Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]=O.[OH-].[Na+]>C(O)=O>[CH3:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: C=O
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1C(C)(C)CC(O)CC1(C)C

Procedure:
A mixture of 18 grams of commercially available 2, 2, 6, 6-tetramethyl-4-hydroxypiperidine, 18 grams of an aqueous solution containing 37% of formaldehyde and 4 milliliters of formic acid containing 1% water is placed in a 100-ml., round-bottomed flask and heated on a steam bath for 7 hours. The contents are cooled, made basic with sodium hydroxide and extracted with ether. The ether extract is dried using anhydrous magnesium sulfate and the ether evaporated. The residue, a white solid, is purified by sublimation at 90°C. at 0.05 torr. The purified 1, 2, 2, 6, 6-pentamethyl-4-hydroxypiperidine has a melting point of 70°-71°C.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:31][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])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([OH:30])=O)[CH:25]([CH3:27])[CH3:26])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:46][C@H:47]([C:55]([OH:57])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:18][CH:19]([CH2:31][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])[CH2:20][C:21]([NH:23][C@H:24]([C:28]([NH:46][C@H:47]([C:55]([OH:57])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:30])[CH:25]([CH3:26])[CH3:27])=[O:22])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)O)C(C)C
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)C
Yield: 73.1 %

Procedure:
Starting from N-(3-hexadecanoyloxyoctadecanoyl)-L-valine (1 g) prepared by the method of Example 28 and L-phenylalanine (777 mg), N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-valyl]-L-phenylalanine (900 mg) was obtained as powders according to a similar manner to that of Example 29.
Reaction SMILES: CN.[CH3:3][O:4][CH:5]([O:18][CH3:19])[C:6]1[C:15]([CH:16]=O)=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[N:7]=1.Cl.CN.[C:23]([BH3-])#[N:24].[Na+]>CO.O>[CH3:3][O:4][CH:5]([O:18][CH3:19])[C:6]1[C:15]([CH2:16][NH:24][CH3:23])=[CH:14][C:13]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]=2[N:7]=1
Reactant: [BH3-]C#N
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1cc2c(nc1C(OC)OC)NCCC2
Temperature: 70 °C

Procedure:
A solution of methylamine in MeOH (8M, 1.06 ml, 8.46 mmol) was added to a mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 1.0 g, 4.23 mmol) and methylamine hydrochloride (0.57 g, 8.46 mmol), in MeOH (20 ml) at room temperature. Sodium cyanoborohydride (1.06 g, 16.93 mmol) was then added and the reaction mixture heated at 70° C. for 2 h. Water was added to the cooled reaction mixture and the volume reduced under vacuum. The remaining predominantly aqueous phase was then extracted with DCM (3×), dried over Na2SO4 and evaporated to give the title compound. (UPLC-MS 7) tR 0.33; ESI-MS 252.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[SH2:11].[K].Cl>>[SH:11][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2nccn12
Reactant: S
Agent: Cl
Agent: [K]
Product: Sc1cccc2nccn12
Temperature: 25 °C
Reaction time: 6 h
Yield: 33 %

Procedure:
A mixture of 2.5 g of 5-chloroimidazo[1,2-a]pyridine and 30 ml of 2N-potassium hydrogen sulfide solution is stirred at room temperature for 6 hours and then at 80° C. for 3 days. The pH of the reaction mixture is adjusted to 2 with concentrated hydrochloric acid. The reaction mixture is extracted twice with 200 ml of ethyl acetate, and dried over magnesium sulfate, followed by evaporation of the solvent under reduced pressure, and the resulting powder is collected by filtration. Yield:33%.
Reaction SMILES: [CH3:1][C@H:2]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]=[O:4].[CH2:16]([Mg]Br)[CH:17]=[CH2:18].O>O1CCCC1>[OH:4][CH:3]([CH2:18][CH:17]=[CH2:16])[C@@H:2]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:1]
Reactant: C=CC[Mg]Br
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution (30 mL) of benzyl [(1S)-1-methyl-2-oxoethyl]carbamate (3.0 g) in tetrahydrofuran was added 1.0 mol/L solution (28.8 mL) of allylmagnesium bromide in tetrahydrofuran under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) to give benzyl [(1S)-2-hydroxy-1-methylpent-4-en-1-yl]carbamate as a colorless oil. To a solution (10 mL) of the obtained benzyl [(1S)-2-hydroxy-1-methylpent-4-en-1-yl]carbamate in tetrahydrofuran were added 2,6-lutidine (0.629 mL) and tert-butyldimethylsilane trifluoromethanesulfonate (0.91 mL) and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield: 610 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:16]([NH:18][C@H:19]([C:24]([NH:26][C@H:27]([C:29](O)=[O:30])[CH3:28])=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2].[CH2:32]([O:34][CH:35]([O:47][CH2:48][CH3:49])[CH2:36][C@@H:37]([NH2:46])[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH3:33]>>[CH2:48]([O:47][CH:35]([O:34][CH2:32][CH3:33])[CH2:36][C@@H:37]([NH:46][C:29](=[O:30])[C@H:27]([CH3:28])[NH:26][C:24](=[O:25])[C@H:19]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH:18][C:16](=[O:17])[C@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:38][C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH3:49]
Reactant: CCOC(C[C@@H](N)CC(=O)OC(C)(C)C)OCC
Reactant: CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)[C@@H](C)CC
Product: CCOC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)CC(OCC)OCC)[C@@H](C)CC

Procedure:
Starting from 0.22 g (0.5 mmol) of ethoxycarbonyl-L-tyrosyl-L-isoleucyl-L-alanine (Example 3, Step A6) and 0.13 g (0.5 mmol) of (3R)-3-amino-4-t-butoxycarbonyl-butyraidehyde diethyl acetal (Example 1, Step B4) and using proportional amounts of reagents and solvents, the components are coupled and the end product isolated according to the process described in Example 1, Step A1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:23])[C:9]3[CH2:14][CH:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[N:7]=[C:6]3[N:8]([CH3:23])[C:9]4[CH2:14][CH:13]([CH3:15])[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:10]=4[C:5]3=[CH:4][CH:3]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CC1Cc2c(c3ccc(Br)nc3n2C)CN1C(=O)OC(C)(C)C
Product: CC1Cc2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)nc3n2C)CN1C(=O)OC(C)(C)C
Yield: 29.6 %

Procedure:
tert-Butyl 2-bromo-7,9-dimethyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (enantiomer B) (100 mg, 0.263 mmol) and 4-(benzyloxy)pyridin-2(1H)-one (53 mg, 0.263 mmol) were reacted following the procedure for Example 2 (step e) to provide the title compound (39 mg, 30%) as a yellow oil: ESI MS m/z 501 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10]Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)c2ccc(Cl)cc2Cl)CC1

Procedure:
1-(2,4-dichlorophenyl)-2-chloroethan-1-one(1 mmol) and methylpiperazine(4 mmol) in 8 ml DMF was stirred for 8 h at room temperature. The reaction mixture was then concentrated in vacuo and extracted into ethyl acetate and the organic layer was washed with water and dried with sodium sulfate. The residue after concentration in vacuo was purified by column chromatography eluting with 10% methanol in methylene chloride to yield 1-(2,4-dichlorophenyl)-2-(4-methylpiperazinyl)ethan-1-one. 1-(2,4-dichlorophenyl)-2-(4-methylpiperazinyl)ethan-1-one was heated to 80° C. in neat DMF-DMA for six hours. The reaction mixture was concentrated in vacuo and the residue obtained was purified by trituration with diethyl ether to yield the enaminone. 1 mmol of the enaminone obtained above, 1 mmol of amino{2-[(5-nitro(2-pyridyl))amino]ethyl}carboxamidine hydrochloride and 1.3 mmol of Cs2CO3 were dissolved in DMF and heated to 90° C. for fourteen hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Water was added and then extracted 3× with ethyl acetate. The combined organic layers were dried with sodium sulfate. The residue after solvent evaporation was purified by column chromatography eluting with 5-10% methanol in methylene chloride to yield [4-(2,4-dichlorophenyl)-5-(4-methylpiperazinyl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine as a yellow powder after lyophilization.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[OH:3][CH:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(C)=O)c1ccccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(C)O)c1ccccc1C

Procedure:
A stirred solution of ethyl (RS)-4-[2-acetyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (1 g) in methanol (50 mL) is treated, portionwise, with sodium borohydride (0.1 g), and stirred at ambient temperature for one hour. It is then treated with dilute acetic acid (50 mL; 1 N) and extracted with ethyl acetate (2×50 mL). The combined organic extracts are washed with water (2×50 mL) dried over magnesium sulphate, filtered and concentrated in vacuo. Flash chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:5 v/v) gives ethyl (RS,RS)-4-[2-(1-hydroxyethyl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[NH2:24])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:45](Cl)(=[O:47])[CH3:46].[Li+].[OH-]>ClCCl.CCOC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[NH:24][C:45](=[O:47])[CH3:46])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC[C@@H]4N)n3)c3cc(Cl)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CCCC[C@@H]1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
(1S,2S)—N-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,2-diamine, 15b, (0.100 g, 0.194 mmol) was dissolved in dichloromethane (2 mL) and treated with iPr2NEt (0.075 g, 0.101 mL, 0.583 mmol). Acetyl chloride (0.021 mL, 0.291 mmol) was added and the reaction was allowed to stir at room temperature for 30 minutes. The volatiles were evaporated under reduced pressure, and the residue was dissolved in dichloroethane (2 mL) and treated with LiOH (0.097 mL of 1 M solution, 0.971 mmol). The reaction mixture was heated in the microwave at 150° C. for 10 minutes. The reaction was diluted with EtOAc (5 mL) and water (5 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2×5 mL), and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo to provide the crude product, which was purified by silica gel chromatography (0%-15% MeOH/CH2Cl2) to provide N-[(1S,2S)-2-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]acetamide, 433, (34 mg, 44% yield).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[NH:13][C:12](=O)[CH:11]=[C:10]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:26])=O.N1C=CC=CC=1>>[Cl:26][C:12]1[CH:11]=[C:10]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[N:9]=[C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: O=c1cc(-c2c[nH]c3ncccc23)nc(NC2CCCCC2)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Clc1cc(-c2c[nH]c3ncccc23)nc(NC2CCCCC2)n1
Yield: 25.5 %

Procedure:
A mixture of Example 49d (100 mg, 0.323 mmol), phosphoryl trichloride (1 ml, 10.92 mmol) and pyridine (0.05 ml, 0.618 mmol) was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and purified by HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (30 mm×75 mm), eluting with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A) to give the title product (27 mg, 25.5% yield). MS (ESI) m/e 328 (M+H)+; 1H NMR (400 MHz, DMSO-d6) ppm 1.15-1.48 (m, 5H) 1.58-1.69 (m, 1H) 1.73-1.83 (m, J=9.31, 3.51 Hz, 2H) 1.94-2.03 (m, 2H) 3.76-3.90 (m, 1H) 6.93-7.04 (m, 1H) 7.07 (s, 1H) 7.17 (dd, J=7.93, 4.58 Hz, 1H) 8.28 (d, J=3.36 Hz, 1H) 8.34 (s, 1H) 8.79 (d, J=7.63 Hz, 1H) 12.01 (s, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]=2)=[N:7][CH:8]=1.[CH3:23][C:24]1[C:28]([CH3:29])=[C:27]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[O:26][N:25]=1.NC1ON=C(C)C=1C.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:31]([NH:30][C:27]3[O:26][N:25]=[C:24]([CH3:23])[C:28]=3[CH3:29])=[O:32])[CH2:19][CH2:18]2)=[N:7][CH:8]=1
Reactant: Cc1noc(NC(=O)Oc2ccccc2)c1C
Reactant: Cc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cc1noc(N)c1C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4onc(C)c4C)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Methyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine hydrochloride (150 mg, 0.473 mmol, from Example 44, Step 5), phenyl 3,4-dimethylisoxazol-5-ylcarbamate (110 mg, 0.473 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 5-amino-3,4-dimethylisoxazole) and diisopropylethylamine (0.20 mL, 1.15 mmol) were combined in acetonitrile (5 mL) and stirred at room temperature. After 16 h, the reaction was concentrated and the residue was purified by silica gel chromatography (0-30% EtOAc:CH2Cl2) to afford the title compound (86 mg) as a foamy white solid. MS APCI M+ 419.3, 378.2, 281.3; 1H NMR (400 MHz, CD3OD) δ ppm 1.83 (s, 3H) 2.18 (s, 3H) 2.29 (s, 3H) 2.43 (td, J=5.86, 1.16 Hz, 2H) 2.55 (td, J=5.73, 1.20 Hz, 2H) 3.48-3.54 (m, 2H) 3.57-3.65 (m, 2H) 6.44 (s, 1H) 6.82-6.87 (m, 1H) 6.89-6.96 (m, 2H) 7.02-7.11 (m, J=7.60, 1.50, 1.06, 0.74 Hz, 1H) 7.35 (dd, J=8.77, 7.65 Hz, 1H) 7.61-7.69 (m, J=8.38, 2.46, 1.15, 0.45 Hz, 1H) 7.96 (td, J=1.60, 0.72 Hz, 1H).
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[CH:9][N:8]=1.[I:15]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[F:13][C:12]1[C:7]([NH2:6])=[N:8][CH:9]=[C:10]([F:14])[C:11]=1[I:15]
Reactant: II
Reactant: Nc1ncc(F)cc1F
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncc(F)c(I)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (41 ml, 1.6 M solution in hexanes, 66 mmol) was added drop wise to a solution of 2-amino-3,5-difluoropyridine (3.4 g, 26 mmol) in THF (100 ml) at −78° C. The mixture was allowed to stir at that temperature for 1.5 hr, then a solution of iodine (20 g, 78 mmol) in THF (30 ml) was added. The mixture was stirred at −78° C. for 15 min, then it was allowed to warm to rt. Saturated aqueous sodium thiosulfate was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-25% ethyl acetate in hexanes eluant) to provide the title compound. MS m/z: 297.9 (M+MeCN+1).
Reaction SMILES: [Li+].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH:15]3[CH2:17][N:18]([CH2:20][CH2:21][C:22]([O-])=[O:23])[CH2:19][CH:14]3[CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:50]([C:53]1[CH:58]=[CH:57][C:56]([NH:59][CH:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][C:54]=1[C:66]([F:69])([F:68])[F:67])([O-:52])=[O:51].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>CN(C)C=O.O1CCCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:16][CH:15]3[CH2:17][N:18]([CH2:20][CH2:21][C:22]([N:63]4[CH2:64][CH2:65][CH:60]([NH:59][C:56]5[CH:57]=[CH:58][C:53]([N+:50]([O-:52])=[O:51])=[C:54]([C:66]([F:67])([F:68])[F:69])[CH:55]=5)[CH2:61][CH2:62]4)=[O:23])[CH2:19][CH:14]3[CH2:13]2)=[CH:10][CH:11]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: CC(C)(C)c1ccc(N2CC3CN(CCC(=O)[O-])CC3C2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(N2CC3CN(CCC(=O)N4CCC(Nc5ccc([N+](=O)[O-])c(C(F)(F)F)c5)CC4)CC3C2)cc1
Reaction time: 4 h
Yield: 24 %

Procedure:
3-[5-(4-tert-Butyl-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-propionic acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 127) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (0.75 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide and (0.25 mL) diisopropylethyl amine (25 μL; 0.15 mmol) are added and the reaction is then stirred. After 4 hours at room temperature, aluminium oxide (90 active basic) is added and stiffing is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (7 mg; 0.012 mmol). The structure was confirmed using Protocol I-D. Calculated mass=588; observed mass=588; HPLC retention time=1.66 min.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCCCCCCC.CN(C)C=[O:24].C(=O)(O)[O-].[Na+].OO>O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[CH2:1]1[O:24][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)C=O
Reactant: C=Cc1ccccc1
Agent: [Mn+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Solvent: CCCCCCCCCCCC
Product: c1ccc(C2CO2)cc1
Yield: 56 %

Procedure:
To a mechanically stirred solution of styrene (0.01 mol), dodecane (0.001 mol), dimethylformamide (0.208 mol), sodium bicarbonate (0.003 mol) and manganese (II) acetate (0.15 mmol) in 10.0 ml of water at 30° C. is added 30% aqueous hydrogen peroxide (0.45mol) in three equal portions over a period of 3 hours. After 8 hours the reaction mixture was extracted with 4×5 ml diethyl ether. The combined organic layer was dried over anhydrous sodium sulphate. Removal of solvent yielded styrene oxide in 56% yield with selectivity 80%.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7](OC1C=CC=CC=1)=[O:8].Br.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][CH3:29])=[CH:21][CH:20]=1.C(N(CC)CC)C.C(OCC)(=O)C>CC(N(C)C)=O>[CH3:29][N:28]([CH2:27][CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[C:7]([N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])=[O:8]
Reactant: CNCCOc1ccc(OC)cc1
Reactant: O=C1CCCN1C(=O)Oc1ccccc1
Agent: Br
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(OCCN(C)C(=O)N2CCCC2=O)cc1
Yield: 88.8 %

Procedure:
A mixture of 1.87 g (9.13 mmol) of 2-oxo-1-phenoxycarbonylpyrrolidine (II), 2.39 g (9.13 mmol) of 2-(4-methoxyphenyloxy)ethyl-N-methylamine hydrobromide and 2.30 g (22.8 mmol) of triethylamine in 0.5 ml of DMA was heated at 115°-125° C. for 6.5 hr. and ethyl acetate was added to the reaction solution. The mixture was washed with aqueous NaHCO3 and water, and dried, then the solvent was distilled off. The residue was refined by silica gel column chromatography, whereby 2.37 g of an oily compound (I a-41) was obtained from the eluate with toluene/ethyl acetate (5/1-3/1 v/v). Yield: 88.8%
Reaction SMILES: [Si:1]([O:18][C@H:19]1[CH2:24][C@@H:23]([C:25]([O:27]C(C)(C)C)=[O:26])[C@H:22]([C:32](=[O:41])[N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:18][C@H:19]1[CH2:24][C@@H:23]([C:25]([OH:27])=[O:26])[C@H:22]([C:32](=[O:41])[N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of compound 39 (1.07 mmol) in anhydrous DCM (70 mL) was added TFA (42.6 mmol) slowly. The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated and purified by silica gel chromatography (DCM/MeOH) to yield compound 40 as a yellow oil in 48% yield. MS (ESI, EI+): m/z=522 (MH+).