Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=O)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:7]=1[I:16].Cl.C1N=C[N:21](C(N2C=NC=C2)=O)C=1.N>O.CO>[I:16][C:7]1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH3:15])=[CH:11][C:6]=1[C:5]([NH2:21])=[O:4]
Reactant: CCCOc1ccc(I)c(C(=O)OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCOc1ccc(I)c(C(N)=O)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
129 mL (258 mmol) 2N NaOH are added to 4.12 g (12.9 mmol) methyl-5-propoxy-2-iodobenzoate (XXVII.1) 60 mL MeOH. The mixture is stirred at 50° C. for 3 h. After that time, the mixture was acidified to pH 5 with 1N aq. HCl and extracted with EtOAc (2×). The combined organic layers are washed with water and brine, dried over sodium sulphate and the solvent is removed in vacuo. The crude product is taken up in 30 mL THF and 2.04 g (12.6 mmol) CDI are added. The mixture is stirred at rt for 1 h. Additional 0.5 eq CDI are added and stirring is continued for 20 min. 20 mL of 35% ammonia in water are added and the resulting mixture is stirred at rt for 5 min. The solvent was partly removed in vacuo until precipitation of a white solid. The product is filtered off and dried at 40° C. in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]2[NH+:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:20])[C:4]=2[CH:3]=1.[OH-].[K+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:20])[C:4]=2[CH:3]=1
Reactant: C[NH+]1C2=c3ccccc3=NC2=C(Cl)c2cc(F)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cn1c2c3ccccc3nc-2c(Cl)c2cc(F)ccc21
Yield: 96.6 %

Procedure:
To a suspension of the triflate salt obtained in Example 23 (2.34 g, 5.38 mmol) in chloroform (500 mL) was added aqueous 5% KOH. The chloroform layer was separated and the aqueous layer was extracted with chloroform (5×350 mL). The ensuing emulsion was separated from the aqueous layer. Anhydrous Na2CO3 was added to the emulsion until it obtained a paste-like consistency. The aqueous layer was repeatedly extracted with chloroform until the aqueous layer was no longer purple. The Na2CO3 paste was ground with a mortar and pestle and exhaustively extracted with chloroform. All chloroform extracts were combined, dried over anhydrous Na2CO3, filtered and concentrated. The resulting solid was resuspended in chloroform (800 mL), solid anhydrous Na2CO3 was added to the suspension (100 g), and the mixture was sonicated and then concentrated. The resulting solid was poured onto a basic alumina column, eluted sequentially with chloroform (1000 mL), EtOAc-chloroform (1:9, 1000 mL), EtOAc-chloroform (1.5:8.5, 1000 mL), EtOAc-chloroform (2.5:7.5, 1000 mL), and EtOAc-chloroform (3.5:6.5, 1000 mL) to remove the impurities. Elution with 4% methanol in chloroform afforded 1.48 g (96.7%) of the title compound as a purple solid.
Reaction SMILES: [Cl-].[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:28])[CH2:8][P+:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>O>[Cl:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH:8]=[P:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:28]
Reactant: O=C(CCCCCl)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCCCCl

Procedure:
A solution of 20 parts of (6-chloro-2-oxohexyl)-triphenylphosphonium chloride in 200 parts of water is made alkaline by the addition of a 50% aqueous sodium hydroxide solution and extracted with benzene. The combined organic extracts are dried over anhydrous sodium sulfate, then stripped of solvent under reduced pressure to afford (5-chloropentanoylmethylene)triphenylphosphorane. Alternatively, this may be used immediately as a solution in benzene.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C:5]([CH2:7][CH:8](C=C)[CH3:9])=[O:6])[CH3:3].[C:12](=[O:15])([O-])[O-:13].[K+].[K+].I([O-])(=O)(=O)=O.[K+].[Mn]([O-])(=O)(=O)=O.[K+].[K].[OH-].[K+]>O1CCOCC1.O>[CH3:9][CH:8]([CH2:7][C:5](=[O:6])[CH2:4][CH:2]([CH3:3])[CH3:1])[C:12]([OH:13])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: C=CC(C)CC(=O)CC(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)CC(=O)CC(C)C(=O)O
Temperature: 6 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a vigorously stirred solution of dihydrotagetone (4) (5 g, 33 mmole) in 1,4-dioxane-water (250 mL, 4:1) is added potassium carbonate (7 g,) followed by powdered potassium metaperiodate (15 g, 70 mmol) and then 0.25 g of powdered potassium permanganate. The remaining powdered potassium metaperiodate (35 g, 163.6 mmole) and potassium permnaganate (0.4-0.6 g) was added in small fractions within 30-40 minutes. The reaction mixture was left at room temperature for overnight and the solution, which was initially deep purple turned into light brown solution. The mixture was made alkaline with 10% potassium hydroxide and filtered and then residue was further washed with aqueous-dioxane mixture. The filtrate and washings were combined and the dioxane was evaporated under reduced pressure. The aqueous layer was extracted with ethylacetate (15 mLx 2) to remove unwanted impurities. The aqueous layer was cooled at 4-8° C. and acidified with dilute acid and then extracted with ethylacetate (3×25 mL). The ethylacetate layers were then combined and washed with saturated sodium bisulphate (to destroy the excess permanganate), sodium chloride (3×15 m), dried over anhydrous sodium sulphate and filtered. The solvent was removed to afford a crude liquid which was loaded on silica gel column and the column was eluted with an increasing amount of hexane/ethyl acetate (100:0 to 95:5). The fractions were monitored on TLC plate and the desired fractions were combined and solvent was removed under vacuum to afford 2,6-dimethyl-4-oxo-heptanoic acid in 68% yield as a viscous liquid; Rf=0.69 (toluene:ethylacetate:methanol:6.5:3.5:0.1 mL); IR (film) λmax 2958, 1709, 1465, 1376, 937 cm−1; 1H NMR δ10.53 (s, 1H, COOH), 3.03-2.94 (m, 1H, 2-CH), 2.91-2.82 (m, 1H, 6-CH), 2.50-2.06 (m, 4H, 3-CH2 and 5-CH2), 1.23-1.20 (d, 3H, 9-CH3), 0.99-0.97 and 0.92-0.90 (2d, 6H, 7-CH3 and 8-CH3) (FIG. 1); 13C NMR 208.66 (COOH, C-1), 181.94 (C═O, C-4), 51.71 (C-2), 45.89 (C-6), 34.39 (C-3), 24.54 (C-5), 22.39 (2×C-7 and C-8), 16.73 (C-9) (FIG. 2).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.CCOCC>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(=O)c5cccnc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 90 °C
Yield: 95.3 %

Procedure:
To 3α-hydroxy-5α-pregnan-20-one (464 mg, 318.5 g/m, 1.5 mmol) and 4-dimethylaminopyridine (DMAP, 195 mg, 122.17 g/m, 1.6 mmol) dissolved in 10 mL of dry pyridine was added nicotinoyl chloride hydrochloride (285 mg, 178.02 g/m, 1.6 mmol). The reaction mixture was heated at 90° C. for 5 hours and poured into 300 mL of ether. The organic layer was washed twice with saturated sodium bicarbonate, twice with water, dried over magnesium sulfate, and concentrated in vacuo to give the crude product. The crude material was filtered through a bed of silica gel using hexane/ethyl acetate (50:50) elution. The first two fractions gave the title compound (604 mg, 421 6/m, 1.43 mmol, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[CH:3]=1.[C:36]1([NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>[Cu]>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:42]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:7][C:6]=3[C:5]2([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:14]=1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(I)cc21
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reaction time: 6 h
Yield: 61 %

Procedure:
A mixture of 2-bromo-7-iodo-9,9-didecylfluorene (52.13 g, 0.08 mol), diphenylamine (15.6 g, 0.0922 mol, 1.152 eq), potassium carbonate (25.5 g, 0.1844 mol), tris(2-(2-methoxyethoxy)ethyl)amine (TDA-1, 5 mL), copper bronze (3.0 g, 0.05 g atom) and xylenes (75 mL) was brought to reflux, and 35 mL, of xylenes were distilled off to reach a reaction temperature of 160° C. The reaction was maintained at this temperature for 18 hours. Some more solvent was distilled off to reach a reaction temperature of 175° C., where the reaction was held for additional 6 hours. The mixture was then cooled, diluted with 100 mL toluene, filtered, the filtrate was concentrated, and the residue was transferred to a column of 600 g of silica gel. Elution with 750 mL hexanes returned a mixture of dibromo and bromoiodo fluorenes as an oil, 10.3 g Elution with heptane-toluene, 1:1, gave the product, 33.48 g (61 % yield, 77% yield on consumed bromoiodo fluorene), m.p. 66.8-69.2° C. Mass Spec: 691, 693 (M+).
Reaction SMILES: NN1CCCC1.[C:7]1([CH2:13][C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22]3[N:31]=[C:30]([N:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:17]2)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:7]1([CH2:13][C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22]3[N:31]=[C:30]([N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:17]2)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccccc4)C3)nc3ccccc23)CC1
Agent: NN1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Cc1ccccc1)N1CC[C@H](Nc2nc(N3CCNCC3)c3ccccc3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a mixture of t-butyl 4-(2-((S)-pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.15 g), pyridine (60 mg), and chloroform was added phenylacetic acid chloride (87 mg), and the mixture was stirred at room temperature for 16 h. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, the mixture was extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=2:1−ethyl acetate) to obtain t-butyl 4-(2-((S)-1-(2-phenylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.12 g). (2) To t-butyl 4-(2-((S)-1-(2-phenylethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.12 g) was added a mixed solution (7.5 mL) of chloroform and trifluoroacetic acid (10:1), and the mixture was stirred overnight at room temperature. To the reaction mixture was added 1 M aqueous sodium hydroxide, the mixture was extracted with chloroform, and the organic layer was dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, then the solvent was evaporated, and the residue was purified by preparative TLC to obtain title compound (69 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([O:30][CH3:31])=[C:4]([C@H:8]([CH3:29])[CH2:9][C@@:10]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH:11]=NC2C=CC=C3C=2C=CC(C)=N3)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.C([O-])(O)=[O:37].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([O:30][CH3:31])=[C:4]([C@@H:8]([CH3:29])[CH2:9][C@:10]([OH:24])([C:25]([F:26])([F:27])[F:28])[CH:11]=[O:37])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cccc2nc(C)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(F)cccc1[C@@H](C)C[C@@](O)(C=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
175 mg (0.60 mmol) of (2R*,4R*-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 103 mg (0.63 mmol) of 5-amino-2-methylquinoline and 0.3 ml of titanium tetraethoxide are stirred in 20 ml of toluene at 100° C. for 2 h. After the mixture is cooled, it is poured into water, with vigorous stirring to follow. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again using ethyl acetate. The extracts are dried over sodium sulphate and the solvent is removed in vacuo to give 230 mg of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol as a crude product. 230 mg of the crude imine in 12 ml of CH2Cl2 are admixed dropwise at −30° C. with 6 ml (6 mmol) of a 1 M boron tribromide solution. The batch is allowed to warm to room temperature and is stirred for 2 hours. It is admixed with saturated NaHCO3 solution, the phases are separated, the aqueous phase is extracted with CH2Cl2 and the combined organic phases are dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 145 mg of product.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH3:29][N:30]1[CH:35]2[CH2:36][CH2:37][CH:31]1[CH2:32][CH:33]([O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1)[CH2:34]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>ClCCCl.O1CCCC1.C(O)(=O)C>[CH2:1]([N:3]([CH2:43][C:42]1[CH:41]=[CH:40][C:39]([O:38][CH:33]2[CH2:34][CH:35]3[N:30]([CH3:29])[CH:31]([CH2:37][CH2:36]3)[CH2:32]2)=[CH:46][CH:45]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN1C2CCC1CC(Oc1ccc(C=O)cc1)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCN(Cc1ccc(OC2CC3CCC(C2)N3C)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a solution of pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (65 mg) and 4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)benzaldehyde (65 mg) in 1,2-dichloroethane (2 ml) were sequentially added acetic acid (0.07 ml) and sodium triacetoxyborohydride (120 mg) under a nitrogen atmosphere, and the solution was stirred overnight at room temperature. Tetrahydrofuran and aqueous ammonia were sequentially added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (58 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:22]=2)=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:22]=2)=[CH:15][C:14]=1[C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1noc2cc(Br)ccc12
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc2c(C)noc2c1
Yield: 36.9 %

Procedure:
A mixture of 6-bromo-3-methyl-1,2-benzisoxazole (11 mg), N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-1-yl-isonicotinamide (Intermediate 13, 15 mg) and aqueous sodium carbonate (0.5M, 0.25 ml) in anhydrous DME (1 ml) was degassed then stirred under nitrogen. A solution of tetrakis(triphenylphosphine)palladium(0) (2.5 mg) in DME (0.25 ml) was added and the mixture was stirred at 80° for 16 h. The solvent was removed under vacuum and the residue was partitioned between dichloromethane and water. The organic layer was separated using a hydrophobic filter, the solvent was evaporated and the residue was purified by column chromatography on silica, eluting with a cyclohexane-ethyl acetate gradient to give the title compound as an oil (5.6 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4ccc(Br)cc4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 4-bromobenzoyl chloride (66 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a free base.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]butanoate (D53) (40 mg) in THF (5 mL) was added aqueous NaOH (2 M, 2 mL). The reaction mixture was stirred at 60° C. overnight. The mixture was acidified with HCl (2 M) to pH 4-5, and then partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]butanoic acid (E32) (22 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 1.90 (2H, m), 2.28 (2H, t), 2.77 (2H, t), 4.89 (1H, m), 7.20 (1H, t), 7.26 (1H, d), 7.44 (1H, d), 7.80 (1H, d), 7.93 (1H, d), 8.20 (1H, dd), 8.37 (1H, d), 10.83 (1H, s), 12.05 (1H, br s). MS (ES): C23H22ClN3O4 requires 439; found 440.2 (M+H+).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]#[N:5].C(Cl)Cl.C(N(CC)CC)C.[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>O>[CH3:27][Si:28]([CH3:30])([CH3:29])[O:1][C@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]#[N:5]
Reactant: CCCCCCCCCCC[C@@H](O)CC#N
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCC[C@H](CC#N)O[Si](C)(C)C
Temperature: 0 °C
Yield: 100 %

Procedure:
5 g of (R)-3-hydroxy-tetradecanenitrile and 35 ml of methylene chloride were placed in a reactor and stirred. The mixture was cooled to 0° C., and 3.87 ml of triethylamine was added thereto, to which 3.38 ml of trimethylsilyl chloride was added over about 30 minutes, and stirred for about 1 hour. Subsequently, the resulting mixture was slowly heated to room temperature and stirred for about 1 hour, 50 ml of water was added thereto, and stirred vigorously for 5 minutes. The aqueous layer was removed. The organic layer was combined with 50 ml of water, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure, to give 6.66 g of the title compound (yield: 100%) as an oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)=[CH2:2].[Li]CCCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:22](=[O:24])[CH3:23])=[N:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)=[CH2:2]
Reactant: C=Cc1ccc(-n2cncn2)cc1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(-n2ncnc2C(C)=O)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy-N-methyl acetamide in THF (0.66 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×50 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (280 mg, 23%): mp 97-98° C.; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.68 (dd, 1H), 5.85 (d, 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMS m/z 214.14 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(F)c(C(=O)O)cc1F
Product: Cc1cc(F)c(C(=O)Cl)cc1F

Procedure:
250 ml of thionyl chloride are taken and 120 g of 2,5-difluoro-4-methyl-benzoic acid are introduced in portions at room temperature, with brisk evolution of gas. When the evolution of gas has subsided, the mixture is heated slowly to the reflux temperature and stirred until the evolution of gas has ended. The excess thionyl chloride is distilled off, the reaction product is coarsely distilled over and the distillate is fractionated on a small column. Yield: 97 g (72.9% of theory) of 2,5-difluoro-4-methylbenzoyl chloride of boiling point b.p.: 103°/20 mbar, nD20 : 1.5232.