Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH3:14].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C1COCC1>[Si:29]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:17]([CH3:19])([CH3:18])[C:16]([O:15][CH2:13][CH3:14])=[O:20])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCCCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (32.8 mL) was added to a solution of diisopropylamine (1M in toluene, 11.64 mL) in THF (60 mL) at 0° C. to 5° C. over 15 minutes, and this mixture was stirred for 30 minutes. The reaction mixture was cooled to −78° C. then isobutyric acid ethyl ester (10 mL) was added dropwise over 15 minutes. The mixture was stirred at −78° C. for 1 hour, then (6-bromohexyloxy)-tert-butyldimethylsilane (23 mL) was added dropwise and the reaction mixture was stirred at −78° C. for a further 60 minutes. The cooling bath was removed and the mixture stirred at room temperature overnight before being poured onto a saturated aqueous solution of ammonium chloride (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with water (250 mL), dried over magnesium sulfate, filtered and evaporated to give the crude product. Purification was by silica gel chromatography eluting with 0-40% ethyl acetate in cyclohexane to afford the subtitled compound as a pale amber liquid. Yield 20 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].S([O-])(=O)(=O)C.[C:33]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.C(O)C.O.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:42]2[CH2:43][CH2:44][CH:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:40][CH2:41]2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(CN2CCC(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5.0 g (21.07 mM) of 4-[N-(tert-butoxycarbonyl)aminomethyl]-1-phenylmethanol and 5.9 ml (42.33 mM) of triethylamine in THF (42 ml) was added 2.5 ml (32.3 mM) of methanesulfonyl chloride at 0° C. and the mixture was stirred at the prevailing temperature for one hour. The reaction was then stopped by adding saturated aqueous solution of sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 6.72 g (21.07 mM) of crude product as light-brown solid. To a solution of 6.72 g (21.07 mM) of this crude mesylate in ethanol (42 ml) was added 5.9 ml (42.33 mM) of triethylamine as well as 3.40 g (21.09 mM) of 4-phenylpiperidine and the mixture was refluxed for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After concentration, the crude product was purified by column chromatography (ethyl acetate-hexane: 50%) to provide the title compound as light-yellow solid.
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)C=CC=CC=1.N[CH2:29]CCNC1C(C)=CC=CN=1>>[NH2:17][CH2:16][CH2:15][CH2:14][N:7]([C:8]1[CH:13]=[C:12]([CH3:29])[CH:11]=[CH:10][N:9]=1)[CH3:1]
Reactant: Cc1cccnc1NCCCN
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ccccn1
Product: Cc1ccnc(N(C)CCCN)c1

Procedure:
Substituting 2-bromo-4-methylpyridine (25.8 g) for 2-bromo-3-methylpyridine and using the corresponding molar proportions of the other reagents in the method of Example 36(i) gave 2-(3-aminopropylamino)-4-methylpyridine (16.1 g), bp 120°-24° C.; 0.01-0.02 mm Hg. (ii) Substituting 2-(3-aminopropylamino)-4-methylpyridine (7.5 g) for 2-(3-aminopropylamino)-3-methylpyridine and using corresponding molar proportions of the other reagents in the method of Example 36(ii) gave 2-[N-(3-aminopropyl)-N-methylamino]-4-methylpyridine (3.53 g) as an oil. (iii) Substituting 2-[N-(3-aminopropyl)-N-methylamino]-4-methylpyridine (1.0 g) for 2-[N-(3-aminopropyl)-N-methyl amino]-3-methylpyridine and using corresponding molar proportions of the other reagents in method of Example 36(iii) gave 2-[3-[N-methyl-N-(4-methylpyrid-2-yl)amino] propylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 1H2O, 0.56 g (26%) mp indeterminate (from ethanol/water).
Reaction SMILES: S([CH2:11][N+:12]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[CH2:14]([CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O)[CH2:15][CH2:16][CH2:17][CH3:18].C(O[K])(C)(C)C.O>COCCOC.C(O)C>[CH2:14]([CH:19]1[CH2:23][CH2:22][CH2:21][CH:20]1[C:11]#[N:12])[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC1CCCC1=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[K]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CCCCCC1CCCC1C#N
Temperature: 0 °C
Yield: 58.7 %

Procedure:
27.6 g of tosylmethyl isocyanide and 17 g of 2-pentylcyclopentanone were dissolved in 400 ml of 1,2-dimethoxyethane and 10 ml of ethanol. The solution was cooled to 0° C. with an ice-bath, and 29 g of tBuOK were added in 1 hour maintaining the temperature between 0 and 10° C. After completion of the reaction, the reaction mixture was poured into water and extracted with cyclohexane. The organic layer was washed 3 times with water until neutral pH. Purification by bulb-to-bulb distillation (130° C./0.06 mbar) gave 10.7 g of the pure 2-pentylcyclopentanecarbonitrile.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH3:24])=[CH:16][CH:15]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[K+]>C1COCC1>[CH3:25][C@@H:22]([CH2:23][CH3:24])[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:4]([NH2:3])[CH2:5][N:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[CH:15][CH:16]=1
Reactant: CC[C@H](C)COc1ccc([C@@H](N)C(=O)N2CCN(C)CC2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC[C@H](C)COc1ccc([C@@H](N)CN2CCN(C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To 200 mg (0.49 mmol) of (R)-2-Amino-2-[4-((S)-2-methyl-butoxy)-phenyl]-1-(4-methyl-piperazin-1-yl)-ethanone di-HCl salt in 10 mL of THF was added 5.9 mL LAH (1.0 M solution, 4.9 mmol). The resulting mixture was refluxed overnight. On the next day it was cooled to 0° C. and 0.5 mL of concentrated aq. KOH was slowly added. The ice bath was removed, and allowed it to stir for 1 hr, and then diluted with EtOAc, dried over MgSO4, filter and concentrated to obtain 68 mg (44%) of the product. The product obtained was pure enough to be used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH2:29])([CH3:20])[C@@H:18]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:66])([C:56]([F:65])([F:64])[C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[CH2:40][CH2:41][CH:42]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C=C)[C:43]([O:45][CH2:46][CH3:47])=[O:44]>ClCCl.C(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)(P(C1CCCCC1)(C1CCCCC1)C1CCCCC1)C1C=CC=CC=1.Cl[Ru]Cl>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27][CH:28]=[CH:29][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH:42]([CH2:41][CH2:40][C:39]([F:38])([F:66])[C:56]([F:64])([F:65])[C:57]([F:62])([F:63])[C:58]([F:59])([F:61])[F:60])[C:43]([O:45][CH2:46][CH3:47])=[O:44])([CH3:20])[C@@H:18]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1
Reactant: C=CCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCCC=CCC1=C2c3ccc(OCc4ccccc4)cc3CC[C@H]2[C@@H]2CC[C@H](OCc3ccccc3)[C@@]2(C)C1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 47.6 %

Procedure:
Benzylidenebis(tricyclohexylphosphine)-dichlororuthenium (90 mg, 0.1 mmol) was added to a solution of 3,17β-bis(benzyloxy)-11-(2-propenyl)estra-1,3,5(10), 9(11)-tetraene (1.0 g, 2.0 mmol) and ethyl 2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-decenoate (1.81 g, 4.1 mmol) in dichloromethane (20 ml), followed by heating under reflux for 5 hours under nitrogen atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel flash chromatography (eluent: hexane/ethyl acetate=4/1) to give ethyl 11-[3,17β-bis(benzyloxy)estra-1,3,5(10), 9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoate (863 mg, Yield 48%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:17](O)(=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]1[O:1][C:2]([C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[N:3][CH:4]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)c1ncc(-c2ccccn2)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.9 %

Procedure:
(184) A solution of 2-(oxazol-5-yl)pyridine (97 mg, 0.66 mmol) in anhydrous THF (5 mL) cooled to −75° C. under N2 was treated with n-BuLi (2.5 M in hexanes, 1.1 equiv, 0.73 mmol, 0.29 mL), and stirred for 20 min. ZnCl2 (0.5 M in THF, 2.0 equiv, 1.32 mmol, 2.7 mL) was added at −75° C., and stirred for 45 min at 0° C. Cul (1.0 equiv, 0.66 mmol, 126 mg) was added, and the solution was stirred for 10 min at 0° C. A separate flask was charged with myristic acid (2 equiv, 1.32 mmol, 303 mg) in anhydrous CH2Cl2 (4.2 mL), and to this solution cooled to 0° C. under N2 was added oxalyl chloride (5 equiv, 6.6 mmol, 0.84 g, 0.58 mL). After stirring at rt for 2 h, the solution was concentrated under reduced pressure and dissolved in anhydrous THF (1.5 mL). The solution of myristoyl chloride was added and the solution was stirred for 1 h at 0° C. The reaction was diluted with EtOAc (10 mL), and washed with 15% aqueous NH4OH (1×10 mL), H2O (1×10 mL), and saturated aqueous NaCl (1×10 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5 cm×17.5 cm, 20% EtOAc-hexanes) afforded 1-(5-(pyridin-2-yl)oxazol-2-yl)tetradecan-1-one (184) (102 mg, 0.29 mmol, 44% yield) as a white powder: mp 79-80° C.; 1H NMR (CDCl3, 250 MHz) d 8.65 (br d, J=4.8 Hz,1H), 7.89-7.75 (m, 3H), 7.34-7.25 (m,1H), 3.10 (t, J =7.3 Hz, 2H), 1.80-1.70 (m, 2H), 1.43-1.18 (m, 20H), 0.86 (br t, J=6.6 Hz, 3H); 13C NMR (CDCl3, 62.5 MHz) d 188.6, 157.4, 153.2, 150.1 (2C), 146.4, 137.1, 126.8, 124.1, 120.3, 39.1, 31.9, 29.6 (2C), 29.6, 29.4, 29.3 (2C), 29.2, 24.0, 22.7, 14.1; IR (KBr) umax 2960, 2878, 1705, 1598, 1426, 1387 cm31 1; MALDI-FTMS (DHB) m/z 357.2536 (C22H32N2O2+H+ requires 357.2536).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:35][C:32]2[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: COc1ccc(N)cn1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: COc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)cn1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 6-methoxypyridin-3-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(6-methoxypyridin-3-yl)terephthalamide. MS (Q1) 493 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([CH2:15][C:16](=O)[CH3:17])[C:12]([CH3:14])=O>C1(C)C=CC=CC=1>[CH3:17][C:16]1[N:1]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[C:12]([CH3:14])=[CH:11][CH:15]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ccc2[nH]ccc2c1
Yield: 72.3 %

Procedure:
A mixture of 5-aminoindole (1.32 g, 10.0 mmol), acetonylacetone (4.0 mL, 34 mmol, 3.4 eq) and toluene (25 mL) was heated at reflux under nitrogen using a Dean-Stark trap for 24 hours. The reaction was cooled and then poured through a silica gel (approximately 200 g) filter followed by 10% ether in hexanes to afford the title compound (1.52 g, 72%) as an off-white, crystalline solid: Rf =0.75 in diethyl ether; 13C NMR (CDCl3) δ135.0, 131.4, 129.5, 128.1, 125.6, 122.4, 120.3, 111.3, 105.0, 103.0, 13.2. Anal. calcd for C14H14N2 ; C, 79.97; H, 6.71; N, 13.32. Found: C, 79.72; H, 6.75; N, 13.13.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][O:11][C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][N:23]([CH3:27])[C:24](Cl)=[O:25].N1C=CC=CC=1.[Cl-].[NH+]1C=CC=CC=1>O.C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([NH:16][C:24](=[O:25])[N:23]([O:22][CH3:21])[CH3:27])=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)Cl
Reactant: CC(C)(C)c1ccc(CCOc2ccc(N)cc2)cc1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc(C(C)(C)C)cc2)cc1
Yield: 26.1 %

Procedure:
A mixture of 26.9 g of 4-(4-tert-butylphenethyloxy)aniline, 13 g of N-methoxy-N-methylcarbamyl chloride, 10 ml of pyridine and 300 ml of toluene is heated under reflux for 7 hours. Thereafter, water is added to dissolve pyridinium chloride, and the separated toluene layer is washed with dilute hydrochloric acid, thoroughly washed with water and dried over anhydrous sodium sulfate. The solvent is then removed under reduced pressure, and the crude crystals obtained are repeatedly recrystallized from ethanol to obtain 9.3 g of N'-[4-(4-tert-butylphenethyloxy)phenyl]-N-methoxy-N-methylurea as white needles, M.P. 14°-15° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:7]([CH2:8][CH2:9][C:10]3[C@@H:23]2[CH2:22][C@H:21]([O:28][C:29](=[O:35])[C:30]([CH3:34])([CH3:33])[CH2:31][CH3:32])[C@@:20]2([CH3:36])[C:11]=3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:19])[CH2:16][CH:17]=[CH2:18])[CH2:6]1)(=[O:3])[CH3:2].C(O)(C)(C)C.[OH2:42].[OH2:43].C[N+]1([O-])CCOCC1>C(OCC)(=O)C.CCOCC.[Os](=O)(=O)(=O)=O>[C:1]([O:4][C@@H:5]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:7]([CH2:8][CH2:9][C:10]3[C@@H:23]2[CH2:22][C@H:21]([O:28][C:29](=[O:35])[C:30]([CH3:34])([CH3:33])[CH2:31][CH3:32])[C@@:20]2([CH3:36])[C:11]=3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:19])[CH2:16][CH:17]([OH:43])[CH2:18][OH:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CC[C@@H](C)[C@H]1CCC2=C3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(=O)C(C)(C)CC)[C@@]21C
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CCC(C)(C)C(=O)O[C@H]1C[C@H]2C(=C3CC[C@H]([C@H](C)CC(O)CO)[C@]31C)CC[C@@H]1C[C@H](OC(C)=O)CC[C@@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3α-acetoxy-12α-(2,2-dimethyl)butyryloxy-5β-chola-8(14),23-diene (2.5 g), osmium tetroxide (0.092 g), tert-butyl alcohol (8 ml), and water (2.3 ml) is added 4-methylmorpholine-N-oxide hydrate (0.334 g). The mixture is stirred for about 2 hours at room temperature, diluted with 20% ethyl acetate in ether and washed with aqueous sodium bisulfite. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product which is used, without further treatment, for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cccc(CC(=O)OC)c1
Yield: 79.6 %

Procedure:
A mixture of 1.0 g (6 mmol) of 3-hydroxyphenylacetic acid methyl ester, 2.2 g (6.6 mmol) of 1-bromooctadecane and 3.7 g (27 mmol) of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 15 ml of DMF was stirred at reflux for 67 hours. The solvent was removed at reduced pressure, water was added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was purified by chromatography on 150 g of silica gel using 10% ethyl acetate-hexane to give 2.0 g (80% yield, mp 43°-45°) of 3-(octadecyloxy) phenylacetic acid methyl ester. The mass and nmr spectra were consistent with the structure.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[CH2:7](O)[CH2:8][CH2:9][OH:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.O.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: O=CCCCBr
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: BrCCCC1OCCCO1

Procedure:
To a solution of 4-bromobutanal (prepared as described in J. Org. Chem., 1979, 44, 3230-3238: 450 mg, 2.98 mmol) in tetrahydrofuran (10 mL) at room temperature was added 1,3-propane diol (1.0 mL, 13.7 mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.26 mmol). The mixture was heated at reflux for 2 hours, cooled and suspended in a mixture of water and diethyl ether (200 mL of 1:1). The two layers were separated and the organic layer was dried over magnesium sulfate, filtered, and then concentrated in vacuo to give the title compound as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](N)[CH:7]=[CH:6][C:5]=1[Cl:11].N([O-])=[O:14].[Na+].N(O)=O.NC(N)=O>O.OS(O)(=O)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:14])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: O=NO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cc(O)ccc1Cl
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
Compound of example 156 (9 g, 48.5 mmol) was subjected to diazotization using NaNO2 (4.5 g 48.5 mmol) in water (50 mL) and H2SO4 (10%, 100 mL). Excess nitrous acid was neutralized with urea. The reaction mixture was poured into a suspension of CuSO4.5H2O (144 g, 577 mmol) and Cu2O (5.22 g, 41.4 mmol) in water (900 mL) at 0° C. The reaction mixture was stirred for 15 min. at 0-5° C. and was then extracted using diethyl ether (3×200 mL). The organic extract was washed, dried (anhydrous Na2SO4), concentrated and purified using a silica gel column and 10% EtOAc in petroleum ether (60-80° C.) as eluant to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2].Cl.[F:12][CH2:13][CH2:14][NH2:15].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C.O>[C:1]([C:3]1[C:8]([NH:15][CH2:14][CH2:13][F:12])=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc(F)cc1F
Reactant: NCCF
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ncc(F)cc1NCCF
Temperature: 115 °C
Yield: 19.1 %

Procedure:
500 mg of 2-cyano-3,5-difluoropyridine, 426 mg of 2-fluoroethylamine hydrochloride, 987 mg of potassium carbonate and 433 mg of triethylamine in 10 ml of dimethyl sulphoxide are introduced into a 20 ml microwave tube reactor. The mixture is then heated in the microwave for 1 and a half hours at 115° C. The reaction medium is run into 100 ml of water and 100 ml of ethyl acetate. The aqueous phase is re-extracted twice with 50 ml with ethyl acetate. The combined organic phases are washed with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. After purification by flash chromatography on 70 g of silica gel, elution being carried out with a mixture of ethyl acetate and cyclohexane (30/70 by volume), and the first eluted product being recovered, 125 mg of 2-cyano-5-fluoro-3-(2-fluoroethylamino)pyridine are thus obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: Br[CH2:2][C:3](=O)[CH3:4].[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[N:12][CH:13]=1)#[N:7]>S1(CCCC1)(=O)=O.CCOC(C)=O>[CH3:4][C:3]1[CH:14]=[C:11]2[N:12]([CH:2]=1)[CH:13]=[C:8]([C:6]#[N:7])[CH:9]=[CH:10]2
Reactant: Cc1ccc(C#N)cn1
Reactant: CC(=O)CBr
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Product: Cc1cc2ccc(C#N)cn2c1
Temperature: 45 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
1-Bromo-propan-2-one (2.26 ml) is added under an atmosphere of argon to a solution of 5-cyano-2-methylpyridine (5.0 g, 41.9 mmol) in sulfolane (30 ml). The reaction mixture is stirred for 48 hours at 45° C., then diluted with EtOAc. The precipitated salt is filtered off and dissolved in water (50 ml). The aqueous solution is washed with EtOAc, then a 10% aqueous solution of NaHCO3 (30 ml) is added, and the mixture is heated to reflux for 1 hour. After cooling, the reaction mixture is filtered, and the filtrate is extracted three times with EtOAc. The combined organic layers are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified via flash chromatography (hexane/EtOAc 8:1, +0.2% NEt3) to afford the title compound (5.50 g, 84%). 1H NMR (400 MHz, d6-DMSO): δ=9.10-9.09 (m, 1H), 7.59 (s, 1H), 7.55 (d, J=9.0 Hz, 1H), 6.90 (dd, J=9.3/1.7 Hz, 1H), 6.55 (s, 1H), 2.39 (s, 3H). MS (ES+): 157 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([O:8]C)[O:4]1.C(O)(C)C.[C:14]1([CH3:24])[CH:19]=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([O:8][CH:14]([CH3:19])[CH3:24])[O:4]1
Reactant: CO[C@@H]1OC[C@@H](CBr)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: c1ccccc1
Product: CC(C)O[C@@H]1OC[C@@H](CBr)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of cis and trans 4-(bromomethyl)-2-methoxy-1,3-dioxolane (example 1) (5.37 g, 27.3 mmol) in benzene (100 mL) was added isopropanol (2.2 mL, 28.6 mmol, 1.05 eq.) and p-toluenesulfonic acid (pTSA, few crystals). The mixture was stirred for 24 hr at 88°-90° C. followed by addition of isopropanol (0.5 mL, 0.24 eq.). The mixture was stirred for further 24 hr at 90° C., cooled to room temperature and benzene was removed under reduced pressure. The crude material was obtained in quantitative yield consisting of a mixture of isopropoxy and methoxy orthoesters in a 9:1 ratio respectively. The ratio of cis and trans isomers was about 1:1. 1H NMR (300 MHz, CDCl3) δ: 1.21 (d, 6H, CH(CH3)2), 3.45 (m, 2H, CH2Br), 3.65 (m, 1H, CH(CH3)2), 3.92 (m, 1H, H-5a), 4.21 (m, 1H, H-5b), 4.42 and 4.55 (2m, 1H, H-4), 5.95 and 5.96 (2s, 1H, H-2).