Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].C([OH:24])C>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([OH:24])(=[O:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Reactant: CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phytanol (19.5 g) was dissolved in acetic acid (250 ml) and cooled in an ice bath. Chromium trioxide (21.0 g) dissolved in a minimum amount of water was added to the above solution and stirred at room temperature for 18 hours. Ethanol (50 ml) was slowly added to the reaction mixture and stirred for a further 3 hours. Most of solvent was removed and water (250 ml) was added. This solution was extracted with ether (2×200 ml) and the combined ether extract was dried (MgSO4), decolourized with activated charcoal and filtered through a thin flash silica bed. The solvent was removed and the crude product chromatographed on flash silica (1-4% methanol in dichloromethane) to give phytanoic acid as a pale yellow liquid. Yield 7.03 g, 34%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[Br:14]N1C(=O)CCC1=O.O>C1COCC1>[Br:14][C:6]1[CH:7]=[C:8]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1ncccc1CC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(Br)cc1CC(C)(C)C
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
To a solution of 2-methoxy-3-neopentylpyridine (4.22 g) in THF (40 mL) was added N-bromosuccinimide (6.29 g) at room temperature, and the mixture was stirred at 100° C. for 20 min. Water was added to the reaction mixture at room temperature, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, hexane) to give the title compound (4.38 g) as a pale-yellow oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH:14]([CH2:16][O:17][CH3:18])[N:13](CC3C=CC=CC=3)[CH:12]([CH2:26][O:27][CH3:28])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([S:7]([N:10]2[CH2:15][CH:14]([CH2:16][O:17][CH3:18])[NH:13][CH:12]([CH2:26][O:27][CH3:28])[CH2:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCC1CN(S(=O)(=O)c2ccccc2)CC(COC)N1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCC1CN(S(=O)(=O)c2ccccc2)CC(COC)N1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
A mixture of the above described (2SR,6SR)-4-benzenesulfonyl-1-benzyl-2,6-bis-methoxymethyl-piperazine (2.355 g, 5.82 mmol) in ethanol (300 ml) with 10% palladium on carbon (620 mg, 10 mol %) was hydrogenated at 50° C. for 2 h. The catalyst was filtered off, washed with ethanol, the filtrate was evaporated totally and dried in high vacuum to give the title compound as a white solid (1.74 g, 95%), MS (ISP) m/e=315.0 [(M+H)+].
Reaction SMILES: I[CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([I:13])[C:9]=2[OH:12])[O:4][C:3]1([CH3:20])[CH3:19].[C-:21]#[N:22].[K+]>C(O)C>[C:21]([CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([I:13])[C:9]=2[OH:12])[O:4][C:3]1([CH3:20])[CH3:19])#[N:22]
Reactant: [C-]#N
Reactant: CCCCCc1cc2c(c(O)c1I)CC(I)C(C)(C)O2
Agent: [K+]
Solvent: CCO
Product: CCCCCc1cc2c(c(O)c1I)CC(C#N)C(C)(C)O2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 21.8 %

Procedure:
3,6-Diiodo-2,2-dimethyl-5-hydroxy-7-pent-1-yl chromane (0.293 g) and potassium cyanide (50 mg) were dissolved in 15 ml absolute ethanol and heated to reflux. After 4.5 hours, the reaction was allowed to cool to room temperature. The solvent was removed in vacuo. Water was added and extracted with methylene chloride. The methylene chloride was removed in vacuo. The residue was chromatographed on a silica gel column eluted with chloroform (TLC Rf=0.2, chloroform). The appropriate fractions were combined to yield 51 mg of product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([C@H:22]1[CH2:26][O:25][C:24](=[O:27])[NH:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:15]([C@H:22]1[CH2:26][O:25][C:24](=[O:27])[N:23]1[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)CCCOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(CCCOCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
4-Benzyloxybutyric acid (238 g), (S)-4-benzyl-2-oxazolidinone (217 g) and chloroform (1300 mL) were mixed. After an addition of 4-dimethylaminopyridine (45 g) and WSC.HCl (282 g) to the mixture at ice temperature, the resulting mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo and toluene (2 L) was poured into the residue. The mixture was washed with 1 N hydrochloric acid (1.5 L), saturated aqueous sodium bicarbonate (2 L) and brine (1.5 L), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (424.8 g) as a crude product.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH2:24]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH:40](O)[CH3:41])[CH2:36][CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH2:24]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH:40]([O:23][C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:11]([CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:10]=[C:9]([C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=2)[N:18]=4)[CH3:41])[CH2:36][CH2:35]1)=[O:33])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(Oc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol (250 mg, 0.80 mmol), 4-(1-hydroxyethyl)piperidine-1-carboxylic acid benzyl ester (233 mg, 0.88 mmol) and PPh3 (316 mg, 1.20 mmol) in dioxane (5 mL) was added DIAD (237 μL, 1.20 mmol) and the resulting yellow solution stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and purified by column chromatography (Si-PCC, gradient 0-10% MeOH in TBME). The resulting residue was dissolved in EtOAc and washed with 1M NaOH, then dried (Na2SO4) and concentrated in vacuo affording 4-{1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}piperidine-1-carboxylic acid benzyl ester (278 mg, 62%) as a white foam. LCMS: RT 4.08 min [M+H]+ 557.5
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[C:7]([NH:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([NH:22][C:23](=[O:26])[CH2:24][Cl:25])=[C:16]2[OH:21])(=[O:9])[CH3:8]>O1CCOCC1>[Cl-:25].[OH:21][C:16]1[C:17]2[C:12](=[C:11]([NH:10][C:7](=[O:9])[CH3:8])[CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[NH:22][C:23]([CH2:24][N:4]1[CH:5]=[CH:6][N+:2]([CH3:1])=[CH:3]1)=[O:26]
Reactant: CC(=O)Nc1cccc2c(O)c(NC(=O)CCl)ccc12
Reactant: Cn1ccnc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc2c(O)c(NC(=O)Cn3cc[n+](C)c3)ccc12
Product: [Cl-]
Yield: 73 %

Procedure:
0.25 ml of N-methylimidazole (3.1 mmol) was introduced into a solution of N-(5-acetylamino-1-hydroxynaphthalen-2-yl)-2-chloroacetamide obtained above in step d) (0.9 g, 3 mmol) in 20 ml of dioxane. The reaction medium was heated under reflux for 7 hours and 30 minutes. The precipitate formed was drained, washed abundantly with dioxane and dried under vacuum to constant weight to give 0.82 g of 3-[(1-hydroxy-5-acetylaminonaphthalen-2-ylcarbamoyl)methyl]-1-methyl-3H-imidazol-1-ium chloride in the form of a red powder melting at 168° C. and with a yield of 73%. Cation mass spectroscopy analysis: m/z=338 of the product obtained was consistent with that of the product obtained.
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[S:14])[S-:13])=[CH:10][C:4]=2[O:3]1.[CH2:16]([NH+](CC)CC)C.BrCBr.C(N(CC)CC)C>CN(C)C=O>[F:15][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]=[C:12]3[S:13][CH2:16][S:14]3)=[CH:10][C:4]=2[O:3]1
Reactant: FC1(F)Oc2ccc(NC(=S)[S-])cc2O1
Reactant: CC[NH+](CC)CC
Solvent: BrCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC1(F)Oc2ccc(N=C3SCS3)cc2O1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
7.36 g (0.021 mol) Triethylammonium N-(2,2-difluoro-1,3-benzodioxol-5-yl)dithiocarbamate was dissolved in 50 ml dimethylformamide. With vigorous stirring, a mixture of 18.25 g (0.105 mol) dibromomethane and 2.12 g (0.021 mol) triethylamine in 20 ml dimethylformamide was added dropwise. It was then stirred for two hours. The reaction mixture was poured into 250 ml ice/water and extracted 3 times with 100 ml diethyl ether. The combined ether phases were dried over magnesium sulphate and concentrated. Purification was then carried out by column chromatography (eluent: hexane/ethyl acetate 4:1).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:21]=[O:22]>O1CCCC1.CCCCCC>[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: O=C/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
Methyl acetoacetate (9.56 g, 82.3 mmole) was added dropwise to a stirred suspension of sodium hydride (50% oil suspension) (3.95 g, 82.3 mmole) in anhydrous tetrahydrofuran at 0° C. under a nitrogen atmosphere. The resulting solution was stirred 15 minutes at 0° C. and then treated with a 1.6 M solution (51.5 ml, 82.3 mmole) of n-butyllithium in hexane over 5 minutes. The resulting yellow solution was stirred 15 minutes at 0° C. and then treated with a solution of (E)-2,4-dichloro-6-phenylmethoxycinnamaldehyde (25.3 g, 82.3 mmole) in anhydrous tetrahydrofuran (150 ml). The resulting orange solution was stirred 15 minutes at 0° C. and then quenched by dropwise addition of 12 N hydrochloric acid (ca. 20 ml). The reaction mixture was diluted with water (100 ml) and extracted with ether (3×300 ml). The organic extracts were combined, washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo leaving the title compound as a yellow oil (34.8 g, 100%): pmr (CDCl3) δ2.75 (2H, d), 3.45 (2H, s), 3.72 (3H, s), 4.71 (H, m), 5.50 (2H, s), 7.37 (5H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:5]=1[NH2:6])([O-])=O>CCOC(C)=O.[Pd]>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([NH2:1])[C:5]=1[NH2:6]
Reactant: Nc1c(-c2ccccn2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2ccccn2)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 103000 %

Procedure:
To a solution of 2-nitro-6-(pyridin-2-yl)aniline (XCIX) (2.4 g, 0.01 mmol, 1 eq) in EtOAc (350 mL) was added Pd/C (1 g) and the mixture was stirred at room temperature overnight, filtered and then concentrated in vacuo, to give 3-(pyridin-2-yl)benzene-1,2-diamine (1.9 g, 10.3 mmol, 89% yield) as a yellow oil. ESIMS found for C11H11N3 m/z 186 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:18].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[C-:27]#[N:28].[K+]>CO.O>[ClH:18].[CH2:19]([NH:26][C:14]1([C:27]#[N:28])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCCN1C(=O)OCc1ccccc1
Reactant: NCc1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: N#CC1(NCc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.65 g (50 mmol) N-(benzyloxycarbonyl)piperidone (prepared from 4-piperidone and benzyl chloroformate according to Chem. Pharm. Bull. 1982, 30, 1084) and 7.2 g (50 mmol) benzylamine hydrochloride were dissolved in a mixture of 20 ml methanol and 10 ml water. The solution was kept at 0° C., while 15 ml of an aqueous solution of 3.26 g (50 mmol) potassium cyanide were added dropwise. After stirring overnight at room temperature a crystalline solid had been formed, which was collected by filtration. The filtrate was treated with a mixture of water and ether. The organic layer was separated and the aqueous layer extracted with ether. The combined organic layers were dried over sodium sulfate and added to the solid material. The title hydrochloride precipitated after treating with a saturated ethereal solution of hydrogen chloride, and it was isolated by filtration and dried in vacuo.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[NH2:13][C:14]([NH2:16])=[S:15]>CO>[NH2:16][C:14]1[S:15][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])[N:13]=1
Reactant: NC(N)=S
Reactant: N#Cc1cccc(C(=O)CBr)c1
Solvent: CO
Product: N#Cc1cccc(-c2csc(N)n2)c1
Temperature: 0 °C

Procedure:
16.9 g of 3-bromoacetyl-benzonitrile were placed in 50 ml of methanol and treated at room temperature with 8 g of thiourea. The mixture was boiled for 2 1/2 hours and then cooled to 0° C. while stirring slowly. The product separated as the salt, was filtered off and converted into the base by the addition of 100 ml of 2N sodium hydroxide solution. The aqueous suspension was extracted with a total of 700 ml of methylene chloride and the organic phase was dried with magnesium sulphate. 9.6 g of 3-(2-amino-thiazol-4-yl)-benzonitrile separated upon concentration.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:20][CH3:21])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:22]([NH2:24])=O.C[O-].[Na+].Cl>CN(C)C=O.CO.O>[CH2:13]([O:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:5])[NH:24][CH:22]=[N:1]2)=[CH:8][C:9]=1[O:20][CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(OC)c(OCc2ccccc2)cc1N
Reactant: NC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc2c(=O)[nH]cnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Methyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (650 mg) was dissolved in N,N-dimethylformamide (15 ml) and methanol (3 ml). Formamide (0.46 ml) and sodium methoxide (373 mg) were added to the solution. The mixture was heated to 100° C. and was stirred overnight. The reaction solution was cooled to room temperature, and 10 ml of water was then added to the cooled reaction solution. The reaction solution was neutralized with a 1 M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, was washed with water and ether, and was then dried through a vacuum pump to give 566 mg (yield 87%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][C@@H:27]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH:38]([Si:31]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:37])[CH3:36])[O:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:40])[CH3:39]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](O[C@@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)[Si](O[C@@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 60 °C
Yield: 27.9 %

Procedure:
To a solution of Intermediate A (123 mg, 0.755 mmol) in DMF (4 mL) was added NaH (60% in oil, 82 mg, 2.06 mmol) and the mixture stirred at RT for 20 min, before Intermediate 38b (260 mg, 0.687 mmol) was added. This mixture was heated at 60° C. in the microwave for 3 h. The reaction mixture was applied to an SCX-2 cartridge (25 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-7% [2M NH3 in MeOH] in DCM, gave the title compound as a viscous yellow oil (100 mg, 23%). LCMS (Method 1): Rt 2.90 min, m/z 522 [MH+].
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34](Cl)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:39])[C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([NH:10][CH2:9][CH2:8][CH2:7][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[N:33]=4)=[CH:28][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1)#[N:12]
Reactant: NCCCN1CCCCC1
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCN5CCCCC5)n4)cc3)cc12

Procedure:
Using 3-(piperidin-1-yl)-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:41])([CH3:40])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([S:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=CC=C(C(OO)=[O:52])C=1>ClCCl>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:41])([CH3:40])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([S:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)=[O:52])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COc1cccc(Sc2cc(-c3ccccc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cccc(S(=O)c2cc(-c3ccccc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)c1
Temperature: 25 °C
Yield: 6.8 %

Procedure:
To a solution of 130 mg (0.210 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-methoxy-phenylsulfanyl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide (Example 103) in 1 ml dichloromethane a solution of 52 mg (0.21 mmol) 3-chloroperbenzoic acid in 1.5 ml dichloromethane was added at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with three portions of dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated. Column chromatography afforded 9 mg (7%) of the title compound as a colorless viscous oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH:6]=[O:7])[CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28]>O1CCCC1>[F:26][C:27]([F:29])([F:28])[CH:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)[OH:7]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CC1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1CCOC1)C(F)(F)F
Yield: 31.3 %

Procedure:
According to Reference Example 8-12, by use of a 50 wt % aqueous tetrahydrofuran-3-carbaldehyde solution (1.00 g, 5.00 mmol) dissolved in tetrahydrofuran (15 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (1.00 mL, 1.00 mmol) and (trifluoromethyl)trimethylsilane (0.887 mL, 6.00 mmol), the mixture was stirred and reacted at room temperature for 1.8 hours. Then, purification by extraction gave 2,2,2-trifluoro-1-(tetrahydrofuran-3-yl)ethanol (Compound EJ) (266 mg, yield: 31%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21](O)=[O:22]>O1CCCC1>[CH3:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[O:22]
Reactant: CCCCCCCC/C=C\CCCCCCC(C)C(=O)O
Reactant: N[C@@H](CO)C(=O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCC(C)C(=O)N[C@@H](CO)C(=O)O
Temperature: 35 °C
Reaction time: 8 h

Procedure:
A solution of L-serine (190 mg, 1.8 mmol) in 20 ml. of 0.1 N sodium carbonate and 0.1 N sodium bicarbonate was added to a solution of N-hydroxysuccinimide ester of 2-methyl oleic acid (204.5 mg, 0.5 mmole) in 20 ml tetrahydrofuran. The reaction mixture was stirred overnight at 35° C., evaporated down to 20 ml, and acidified to pH 1 with 1 N HCl. The product was extracted with methylene chloride (2×20 mL), dried (MgSO4), and the solvent evaporated under reduced pressure. The crude material was chromatographed on silica gel (eluting with chloroform:methanol) to give 86 mg (45%) as a yellowish oil 1H NMR (CDCl3) δ 0.912 (t, 3H), 1.129 (d, 3H), 1.288 (s, 20H), 1.611 (m, 2H), 2.018 (m, 4H), 2.323 (m. 1H), 3.787 (dd, 1H), 3.980 (dd, 1H), 4.503 (t, 1H), 5.353 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][OH:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][OH:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCO)ccc21
Yield: 88.7 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (40.0 mg, 0.0974 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 2-aminoethanol (0.024 mL, 0.39 mmol), acetic acid (0.112 mL, 1.96 mmol) and sodium triacetoxyborohydride (103 mg, 0.486 mmol), followed by purification by preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(2-hydroxyethyl)aminomethyl]indol-2-yl)isoindolinone (39.4 mg, yield 871).