A solution of 2 g of 4-(3-chloro-4-methoxybenzylamino)-2-chloromethyl-5,6,7,8 tetrahydrobenzothieno[2,3-d]pyrimidine in 10 ml of DMF is treated with 5 ml of 3-aminopropanol and heated at 80° for one hour. It is then diluted with water and extracted with ethyl acetate. The crystalline product obtained after customary work-up is dissolved in alcoholic HCl and treated with ether until turbidity. 2.1 g of 4-(3-chloro-4-methoxybenzylamino)-2-(3-hydroxypropylaminomethyl)-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine are obtained in the form of its dihydrochloride.
Reaction SMILES: CCCCC.C(NC(C1C=C2C=C(C([C:26]3[CH:31]=[CH:30][C:29](S(C)(=O)=O)=[CH:28][CH:27]=3)CC(C)C)NC2=NC=1)=O)(C)C.C([Li])(C)(C)C.[Cl:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH:45]=[O:46]>C(OCC)C>[CH:28]1([CH2:27][C:45]([C:44]2[CH:47]=[CH:48][C:49]([Cl:50])=[C:42]([Cl:41])[CH:43]=2)=[O:46])[CH2:29][CH2:30][CH2:31][CH2:26]1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)CC(c1ccc(S(C)(=O)=O)cc1)c1cc2cc(C(=O)NC(C)C)cnc2[nH]1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: O=C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
A solution of pentane (50 mL), diethyl ether (50 mL) and iodomethylcyclopentane (prepared as in PCT WO2004/052869 A1 Example 1, 3.9 g, 18.6 mmol) was cooled to −78° C. and a solution of t-butyl lithium in pentane (1.7 M, 18.5 mL, 31.5 mmol) was added dropwise. The mixture was then stirred at −78° C. for 30 min and then warmed to room temperature and stirred for 30 min and finally recooled to −78° C. To this mixture was then added a solution of 3,4-dichlorobenzaldehyde (5.0 g, 28.6 mmol) in diethyl ether (20 mL) dropwise. The mixture was then stirred at −78° C. for 1 h and then warmed up to room temperature and stirred overnight. The mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (50 mL). The organic layer was then separated and washed with a saturated brine solution (50 mL), dried over magnesium sulfate, filtered and the filterate concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 10% ethyl acetate/hexanes) afforded 2-cyclopentyl-1-(3,4-dichloro-phenyl)-ethanone (2.36 g, 50%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12](CC4C=CC=CC=4F)[CH2:11]3)[C:9](=[O:24])[N:8]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:5]2=[CH:6][CH:7]=1.Br[CH2:34][C:35]1[C:36]([CH3:46])=[N:37][O:38][C:39]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12]([CH2:34][C:35]4[C:36]([CH3:46])=[N:37][O:38][C:39]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:11]3)[C:9](=[O:24])[N:8]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CC(=O)N(Cc3ccccc3F)C2)c2cc(Cl)ccc21
Reactant: Cc1noc(-c2ccccc2)c1CBr
Product: Cc1noc(-c2ccccc2)c1CN1CC2(CC1=O)C(=O)N(CC(=O)OC(C)(C)C)c1ccc(Cl)cc12
Yield: 53 %

Procedure:
Following the general method as outlined for Intermediate 33, starting from tert-butyl (5-chloro-2,5′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetate (intermediate 32) and 4-(bromomethyl)-3-methyl-5-phenylisoxazole, the title compound was isolated, after purification by chromatography (silica) eluting with cyclohexane containing increasing amounts of ethyl acetate (10 to 50%), as a white solid in 53% yield (HPLC purity 89%). MS (ESI+): 522.4; MS (ESI−):520.1
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:18][CH2:19][OH:20])([CH2:15][CH2:16][CH3:17])[O:12][CH2:13][CH2:14][C:7]2=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:18][CH:19]=[O:20])([CH2:15][CH2:16][CH3:17])[O:12][CH2:13][CH2:14][C:7]2=1
Reactant: CCCC1(CCO)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCC1(CC=O)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
The mixture of [8-fluoro-1-(2-hydroxy-ethyl)-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-5-yl]-morpholin-4-yl-methanone (100 mg, 0.256 mmol) and o-iodoxybenzoic acid (IBX, 430 mg, 1.54 mmol) in DMSO (3.5 mL) was stirred overnight at room temperature. The solution was diluted with H2O (7 mL) and the precipitates were filtered and the filter cake was rinsed with EtOAc. The filtrate was extracted with EtOAc (3×10 mL) and the combined organic solution was washed with brine (20 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 60% EtOAc in hexanes) to give 89 mg (90%) of the title compound as a pale yellow solid. 1H NMR (CDCl3): 300 MHz δ 9.75 (bs, 1H), 9.05 (bs, 1H), 6.89 (m, 2H), 4.00–2.64 (m, 14H), 1.89 (m, 1H), 1.63 (s, 1H), 1.26 (m, 2H), 0.88 (t, J=5.49 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:7]=[C:6]([OH:29])[CH:5]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:5]=[C:6]([O:29][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH3:32])[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[CH:9]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Yield: 92.5 %

Procedure:
A mixture of 1.0 g (2.45 mmol) of 3-hydroxy-5-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester, 0.73 ml (2.69 mmol) of 1-bromotetradecane and 0.7 g (4.9 mmol) of potassium carbonate in 20 ml of anhydrous DMF was stirred and heated at 80° for 22 hours. The usual workup followed by chromatography on 30 g of silica gel using 10% ethyl acetate-hexane, trituration of the combined pure fractions with methanol and filtration gave 1.37 g (93% yield, mp 69°-70°) of 3-[3-[4-(phenylmethoxy)phenoxy]propoxy]-5-(tetradecyloxy)benzoic acid methyl ester.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[F:18])[CH:6]=[C:7]([F:9])[CH:8]=1.S(=O)(=O)(O)O.CC(O)=O.C1C(=O)N([I:36])C(=O)C1>C(Cl)Cl>[F:19][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([I:36])=[CH:12][C:11]=2[F:18])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: COc1ccc(F)c(-c2cc(F)cc(C(F)F)c2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(-c2cc(F)cc(C(F)F)c2)c(F)cc1I
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a 250-mL RBF was added 3′-(difluoromethyl)-2,5′-difluoro-5-methoxy-1,1′-biphenyl (642 mg, 2.376 mmol) and sulfuric acid (69.7 μl, 1.307 mmol). DCM (3960 μl) and AcOH (3960 μl) were added to give a colorless clear solution. To this solution was added n-iodosuccinimide (238 μl, 2.376 mmol) as a solid in a single portion to give a maroon-colored solution. After 3 h at rt, the mixture was diluted with DCM (30 mL), washed with water (10 mL), washed with saturated aq. sodium thiosulfate (10 mL, DCM was upper layer for separation), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g silica gel column, 0-5% EtOAc/Heptane) to provide 3′-(difluoromethyl)-2,5′-difluoro-4-iodo-5-methoxy-1,1′-biphenyl (771 mg, 1.946 mmol, 82% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.87 (m, 1H), 7.67-7.73 (m, 1H), 7.63-7.67 (m, 1H), 7.48-7.57 (m, 1H), 7.08-7.18 (m, 2H), 3.91 (d, J=2.54 Hz, 3H)
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].OC1C2N=N[NH:23]C=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.N.CC(O)C.C([O-])(O)=O.[Na+]>ClCCl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:23])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(C(N)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-tert-butyl-3-nitrobenzoic acid (0.1 mole), hydroxybenzotriazole (HOBt, 0.12 mole) and dicyclohexylcarbodiimide (DCC, 0.11 mole) in dichloromethane (100 mL) is stirred at room temperature while a solution of ammonia in 2-propanol (2.OM, 75 mL, 0.12 mole) is added rapidly. The mixture is stirred for two hours at room temperature, and poured into aqueous NaHCO3 (5%, 200 mL). The layers are separated, and the aqueous phase is extracted with dichloromethane (2×200 mL). The combined organics are washed (2×200 mL 5% aq. NaHCO3), dried (sat'd aq. NaCl, Na2SO4), filtered and concentrated. The product is recrystallized from EtOH-water to afford pure 4-tert-butyl-3-nitrobenzamide.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:11]1(Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1](=[O:10])[CH2:2]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrC1CCCCC1
Reactant: O=C1CCc2ccccc21
Product: O=C1CC(C2CCCCC2)c2ccccc21

Procedure:
This compound was prepared according to the method described by B. M. Trost and L. H. Latimer in J. Org. Chem. 42 (1977) 3212. The starting compounds were 1-indanone and cyclohexyl bromide.