Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13].[NH2:14][OH:15]>CO>[OH:15]/[N:14]=[C:12](\[NH2:13])/[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: NO
Reactant: N#CCCCCNc1ccccn1
Solvent: CO
Product: N/C(CCCCNc1ccccn1)=N\O
Temperature: 40 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
5-(Pyridin-2-ylamino)pentanenitrile (1.00 g; 5.71 mmoles) was dissolved in methanol (10 mL) and hydroxylamine (1.4 mL of a 50% aqueous solution; 22.83 mmoles) was added. The reaction mixture was stirred at 40° C. under nitrogen for 2 days. The solvent was removed under vacuum and the resulting oil was placed under vacuum at 40° C. for 6 hours. The product (1Z)-N′-hydroxy-5-(pyridin-2-ylamino)pentanimidamide (A) (1.16 g; 98%) was obtained as a pale yellow oil. 1H NMR (DMSO-d6) δ 8.68 (1H, s, br), 7.91-7.95 (1H, m), 7.29-7.35 (1H, m), 6.35-6.45 (3H, m), 5.25-5.35 (2H, s, br), 3.15-3.23 (2H, m), 1.97 (2H, t, J=7.5 Hz), 1.45-1.60 (4H, m).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[S:21][CH:22]=1)[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].[CH2:26]([O:28][CH2:29][CH2:30]O)[CH3:27].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([NH:17][C:18]1[CH:19]=[C:20]([C:23]([O:25][CH2:27][CH2:26][O:28][CH2:29][CH3:30])=[O:24])[S:21][CH:22]=1)[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: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1
Reactant: CCOCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)OCCOCC)c1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(hexadecylamino)-2-thiophenecarboxylic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 4-(hexadecylamino)-2-thiophenecarboxylate as a white solid.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(F)ccc1C
Reactant: Nc1ccc(Cl)cn1
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
Trimethylaluminium (2M in toluene) (0.556 mL, 1.11 mmol) was added dropwise to a stirred solution of 5-chloropyridin-2-amine (143 mg, 1.11 mmol) in toluene (10 mL), under nitrogen at 0° C. The resulting solution was allowed to stir at this temperature for a further 20 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AK4) (466 mg, 0.74 mmol) in toluene (5 mL) was added slowly to the mixture at 0° C. The reaction mixture was then heated to 100° C. and was stirred for 6 hours using the microwave. The reaction mixture was allowed to cool to ambient temperature, then evaporated to afford a gum. This was dissolved in EtOAc (75 mL), and washed sequentially with Rochelle's solution (20 mL), and water (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 30% EtOAc in isohexane to afford the product (390 mg, 72.6%). 1H NMR (400 MHz, DMSO) δ 0.88 (9H, s), 2.03 (3H, s), 3.82-3.67 (4H, m), 4.05 (1H, m), 4.15 (1H, m), 6.00 (1H, m), 7.45-7.31 (8H, m), 7.50 (1H, t), 7.60 (4H, m), 7.87 (1H, dd), 8.02 (1H, d), 8.40 (1H, d), 8.51 (1H, s), 8.56 (1H, s), 11.25 (1H, s); m/z (ES+) (M+H)+=725; HPLC tR=3.63 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].[OH-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O.C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trans-2-Aminocyclohexanecarboxylic acid (0.150 g, 1.05 mmol) is dissolved in 1.5 ml of water and NaOH (0.09 g, 2.25 mmol) in 1.5 ml of water is added at 0° C. 4-Chlorobenzene sulfonyl chloride (0.243 g, 1.15 mmol) in 1.5 ml of toluene is added. The reaction mixture is stirred at room temperature for 16 hours. The toluene layer is separated and the aqueous layer is washed twice with toluene. The toluene layers are discarded. Ethyl acetate is added to the aqueous layer (15 ml) and 2M HCl until pH<7. The two phases are separated and the aqueous layer is extracted with ethyl acetate (3×15 mL). The combined organic phases are washed with brine (20 ml), dried over MgSO4 and the ethyl acetate is removed under reduced pressure leaving a white solid that is dissolved in toluene (2×10 ml) and concentrated .The product is dried in vacuum.
Reaction SMILES: N#N.CC([O-])(C)C.[K+].[CH2:9]([OH:12])[CH2:10][OH:11].Cl[C:14]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]=[O:29])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2>O>[OH:11][CH2:10][CH2:9][O:12][C:14]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:28]=[O:29])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:19]2
Reactant: OCCO
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [K+]
Solvent: O
Product: O=Cc1c2ccccc2c(OCCO)c2ccccc12
Reaction time: 0.5 h

Procedure:
A 3 L 2-neck flask fitted with thermometer, condenser, stirring bar, N2 line and bubbler was charged with KOtBu (MCB, 25 g, 0.22 mol), 1,2-ethylene glycol (Fisher, 1.5 L) and 10-chloro-9-anthraldehyde (Aldrich, 50 g, 0.207 mol). The mixture was stirred at 100° for 1.5 h. An additional 5 g (45 mmol) of KOtBu was added and the stirring continued for an additional 0.5 h. The reaction mixture was cooled poured into cold H2O (1.5 L), then stirred for 10 min before the precipitate was collected by filtration. The yellow solid was dissolved in CH2Cl2 (1 L) and passed through a plug of SiO2 (100 g) using CH2Cl2 (9 L) as the eluting solvent. The CH2Cl2 contained impurities only and was discarded. The desired material was then eluted with EtOAc (12 L). The appropriate fractions were combined and the solvent removed to give (after drying at 50°) 28.82 g (53%), 10-(2-hydroxyethyloxy)-9-anthracenecarbaldehyde mp 142°-144°, (CH2Cl2 /hexane), (C, H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH:37]([NH2:40])([CH3:39])[CH3:38].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:40][CH:37]([CH3:39])[CH3:38])=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Reactant: CC(C)N
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NC(C)C)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and isopropylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 550.14 (M+H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH:7]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([NH:15][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCCCCCC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCCCCCC1
Temperature: -5 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
84 g of diketene were added over 30 minutes to a stirred mixture of 127 g of cyclooctylamine and 800 ml of tetrahydrofuran cooled to -5° C. and the mixture was stirred for 4 hours at 20° C. and then evaporated to dryness under reduced pressure to obtain 210 g of N-cyclooctyl-acetylacetamide melting at 44° C. 63 g of the said product and 1 g of p-toluene sulfonic acid were added to a mixture of 150 ml of methanol and 40 g of methyl orthoformate and after stirring the mixture for 16 hours, 1.5 ml of quinoline were added thereto. The mixture was distilled to dryness under reduced pressure and the residual oil was dissolved in toluene. The solution was heated at 145° C. for 4 hours while distilling off a methanol-toluene azeotrope. The mixture was distilled to dryness under reduced pressure and the oil residue was chromatographed over silica gel. An 8-2 methylene chloride-acetone mixture was used as the eluant and the product was empasted with isopropyl ether to obtain 45 g of N-cyclooctyl-3-methoxy-crotonamide melting at 116° C.
Reaction SMILES: [F:1][C:2]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:35][CH:34]([O:36][CH3:37])[CH2:33]4)=[N:30][CH:31]=3)[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CCO>[F:1][C:2]1[C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[N:28][C:29]([N:32]4[CH2:33][CH:34]([O:36][CH3:37])[CH2:35]4)=[N:30][CH:31]=3)[CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][NH2:5]
Reactant: COC1CN(c2ncc(N3CCN(c4cccc(CN5C(=O)c6ccccc6C5=O)c4F)CC3)cn2)C1
Agent: NN
Solvent: O
Solvent: CCO
Product: COC1CN(c2ncc(N3CCN(c4cccc(CN)c4F)CC3)cn2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
2-(2-Fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl)-1H-isoindole-1,3(2H)-dione (135 mg) was suspended in EtOH (3 ml), and hydrazine hydrate (67 mg) was added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (28% aqueous ammonia/MeOH/CHCl3) to obtain 1-(2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}phenyl)methan amine (100 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:13]=1)=[O:11].C(N(CC)CC)C.[C:35](Cl)(=[O:38])[O:36][CH3:37]>C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]([C:12]1[C:21](=[O:22])[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C@H:23]2[CH2:27][CH2:26][N:25]([C:35]([O:36][CH3:37])=[O:38])[CH2:24]2)[CH:13]=1)=[O:11]
Reactant: O=C(Nc1c(Cl)cccc1Cl)c1cn([C@H]2CCNC2)c2ncccc2c1=O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](n2cc(C(=O)Nc3c(Cl)cccc3Cl)c(=O)c3cccnc32)C1
Reaction time: 0.67 h
Yield: 67 %

Procedure:
Then, to a 4 ml anhydrous methylene chloride solution of (S)-N-(2,6-dichlorophenyl)-1-(3-pyrrolidyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, 28 μl (0.20 mmol) of triethylamine and 12.4 μl (0.16 mmol) of methyl chlorocarbonate were added at room temperature and stirred for 40 minutes. The reaction solution was concentrated under vacuum and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=1/2) to obtain 55 mg (67%) of the above-identified compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1N2CN3CN(C2)CN1C3.[C:21](O)(=[O:23])C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:21]=[O:23]
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C

Procedure:
To a solution of 5-chloro-7-azaindole (0.50 g, 3.3 mmol) in acetic acid (5.0 mL), hexamethylenetetramine (0.69 g, 4.9 mmol) was added at ambient temperature. The mixture was refluxed for 8 h. Cooled to ambient temperature, the reaction mixture was diluted with water, extracted with ethyl acetate for 2 times. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 5-chloro-7-azaindole-3-carboxaldehyde as solid (0.13 g, y. 22%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:13]=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:18]([O-:20])=[O:19].[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:13]=[C:12]([S:14](=[O:16])(=[O:15])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:22])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)cc(C(=O)OC)c1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCNC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1cc(C(=O)OC)c([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Solid dimethyl-2-nitro-5-chlorosulfonylisophthalate (2.78 g.) is added in portions to a stirred solution of 2.5 g. of N-methyloctadecylamine and 1.0 g. of triethylamine in 50 ml. of tetrahydrofuran. After the addition the reaction is stirred at room temperature for 30 min. The precipitated amine hydrochloride is removed by filtration and the filtrate concentrated under reduced pressure. The residue is recrystallized from acetonitrile, giving 2.7 g. of product, m.p. 70°-72° C. Additional material is obtained by concentration of the mother liquor.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2=[CH:12][CH:13]=[CH:14][C:15]3[C:16]([CH3:22])([CH3:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:7]5[C:8]=4[N:9]([C:10]=32)[C:4]2[C:5](=[CH:25][CH:26]=[CH:27][C:3]1=2)[C:6]5([CH3:24])[CH3:23].[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:29][C:19]1[CH:20]=[C:7]2[C:6]([CH3:24])([CH3:23])[C:5]3[CH:25]=[CH:26][CH:27]=[C:3]4[C:2]([CH3:28])([CH3:1])[C:11]5[C:10]6[N:9]([C:4]=34)[C:8]2=[C:17]([C:16]([CH3:21])([CH3:22])[C:15]=6[CH:14]=[CH:13][CH:12]=5)[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2cccc3c2N2c4c1cccc4C(C)(C)c1cccc(c12)C3(C)C
Solvent: ClC(Cl)Cl
Product: CC1(C)c2cccc3c2N2c4c1cccc4C(C)(C)c1cc(Br)cc(c12)C3(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of 4,4,8,8,12,12-hexamethyl-8,12-dihydro-4H-benzo[1,9]quinolizino[3,4,5,6,7-defg]acridine (5 g, 13.68 mmol) in CHCl3 (133 mL) at 0° C. was added N-bromosuccinimide (2.44 g, 13.68 mmol) over a period of 20 min. While warming up to room temperature, the resulting solution was stirred in the absence of light overnight. The reaction was quenched with a saturated aqueous solution of Na2S2O3. The resulting mixture was extracted with CH2Cl2 (3×) and the combined organic fractions were dried with MgSO4. After filtration and evaporation of the solvent, the residue was subjected to column chromatography (silica, n-hexane/CH2Cl2 4:1). Final recrystallization from ethanol yielded 2-bromo-4,4,8,8,12,12-hexamethyl-8,12-dihydro-4H-benzo[1,9]quinolizino[3,4,5,6,7-defg]acridine as a white powder (5.6 g, 92%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39]>CN(C=O)C.O>[F:31][C:29]1[CH:28]=[C:27]([F:32])[CH:26]=[C:25]2[C:30]=1[C:21]([O:13][C:9]1[CH:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=[N:11][CH:10]=1)=[C:22]([CH3:39])[C:23]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)=[N:24]2
Reactant: Oc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Oc1cncc(N2CCOCC2)c1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a vial containing 5-morpholinopyridin-3-ol (67.3 mg, 0.37 mmol) in DMF (3 mL) was added cesium carbonate (0.26 g, 0.8 mmol) in portions. The mixture was stirred at 23° C. for 15 minutes, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (90.7 mg, 0.31 mmol) was added in portions. Upon complete addition, the mixture was warmed to 100° C. After 18 h, the reaction mixture was diluted with water then subsequently extracted five times with EtOAc. The organic extractions were then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:methanol:ammonium hydroxide in DCM) to afford light yellow film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution.) The desired fractions were concd then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 4-(5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yloxy)pyridin-3-yl)morpholine. 1H NMR (500 MHz, CDCl3) δ ppm 8.74 (1H, d, J=4.6 Hz), 8.12 (1H, d, J=2.4 Hz), 7.98 (2H, m), 7.68 (1H, dd, J=9.4, 1.3 Hz), 7.59 (1H, d, J=2.2 Hz), 7.43 (1H, sxt, J=4.4 Hz), 7.02 (1H, ddd, J=11.4, 8.9, 2.4 Hz), 6.87 (1H, s), 3.93 (4H, m), 3.29 (4H, m), 2.41 (3H, s). Mass Spectrum (pos.) m/e: 435.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:38])[CH2:20][NH:21][C:22](=[O:37])[NH:23][C:24]1[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=1)[O:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(OCC(=O)O)c1
Yield: 40 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 3.7 g of ethyl (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenoxyacetate in solution in 80 cm3 of methanol and 0.4 g of potassium hydroxide dissolved in 40 cm3 of water. After treatment and recrystallization in isopropyl acetate, 1.4 g of (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenoxyacetic acid, melting at 192° C., are obtained.
Reaction SMILES: [C:1]([O:7][C@@H:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2]C(C)=O.C(N(CC)CC)C.S([N:34]=[N+:35]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C(#N)C>[N+:34](=[CH:2][C:1]([O:7][C@@H:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])=[O:6])=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)O[C@H](C=C(C)C)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)=C[C@@H](OC(=O)C=[N+]=[N-])C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.2 %

Procedure:
To a solution of (1R)-3-methyl-1-trichloromethyl-2-butenyl acetoacetate (1.63 g., 5.68 mmole) from Example IA.2.(a) and triethylamine (0.57 g, 5.68 mmole) in 10 ml of acetonitrile was added dropwise in small portions at 7-10 minute intervals over a total period of 30 minutes a solution of tosyl azide (1.12 g, 5.68 mmole) in 2 ml of acetonitrile. After stirring at room temperature for 21/4 hours, the mixture was poured into 17 ml of aqueous 1N NaOH. After stirring an additional 45 minutes, the mixture was extracted three times with ether, and the combined ethereal extracts were dried over MgSO4. The dried solution was concentrated to give an orange oil. The oil was chromatographed on 8 (20×20 cm) preparative tlc plates (silica gel) with CH2Cl2 as eluent to afford (1R)-3-methyl-1-trichloromethyl-2-butenyl diazoacetate (0.96 g, 62% isolated yield) as a yellow oil; [α]D31 =+59° (hexane).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.[CH:10]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11]1>O1CCOCC1.C(#N)C>[CH:10]1([NH:13][C:14]([N:6]2[CH2:7][CH2:8][C:9]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:5]2)=[O:15])[CH2:12][CH2:11]1
Reactant: c1nc2c([nH]1)CCNC2
Reactant: O=C=NC1CC1
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C(NC1CC1)N1CCc2[nH]cnc2C1
Yield: 34.3 %

Procedure:
A solution of 3.69 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 7.47 g of cyclopropyl isocyanate in 20 ml of dry dioxane is refluxed for 1.5 h. After evaporation to dryness, the residue is dissolved in 44 ml of methanol and treated with 11 ml of 2N sodium hydroxide for 1.5 h at room temperature. After neutralization, the solution is extracted with chloroform. Evaporation of the solvent leaves a residue that is taken up in acetonitrile to give 2.12 g of the title compound, m.p. 215°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:25])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=1)([OH:16])[C:12]([F:14])([F:15])[F:13]
Reactant: COc1ccc(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c(Cl)c1
Agent: BrB(Br)Br
Product: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F

Procedure:
In analogy to Example 147, step 5, 5-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one was reacted with BBr3 to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=360.0 [M−H+].