Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]#[C:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:14]#[C:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC#CC(CC(=O)OC)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 908 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with 30 mL of acetonitrile. To the stirred solvent were added methyl 3-(4-hydroxyphenyl)hex-4-ynoate (3.8 g, 17.4 mmol), potassium carbonate (7.2 g, 52.2 mmol). The reaction mixture was brought to 0° C., was added benzyl bromide (4.47 g, 1.5 mmol) in acetonitrile (20 mL) drop wise and stirred at room temperature for 16 h. The reaction mixture was concentrated to distill off the solvent. Water (20 mL) was added and extracted with ethyl acetate (60 mL). The organic layer was washed with water (20 mL) and saturated brine solution (20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The crude material was purified by silica gel column chromatography using ethyl acetate and petroleum ether as elutants to obtain product (4.2 g, yield: 78.35%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[CH3:16]O.Cl>>[OH:1][C:2]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([O:10][CH3:16])=[O:9])=[O:5]
Reactant: CO
Reactant: Cc1ccc(C(=O)CCC(=O)O)c(O)c1
Agent: Cl
Product: COC(=O)CCC(=O)c1ccc(C)cc1O

Procedure:
3-(2-Hydroxy-4-methylbenzoyl)propionic acid was esterified with methanol-hydrogen chloride, in a similar manner to the procedure described in Example 1(i), to give methyl 3-(2-hydroxy-4-methylbenzoyl)propionate, m.p. 61°-63°.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([CH2:23][CH:24](C(OCC)=O)[C:25]([O:27][C:28](C)(C)[CH3:29])=[O:26])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:19]=2)[CH2:7][C:6]([OH:37])=[O:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)C(Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.4 %

Procedure:
A solution of 1-tert-butyl 3-ethyl 2-({5-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-1,2,4-oxadiazol-3-yl}methyl)malonate (Preparation 93) (510 mg, 0.79 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (5 ml) and stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene. The solid was dissolved in xylene (10 ml) and heated at 140° C. for 7 hours. The solvent was removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 95:5:0 (dichloromethane:isopropyl alcohol:acetic acid) gradually changing to 90:10:1 (dichloromethane:isopropyl alcohol:acetic acid) to afford the title compound as a colourless oil (117 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[C:16]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[CH:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2ccnc(N3CCNCC3)c2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCN(c2cc(-c3ccccc3)ccn2)CC1
Yield: 46.1 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (113 mg, 0.418 mmol), 1-(4-phenylpyridin-2-yl)piperazine (75.0 mg, 0.313 mmol), diisopropylethylamine (0.146 ml, 0.836 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 3 hours, then the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduce pressure, and the residue was recrystallized from ethyl acetate to give the titled compound 52.0 mg (46.0%) as solid product.
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C[CH:35](I)[CH:36]([CH3:38])[CH3:37].C(OCC)(=O)C>CN(C=O)C>[CH2:35]([N:15]1[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:18])[N:13]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])[C:14]1=[O:31])[CH:36]([CH3:38])[CH3:37]
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Reactant: CC(C)C(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (51 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, methylisobutyl iodide (23 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 20 mg of white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:34][CH2:35][CH2:36][OH:37]
Reactant: Cc1cc(O)cc(OCc2ccccc2C(F)(F)F)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OCc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of 5-methyl-3-(2-trifluoromethylbenzyloxy)phenol (1.41 g, 5.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.62 g, 8.0 mmol) and 1,3-propanediol (1.90 g, 25 rnmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl) dipiperidine (2.01 g, 8.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (100 mL) was added to the mixture and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (1.50 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 7.74 (d, J=7.8 Hz, 1 H), 7.69 (d, J=7.8 Hz, 1 H), 7.56 (t, J=7.6 Hz, 1 H), 7.41 (t, J=7.7 Hz, 1 H), 6.41 (s, 1 H), 6.37 (s, 2 H), 5.23 (s, 2 H), 4.08 (t, J=6.0 Hz, 2 H), 3.85 (t, J=6.0 Hz, 2 H), 2.29 (s, 3 H), 2.02 (t, J =6.0 Hz, 2 H), 1.76 (s, 1 H).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[CH3:21][N:22]([CH3:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[CH3:21][N:22]([CH3:29])[CH:23]1[CH2:28][CH2:27][N:26]([C:15]([CH:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:17])[CH2:25][CH2:24]1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: CN(C)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)C2c3ccccc3Oc3ccccc32)CC1
Reaction time: 12 h
Yield: 90.4 %

Procedure:
To a stirred solution of 9H-xanthene-9-carboxylic acid (4.4 g, 19.4 mmol) in DCM (200 mL, 3 mol) was added dimethylpiperidin-4-yl-amine (2.5 g, 19.4 mmol). DIPEA (6.8 mL, 38.9 mmol) and HOBt (4.6 g, 34 mmol) were added to the mixture, followed by EDCI (4.5 g, 23.3 mmol). The mixture was stirred for 12 hours, then washed with water (300 mL), NaCl (sat.) (300 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure, and the crude material was purified via silica gel chromatography (10% MeOH/DCM w/1% NH3 (aq)) to yield the title compound (5.9 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[CH2:18][OH:19])=[O:12])[S:10][C:3]=12.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([OH:30])=[CH:25][CH:24]=2>>[OH:19][CH2:18][C@H:14]1[CH2:15][CH2:16][CH2:17][N:13]1[C:11]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[O:30][C:26]2[CH:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21]([CH3:20])=[CH:29]3)[CH:8]=1)=[O:12]
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC[C@@H]1CO
Reactant: Cc1cc2cc(O)ccc2[nH]1
Product: Cc1cc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@@H]5CO)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanone and 2-methyl-1H-indol-5-ol by a procedure analogous to Example 1F. MS: 408.3 (MH+); HPLC Rf: 5.146 min.; HPLC purity: 98%.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)(O)[O-].[Na+].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C(#N)C>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(Br)cccc1NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.5 %

Procedure:
Step 1 A mixture of 3-bromo-2-methylaniline (0.620 mL, 5.03 mmol) and sodium bicarbonate (565 mg, 6.73 mmol) in acetonitrile (4.5 mL) was treated with 2-bromo-1-phenylethanone (500 mg, 2.51 mmol) and the mixture was stirred at rt. After 24 h, the suspension was filtered and the precipitate was suspended and sonicated in water, collected again by filtration, washed with water and dried to provide 2-(3-bromo-2-methylphenylamino)-1-phenylethanone as an off-white solid (508 mg, 67%). 1H NMR (400 MHz, chloroform-d) δ8.00-8.06 (2H, m), 7.61-7.68 (1H, m), 7.53 (2H, t, J=7.6 Hz), 6.94-7.01 (2H, m), 6.51-6.58 (1H, m), 5.06 (1H, t, J=4.1 Hz), 4.62 (2H, d, J=4.4 Hz), 2.40 (3H, s). Mass spectrum m/z 304, 306 (M+H)+.
Reaction SMILES: [NH2+]1CCCC1.CC(C)(OC([NH:12][CH2:13][C:14]([NH:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1)=[O:15])=O)C>C(OCC)(=O)C>[NH2:12][CH2:13][C:14]([NH:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1)=[O:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1nnn[nH]1
Agent: C1CC[NH2+]C1
Solvent: CCOC(C)=O
Product: NCC(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of step (i) (1.4 g) was slurried in ethyl acetate, washed with 1N HCl and filtered. The filtrate was washed with water, dried (MgSO4) and evaporated. The residue was dissolved in dichloromethane (50 ml) and trifluoroacetic acid (8 ml) and stirred at room temperature for 2 hours. The mixture was evaporated. The residue was azeotroped with toluene and triturated with isohexane. The product was collected by filtration. Yield 0.45 g.
Reaction SMILES: Br[C@H:2]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:4][C:3]1=[O:17]>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Ag+]>[C:12]([O:14][C@H:2]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:4][C:3]1=[O:17])(=[O:13])[CH3:5]
Reactant: CCOC(=O)[C@@H]1CCCCCC[C@H](Br)C(=O)N1
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCCCCC[C@H](OC(C)=O)C(=O)N1
Temperature: 100 °C

Procedure:
Cis ethyl 3-bromo-2-oxo-1-azacyclodecane-10-carboxylate (2.96 g, 9.67 mmol) is dissolved in dimethylformamide (30 mL). Silver acetate (6.35 g, 38 mmol) is added, and the reaction is heated to 100° C. for 3 hours. After cooling back to room temperature, the reaction is diluted with ethyl acetate (100 mL), filtered through a pad of silica gel, and the solvent is evaporated to give crude cis ethyl 3-acetoxy-2-oxo-1-azacyclodecane-10-carboxylate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]2[CH:15]=1.Cl.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[N:4]=[C:5]4[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][N:6]4[CH:15]=3)[CH2:27][CH2:26]2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: FC(F)(F)c1ccc2nc(CCl)cn2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(CN3CCN(c4ccc(Cl)cc4)CC3)cn2c1
Yield: 41 %

Procedure:
Following the same general procedure as for Example 49, Step 2, and making non-critical variations, 2-(chloromethyl)-6-trifluoromethylimidazo[1,2-a]pyridine (Example 49, Step 1; 0.435 g), 1-(4-chlorophenyl)piperazine dihydrochloride (Aldrich; 0.550 g), diisopropylethylamine (Aldrich; 0.815 g), and THF (6 mL) give 0.30 g of 2-[[4-(4-chlorophenyl)-1-piperazinyl]methyl]-6-(trifluoromethyl)imidazo[1,2-a]pyridine after crystallization from ethyl acetate/hexane; mp 128-135° C.; MS m/z 394; IR (mineral oil) 1331, 1141, 1127, 1055, 1500, 830 cm-1. 1H NMR (CDCl3) δ 2.74, 3.20, 3.80, 6.83, 7.19, 7.31, 7.66, 7.68, 8.47.
Reaction SMILES: N.[Li].[C:3]1([C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(OC)[CH2:10][CH:11]=[CH2:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C=CC(=C)C>C1COCC1.C(Cl)(Cl)Cl>[C:3]1([CH:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH:11]=[CH2:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CCC(OC)(c1ccccc1)c1ccccc1
Agent: N
Agent: [Li]
Solvent: C=CC(=C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C=CCC(c1ccccc1)c1ccccc1
Temperature: -78 °C
Yield: 102.6 %

Procedure:
Ammonia, 400 mL, was cooled to -78° C. and 1.15 g of lithium wire was added. After the lithium had dissolved, a solution of 15.5 g of 4,4-diphenyl-4-methoxybut-1-ene in 100 mL of THF was added dropwise, over 1 hr. The mixture was warmed to reflux, then cooled to -78° C. Isoprene, 4 mL, was added to the reaction mixture to quench excess lithium, followed by 4 mL of methanol to quench the diphenylalkyl anion. The mixture was acidified with 9 g of ammonium chloride and the ammonia allowed to evaporate at room temperature. The residue was shaken with chloroform and water. The organic layer was dried and concentrated in vacuo to give 14.3 g of crude residue which, after chromatography on silica gel with chloroform as eluent, gave 13.9 g of 4,4-diphenylbut-1-ene which is characterized by:
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.Cl[CH2:39][O:40][CH3:41].[Cl-].[NH4+]>ClCCl>[CH3:39][O:40][CH2:41][O:27][CH:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C:20](=[CH:19][CH:18]=[C:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:21]1
Reactant: COCCl
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.2 %

Procedure:
In dichloromethane (45 mL), 7-dehydrocholesterol (2.0 g, 5.2 mmol) was dissolved, then N,N-diisopropylethylamine (2.70 mL, 15.6 mmol) and chloromethylmethylether (1.00 mL, 13.2 mmol) were sequentially added under ice-cooling, followed by stirring at room temperature for 20 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with dilute aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and concentrated to yied a residue. To the residue, methanol was added to triturate to obtain the title compound (1.9 g, 83%).
Reaction SMILES: [Na+].[Na+].[Na+].C(OC([NH:11][C@H:12]([C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:43])([P:39]([O-:42])(=[O:41])[OH:40])[P:35]([O-:38])(=[O:37])[O-:36])=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH2:24][CH2:25][Cl:26])[CH2:21][CH2:22][Cl:23])=[CH:16][CH:15]=1)=O)(C)(C)C.Cl>CO>[ClH:23].[Cl:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][Cl:26])[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@@H:12]([C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:43])([P:35]([OH:38])(=[O:36])[OH:37])[P:39]([OH:42])(=[O:40])[OH:41])=[O:28])[NH2:11])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)NCCCCC(O)(P(=O)([O-])[O-])P(=O)([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)NCCCCC(O)(P(=O)(O)O)P(=O)(O)O
Yield: 174.4 %

Procedure:
A solution of N-{N'-(tert-butoxycarbonyl)-4-[bis(2-chloroethyl)amino]-(L)-phenylalanyl}-5-amino-1-hydroxypentane-1,1-diphosphonic acid trisodium salt (35 mg) in methanol saturated with hydrochloric acid (2 ml) is heated to 40°-50° C. for 4 hours, then the solution is concentrated to reduced volume and the precipitated sodium chloride is filtered. The filtrate is evaporated to dryness and the residue is triturated with acetone and filtered. After recrystallization from ethanol/ethyl ether, N-{4-[bis(2-chloroethyl)amino]-(L)-phenylalanyl}-5-amino-1-hydroxypentane-1,1-diphosphonic acid monohydrochloride (25 mg) is obtained, m.p. >260° C., [α]D =+7.9 (c=2, methanol), NMR (TMS, D2O): 1.25÷1.40 (m, 2H), 1.42÷1.72 (m, 2H); 1.8÷2.06 (m, 2H); 2.9÷3.2 (m, 4H); 3.65 (t, 4H); 4.0 (t, 4H); 4.1 (t, 1H); 7.35 (s, 4H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22]([C:24]2[C:25]([C:30]3[C:35](F)=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:37])=[N:26][O:27][C:28]=2[CH3:29])=[O:23])[CH2:16]1)=[O:14]>CN(C)C=O>[CH3:11][O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([N:21]2[C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=3[C:25]3=[N:26][O:27][C:28]([CH3:29])=[C:24]3[C:22]2=[O:23])[CH2:16]1)=[O:14]
Reactant: COC(=O)N1CCCC(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)N1CCCC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
Add potassium bis(trimethylsilyl)-amide (5.5 mL, 2.73 mmol, 0.5 M in toluene) to a solution of 3-{[3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-piperidine-1-carboxylic acid methyl ester (0.72 g, 1.82 mmol) in dimethylformamide (56 mL). After 5 minutes, quench the reaction with 1N HCl and concentrate. Partition the resulting material between 20% isopropanol/chloroform and 1N HCl. Wash the organic layer with saturated aqueous sodium bicarbonate solution and brine, dry over magnesium sulfate, and concentrate. Purify by flash chromatography on silica gel (eluting with 0–0.5% methanol/chloroform) to give 632 mg of the title compound as a white solid, 92% yield. 1H NMR: consistent with structure. MS (ion spray) 376 (M+).
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:25])([C:20]([S:22][CH2:23][F:24])=[O:21])[C@:18]2([CH3:26])[C@H:4]([C@H:5]3[C@:15]([F:28])([C@@H:16]([OH:27])[CH2:17]2)[C@:14]2([CH3:29])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[C@@H:7]([F:30])[CH2:6]3)[CH2:3]1>CO.ClCCl>[CH3:8][CH2:9][C:10]([O:25][C@@:19]1([C:20]([S:22][CH2:23][F:24])=[O:21])[C@@:18]2([CH3:26])[CH2:17][C@H:16]([OH:27])[C@:15]3([F:28])[C@:14]4([CH3:29])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]4)=[O:11])[C@@H:7]([F:30])[CH2:6][C@H:5]3[C@@H:4]2[CH2:3][C@H:2]1[CH3:1])=[O:11]
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)SCF
Solvent: CO
Solvent: ClCCl
Product: CCC(=O)O[C@]1(C(=O)SCF)[C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Temperature: 25 °C
Yield: 155.9 %

Procedure:
The fluticasone (4.66 kg) obtained as above is dissolved in mixture of methanol (45 lit) and dichloromethane (45 lit) under stirring at ambient temperature and charcoalized. The methylene chloride is recovered (by distillation) by distillation at atmospheric pressure. The mixture is then gradually cooled to 10° C. and stirred for 60 min. The crystallized product is filtered, washed with methanol (4.5 lit) and dried at 55–60° C. to obtain pure fluticasone propionate (Yield 4.09 kg, overall yield 84.51%, purity 99.37%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20](Cl)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:26])=[N:9][CH:10]=1)=[O:4].[C:27]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]=[N:19][C:20]([O:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[C:21]([CH3:24])[C:22]=3[CH3:23])[CH2:13][C@H:12]2[CH3:26])=[N:9][CH:10]=1)=[O:4]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1cnc(N2CCN(c3nnc(Cl)c(C)c3C)C[C@H]2C)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(N2CCN(c3nnc(Oc4ccccc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 100 °C
Yield: 19.5 %

Procedure:
To a solution of (R)-4-(6-Chloro-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (compound 54, 40 mg, 0.106 mmol) in 2 mL toluene is added phenol (45 mg, 0.48 mmol), potassium phosphate (40.6 mg, 0.19 mmol) and di-tbu X-Phos (5.3 mg, 0.014 mmol) in a 2 drum screw-top vial. The vial is evacuated and flushed with nitrogen, followed with the additon of palladium (II) acetate (2 mg, 0.01 mmol). The reaction mixture is flushed with nitrogen again and heated to 100° C. for 16 h. The mixture is filtered through Celite and the filtrate is concentrated to afford a brown oil. The crude product is purified by HPLC, eluting with 15-95% acetonitrile in water (both mobile phases modified with 3% n-PrOH) to provide the desired product as a white solid (9 mg, 22%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].O.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].C(O)(=O)C>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:12])[C:4]([CH3:11])=[CH:5][CH:6]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1O
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(N)c(C)c1O
Reaction time: 0.33 h
Yield: 62 %

Procedure:
157 g (0.94 mole) of 2,6-dimethyl-3-nitro phenol is added little by little, while stirring, to a reducing mixture consisting of 950 cm3 of water, 30 cm3 of acetic acid and 158 g of iron, which has first been heated to 70°. When this addition has been completed, the heating is continued for 20 minutes. The reaction mixture is then neutralized with sodium carbonate and the boiling liquid is filtered. After cooling the filtrate, drying yields 80 g of 3-amino-2,6-dimethyl phenol which, after recrystallization in benzene, melts at 104°.