Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(C(C)C)CC)(C)C.[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[F:33][C:2]([F:1])([CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:26]
Reactant: BrCc1ccccc1
Reactant: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OCc2ccccc2)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.1 %

Procedure:
To the crude 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (17) (132.1 mmol) in acetonitrile (315 ml), diisopropyl ethylamine (69.0 ml, 369 mmol) and benzyl bromide (47.1 ml, 369 mmol) were added and the mixture was stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate (366 ml) and water (280 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (224 ml). The organic layers were combined and washed with 1N-hydrochloric acid (336 ml), saturated sodium bicarbonate water (336 ml) and saturated aqueous sodium chloride (336 ml). After drying with anhydrous magnesium sulfate (51 g), the solution was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2400 g; ethyl acetate:hexane =1:2) to give benzyl 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (18) (74.44 g; 130.9 mmol; yield: 99.1%) as a colorless oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][N:18]([CH3:30])[CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[CH:1]1([N:6]2[C:10]3=[N:11][C:25]([C:24]4[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH2:20][CH2:19][N:18]([CH3:17])[CH3:30])[CH:23]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCOc1cccc(C=O)c1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cccc(OCCN(C)C)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.50 g, 15.74 mmol), 3-[2-(dimethylamino)ethoxy]benzaldehyde (3.95 g) and xylenes (10 ml) was heated at 160° C. overnight. The reaction mixture was cooled to room temperature, the solvent was stripped, and the residue was partitioned between chloroform and water. The layers were separated, and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with brine, dried over MgSO4, filtered and stripped to afford, as an oil, 1-cyclopentyl-3-ethyl-6-[3-[2-(dimethylamino)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one labelled as [Example 23 (b)]. The free base was treated with ethanolic HCl to afford the product as the hydrochloride salt [labelled as Example 23 (c)].
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)[O:10][CH:11](C2C=CC=CC=2)[CH:12]2[O:16][CH:15]([N:17]3[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]3=[O:24])[CH:14]([O:25][C:26](=[O:28])[CH3:27])[CH:13]2[O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=CC=1>C(O)(=O)C>[C:43]([Si:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[O:29][CH:13]1[CH:12]([CH2:11][OH:10])[O:16][CH:15]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[CH:14]1[O:25][C:26](=[O:28])[CH3:27])([CH3:44])([CH3:45])[CH3:46]
Reactant: COc1ccc(C(OC(c2ccccc2)C2OC(n3ccc(=O)[nH]c3=O)C(OC(C)=O)C2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Product: CC(=O)OC1C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(CO)OC1n1ccc(=O)[nH]c1=O

Procedure:
The 5′-O-DMT group is removed as per known literature procedures 4,4′-dimethoxytrityl ethers are commonly removed under acidic conditions (Oligonucleotides and analogues, A Practical Approach, Eckstein, F., ed, IRL Press, New York.) Generally, Compound 8 (1 eq.) is dissolved in 80% aqueous acetic acid. After several hours, the mixture is evaporated, dissolved in ethyl acetate and washed with a sodium bicarbonate solution. Purification by silica gel chromatography will give compound 9.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]([CH3:12])[N:5]=1)([CH3:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[O:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([CH:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[N:37]=2)[N:34]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(=O)C>[CH:41]1([C:39]([NH:38][C:36]2[N:37]=[C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[CH:45][C:46]([F:47])=[C:25]([NH:24][C:9]([C:7]5[N:6]([CH3:12])[N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=5)=[O:11])[CH:26]=4)=[N:34][N:33]3[CH:35]=2)=[O:40])[CH2:42][CH2:43]1
Reactant: CC(C)c1cc(C(=O)O)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CC(C)c1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of 3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (144 mg, 0.86 mmol) in tetrahydrofuran (3.0 mL) were added N,N-dimethylformamide (30 μL, 0.39 mmol) and oxalyl chloride (75 μL, 0.86 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.62 mmol) in N,N-dimethylacetamide (4.0 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (216 mg, 74%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:9]([CH3:19])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][CH:6]2[C:7]3[C:3](=[C:2]([CH3:1])[C:10]([NH:11][C:12](=[O:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:9]([CH3:19])[CH:8]=3)[CH2:4][CH2:5]2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CCC2=O
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)CCC2Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
A mixture of N-(4,6-dimethyl-1-oxo-indan-5-yl)-3,3-dimethyl-butyramide (5 g, 19 mmol), 4-fluoroaniline (5 g, 45 mmol), and decaborane (4.5 g, 36.8 mmol) in 100 ml of anhydrous methanol was stirred for 2 days at room temperature in an high pressure reaction equipment. The reaction mixture was poured into 500 ml of ice-water with strong stirring and the precipitates were filtered and washed with water. The dried solid was crystallized from hexane/ethyl acetate (5:1) to give white crystals (6 g, 86%). 1H-NMR δ (DMSO-d6, 400 MHz): 9.08 (brs, 1H, exchangeable with D2O, NH), 6.98 (s, 1H), 6.92 (t, J=8.8 Hz, 2H), 6.69 (dd, J=4.8 and 8.8 Hz, 2H), 5.76 (d, J=8.0 Hz, 1H, exchangeable with D2O, NH), 4.86 (q, J=8.0 Hz, 1H), 2.86 (ddd, J=4.8, 8.7 and 16.2 Hz, 1H), 2.70 (quint, J=8.1 Hz, 1H), 2.46 (m, 1H), 2.22 (s, 2H), 2.11 (s, 3H), 2.06 (s, 3H), 1.74 (m, 1H), 1.07 (s, 9H). MS: 369 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.Cl.C(OCC)(=O)C>CS(C)=O>[CH:2]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:1]
Reactant: Cc1cccc(CCC(=O)OC(C)(C)C)c1CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cccc(CCC(=O)OC(C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
To a solution of 770 mg of tert-butyl 3-[2-(hydroxymethyl)-3-methylphenyl]propanoate in 16 ml of dimethylsulfoxide were added 4 ml of triethylamine and 1.22 g of a sulfur trioxide pyridine complex, followed by stirring at room temperature for 5 hours. To the reaction mixture were added diluted hydrochloric acid and ethyl acetate to carry out a layer separation operation. The organic layer was sequentially washed with water, saturated aqueous sodium hydrogen carbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 707 mg of tert-butyl 3-(2-formyl-3-methylphenyl)propanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=1.Cl.O1CCOC[CH2:22]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:22])=[O:16])=[CH:13][N:12]=1
Reactant: O=C(O)c1ccc(-c2cc([N+](=O)[O-])ccc2Cl)nc1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2Cl)nc1

Procedure:
75 mL of (5-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of 1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 935 mg of 2-(2-chloro-5-nitrophenyl)-5-methylpyridine in 5 mL of Sulfuric Acid was slowly added 2.25 g of Chromium (III) Oxide and the reaction was stirred for several hours at room temperature until complete. Icewater was added to dilute the reaction and the aqueous layer was extracted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 6-(2-chloro-5-nitrophenyl)nicotinic acid. 704 mg of 6-(2-chloro-5-nitrophenyl)nicotinic acid was esterified with 3.1 mL of 4N HCl in Dioxane in 20 mL of MeOH. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 6-(2-chloro-5-nitrophenyl)nicotinate. 681 mg of methyl 6-(2-chloro-5-nitrophenyl)nicotinate was treated with 2.1 g of Tin (II) Chloride and 1 mL of HCl in 25 mL of EtOH. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 6-(5-amino-2-chlorophenyl)nicotinate. 296 mg of methyl 6-(5-amino-2-chlorophenyl)nicotinate was coupled to 266 mg of 4-(methylsulfonylmethyl)benzoic acid via Procedure G. To 518 mg of methyl 6-(2-chloro-5-(4-(methylsulfonylmethyl)benzamido)phenyl)nicotinate at 0° C. in 20 mL of EtOH was slowly added 640 mg of Sodium Borohydride. The reaction was subsequently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 431.1 (M)+.
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:37]([C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])[C:36]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:35][CH:34]2[CH2:58][CH:59]2CCCC2)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:37]([C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])[C:36]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:35][CH:34]2[CH2:58][CH3:59])=[CH:29][CH:28]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Agent: CCOc1cc(OC)ccc1C1=NC(CC)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(CC)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1

Procedure:
[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-ethyl-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-ethyl-4,5-dihydro-1H-imidazole (Example 20) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 485.2323, calculated for C26H34N4O3Cl [(M+H)+]485.2314.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Na+].[Cl:9][C:10]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([C:24]([Cl:28])=[C:25]([Cl:27])[Cl:26])[CH:23]=1)[CH2:17][N:18]=[N+:19]=[N-:20])=[C:11]([Cl:13])[Cl:12].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[N:18]([CH2:17][C:16]2[CH:21]=[C:22]([C:24]([Cl:28])=[C:25]([Cl:27])[Cl:26])[CH:23]=[C:14]([C:10]([Cl:9])=[C:11]([Cl:12])[Cl:13])[CH:15]=2)[N:19]=[N:20][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)c1nnn(Cc2cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c2)c1N
Reaction time: 0.33 h
Yield: 48.9 %

Procedure:
To a hot (60° C.) solution of cyanoacetamide (0.692 g) in 25 ml of ethanol, 8.2 ml of a 1N methanolic solution of NaOH was added and the resulting mixture stirred for 20 minutes. 3,5-Di(trichlorovinyl)benzyl azide (1.5 g) was added in one portion and the resulting mixture stirred at 60° C. for 1 hour. The pH of the mixture was adjusted to 6 with acetic acid. The reaction mixture was then concentrated to a reduced volume and diluted with 100 ml of water. The aqueous mixture was extracted with CH2Cl2 (3×100 ml). The combined organic layers were washed with water, dried with MgSO4 and concentrated to give 1.5 g of crude product. This material was chromatographed on silica gel (95:5 CH2Cl2 :CH3OH) to give 890 mg of a solid. Recrystallization from 5 ml of ethanol provided pure triazole, m.p. 167°-169° C..
Reaction SMILES: N1C=CC=[CH:3][CH:2]=1.[CH2:7]([OH:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH3:20]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH:7](=[O:21])[CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:2][CH3:3]
Reactant: CCCC/C=C\CCCCCCCCO
Reactant: c1ccncc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCCCCCCC/C=C\CCCC=O
Reaction time: 0.25 h

Procedure:
Chromium trioxide (0.56 g. 5.6 mM) is added to a stirred solution of pyridine (0.90 g. 11.4 mM) in methylene chloride (14 ml). The flask is stoppered with a Drieritefilled tube. The deep red solution is stirred for approximately fifteen minutes at room temperature after which a solution of cis-9-tetradecen-1-ol (0.9 mM) in a small amount of methylene chloride (approximately 0.2 ml) is added rapidly and the mixture stirred for another 15 minutes. The product is recovered by decantation from the tarry precipitate, concentrated in vacuo, and the residue extracted with redistilled petroleum ether (Skelly B). This extract is washed successively with dilute aqueous hydrochloric acid (approximately 1%), brine, dilute aqueous sodium bicarbonate (approximately 5%), and brine (until neutral), then filtered through anhydrous magnesium sulfate and evaporated in vacuo to yield 0.17 g. G.c. analysis showed the product contained cis-9-tetradecen-1-ol in approximately 1:9 ratio to the aldehyde, so the product was chromatographed on Florisil (2.4 cm o.d. × 30 cm; packed up to 25 cm) using redistilled benzene (15 ml fractions). Fractions 4 - 7 are combined. Final yield of alcohol-free cis-9-tetradecenal is 60 mg. In accordance with the foregoing procedure but starting with cis-11-hexadecenal in place of cis-9-tetradecenal, there is obtained crude cis-5-hexadecenal (0.19 g.) and alcohol-free cis-11-hexadecenal (0.10 g.).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=O)[C:4]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[CH:5][C:6](O)=[O:7].O.[NH2:20][NH2:21]>C(O)C.C(O)(=O)C.ClCCl>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([C:2]([F:18])([F:17])[F:1])=[N:21][NH:20][C:6](=[O:7])[CH:5]=2)=[CH:10][CH:11]=1
Reactant: NN
Reactant: O=C(O)C=C(C(=O)C(F)(F)F)c1ccc(F)cc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1cc(-c2ccc(F)cc2)c(C(F)(F)F)n[nH]1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a stirred solution of 5,5,5-trifluoro-3-(4-fluorophenyl)-4-oxo-pent-2-enoic acid (D5) (1.4 g, 5.3 mmol) in a mixture of ethanol (10 ml) and acetic acid (1 ml), was added hydrazine hydrate (0.49 ml, 9.33 mmol). The reaction mixture was heated at reflux for 16 h, cooled to room temperature, diluted with dichloromethane and then extracted with 0.5 M hydrochloric acid (150 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo to yield D6 (0.96 g, 70%) as a mixture of isomers. C11H6F4N2O requires 258; Found 259 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][O:48]S(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:53]O.[H-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][O:48][CH3:53])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1
Agent: [H-]
Agent: [Na+]
Product: COCCN1CCCc2ccc(CO[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
In analogy to the procedure described in example 14(a), the (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 9(a)] was treated with methanol/sodium hydride to yield the (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(2-methoxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 675 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([O:24]CC3C=CC(OCCCCCCCCCCC4C5C(=C6C=CC=CC6=C6C=CC=CC6=5)C5C4=C4C=CC=CC4=C4C=CC=CC4=5)=CC=3)=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O

Procedure:
The compound obtained in Step (j) may be stirred in a solution of TFA/DCM to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43]([NH2:48])[CH2:44][CH2:45][CH2:46][CH3:47]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:48][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:21])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CCCCCNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and pentylamine (15.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-pentylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (39.6 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.C(N(CC)C(C)C)(C)C.[O:31]=[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34](=[O:41])[N:33]1[CH2:42][CH2:43][CH:44]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.C(O)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=3)[CH:3]=[C:2]2[NH:1][CH2:44][CH2:43][CH2:42][N:33]2[C:34](=[O:41])[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:32]2=[O:31])=[CH:7][CH:8]=1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CNc1nccc(-c2cc(NCCCN3C(=O)c4ccccc4C3=O)c3cc(OC)ccc3c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
To a slurry of 4-(4-amino-6-methoxynaphthalen-2-yl)-N-methylpyrimidin-2-amine (150 mg, 0.42 mmol) in 1,2-dichloromethane (10 ml) was added N,N-diisopropylethylamine (250 μl) followed by acetic acid (0.5 ml), 3-(1,3-dioxoisoindolin-2-yl)propanal (140 mg) and sodium triacetoxyborohydride (200 mg). The mixture was stirred at room temperature for 24 hours before being poured into ethyl acetate (100 ml) washed with water (250 ml) and dried over anhydrous magnesium sulfate. Evaporation to dryness gave a yellow oil which was purified by silica gel chromatography eluting with 40-60% ethyl acetate in hexanes to yield 2-(3-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)amino)propyl)isoindoline-1,3-dione 181 as a yellow foam (95 mg). 1H NMR (CDCl3) 400 MHz δ 8.34 (d, J=5.2 Hz, 1H), 7.87 (s, 1H), 7.86-7.83 (m, 3H), 7.8 (d, J=8.8 Hz, 1H), 7.75-7.71 (m, 2H), 7.34 (s, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.18 (dd, J=2.4 and 8.8 Hz, 1H), 7.08 (d, J=4.8 Hz, 1H), 5.24 (m, 1H), 4.9 (m, 1H), 4.04 (s, 3H), 3.9 (t, J=6.0 Hz 2H), 3.5 (t, J=6.0 Hz, 2H), 3.11 (d, J=5.2 Hz, 3H), 2.24 (m, 2H), 2.2-2.14 (m, 2H), LCMS m/e 468 (M+H)