Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([O-:22])(=O)=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:24]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([Cl:24])(=[O:22])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Yield: 16.8 %

Procedure:
To a solution of the crude 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonic acid sodium salt (2.81 g, 8.7 mmol) was added 2.8 g of phosphorous pentachloride and 50 mL of dichloromethane. The reaction warmed to 40° followed by dissolution of the reagents. The reaction was then quenched with ice, extracted with dichloromethane, washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified via flash chromatography using 20:1 Hex:EtOAc to afford 0.5 g (17%) of 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonyl chloride.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:47])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:22][CH2:23][CH2:24][CH2:25][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=CCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.60 mL (4.3 mmol) of triethylamine was added and dissolved in a suspension of 0.69 g (3.9 mmol) of ascorbic acid in acetonitrile (8 mL). The above crude product of (5,9,13-trimethyltetradec-4-enyl)tosylate was added thereto at room temperature, and the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: Cl.[CH:2]1([N:7]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+]>>[CH:2]1([N:7]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:26])[NH2:27])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)C3CCCC3)ccc21
Yield: 45 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-cyclopentyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 45% of theory, C25H30N3O4 (462.6); EKA mass spectrum: (M+H)+=463; (M+H+Na)++=243; (M+Na)+=485; (M+2Na)++=254.
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=1.[C:21]([O:25][C:26]([NH:28][CH:29](P(OC)(OC)=O)[C:30]([O:32][CH3:33])=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]=[C:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:30]([O:32][CH3:33])=[O:31])=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=Cc1ccc(Br)nc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 84 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (480 uL, 3.2 mmol) was added to a mixture of 6-bromo-pyridine-3-carbaldehyde (Aldrich, Cat. #596280) (500 mg, 3 mmol) and methyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (Fluka, Cat. #09659) (960 mg, 3.2 mmol) in methylene chloride (5 mL) at r.t. under N2. The reaction was stirred for 2 h. The reaction was partitioned between EtOAc and 1 N HCl. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude methyl 3-(6-bromopyridin-3-yl)-2-[(tert-butoxycarbonyl)amino]acrylate (0.9 g, 93%) as an off white solid. Analytical LCMS (M+H)+: m/z=356.8, 358.9.
Reaction SMILES: [C:1]1([OH:9])[C:2]([CH3:8])=[CH:3][C:4]([CH3:7])=[CH:5][CH:6]=1.[C:10]1([OH:18])[C:11]([CH3:17])=[CH:12][CH:13]=[C:14]([CH3:16])[CH:15]=1.[CH3:19][C:20](=[CH2:22])[CH3:21]>>[C:2]([C:13]1[CH:12]=[C:11]([CH3:17])[C:10]([OH:18])=[CH:15][C:14]=1[CH3:16])([CH3:8])([CH3:3])[CH3:1].[C:20]([C:6]1[CH:5]=[C:4]([CH3:7])[CH:3]=[C:2]([CH3:8])[C:1]=1[OH:9])([CH3:21])([CH3:19])[CH3:22]
Reactant: C=C(C)C
Reactant: Cc1ccc(O)c(C)c1
Reactant: Cc1ccc(C)c(O)c1
Product: Cc1cc(C(C)(C)C)c(C)cc1O
Product: Cc1cc(C)c(O)c(C(C)(C)C)c1

Procedure:
butylating the entire 2,4-xylenol/2,5-xylenol mixture with isobutylene at a temperature of from about 20° C. to about 100° C. and pressures of from about ambient to about 200 pounds per square inch gauge in the presence of an acid catalyst to form predominantly 4-t-butyl-2,5-xylenol and 6-t-butyl-2,4-xylenol,
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[NH2:21][CH2:22][CH2:23][P:24](=[O:27])([O-:26])[O-:25].[OH-].[Na+]>C(O)C.O>[P:24]([CH2:23][CH2:22][NH:21][C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6])([OH:27])([OH:26])=[O:25]
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCCP(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncnc2c1nc(NCCP(=O)(O)O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 110 °C

Procedure:
A mixture of 8-bromoadenosine (1 mmol), arninoethylphosphonate (2 mmol), and sodium hydroxide (2 mmol) in ethanol-water in a sealed tube was warmed at 110° C. under nitrogen. After 24 h the cooled reaction mixture was purified through preparative HPLC to give 8-(2-phosphonoethylamino)-adenosine (4.1). mp 175° C.; Anal. calcd. for C12H19N6O7P+0.5 H2O: C, 36.10; H, 5.05; N, 21.05; P, 7.76. Found: C, 36.08; H, 4.83; N, 20.36; P, 7.86.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:39][CH2:40][CH3:41])=[C:33]([NH:35][C:36]([NH2:38])=[S:37])[CH:34]=1>>[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:39][CH2:40][CH3:41])=[C:33]([NH:35][C:36]([NH:38][C:2]([NH:1][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[N:16]=[CH:15][N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:3])=[S:37])[CH:34]=1
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CCCc1ccc(C)cc1NC(N)=S
Product: CCCc1ccc(C)cc1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(5-methyl-2-propylphenyl)thiourea (CA38) isolated as a white solid (0.107 g, 34%): 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.09 (s, 1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.95 (m, 2H), 7.61 (dd, J=8.6, 1.3 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.44-7.34 (m, 2H), 7.13 (d, J=7.8 Hz, 1H), 7.07-6.97 (m, 2H), 3.46 (q, J=6.5 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.48-2.39 (m, 2H), 2.26 (s, 3H), 1.54-1.42 (m, 2H), 0.84 (t, J=7.3 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 583 ([M+H]+), 581 ([M−H]−).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[S:15](Cl)([CH3:18])(=[O:17])=[O:16].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:18][S:15]([O:12][CH2:11][CH2:10][O:9][C:8]1[CH:13]=[CH:14][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(OCCO)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)Oc1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-isopropoxyphenoxy)ethanol (3.50 g), mesyl chloride (2.20 g) and triethylamine (2.0 g) in 20 ml of methylene chloride is stirred at RT for 3 hours. It is then poured into water and extracted with methylene chloride. The solvent is removed from the combined organic layers by rotoevaporation, and the residue is purified by column chromatography to give 2-(4-isopropoxyphenoxy)ethyl methanesulfonate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10]([Si:14]([CH3:24])([CH3:23])[O:15][CH2:16][CH2:17][C:18]1[CH:19]=[N:20][NH:21][CH:22]=1)([CH3:13])([CH3:12])[CH3:11].O>CN1C(=O)CCC1>[Si:14]([O:15][CH2:16][CH2:17][C:18]1[CH:22]=[N:21][N:20]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)[CH:19]=1)([C:10]([CH3:11])([CH3:13])[CH3:12])([CH3:23])[CH3:24]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cn[nH]c1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1
Temperature: 150 °C
Reaction time: 5 h
Yield: 36.5 %

Procedure:
A mixture of 2-chloropyridine-4-carbonitrile (1.38 g, 10 mmol), tert-butyl-dimethyl-[2-(1H-pyrazol-4-yl)ethoxy]silane (2.48 lg, 11 mmol) in NMP (30 mL) was stirred for 5 hr at 150° C. Then the reaction mixture was cooled to room temperature and poured into water and extracted with ethyl acetate three times. Organic extracts collected and washed with water twice, brine and dried with anhydrous Na2SO4. It was then concentrated and purified by flash column chromatograph to give the title compound (1.2 g, 36%). [M+H] Calc'd for C17H24N4O3Si, 329. Found, 329.
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[NH:26][C:9]2[CH2:10][C@@:11]3([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[C@H:16]([CH2:17][C:8]=2[C:7]=1[CH3:27])[CH2:15][NH:14][CH2:13][CH2:12]3)=[O:5])[CH3:2].[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH:35]=O.C([BH3-])#N.[Na+].[ClH:41]>CO.C(O)(=O)C>[ClH:41].[CH2:28]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[NH:26][C:9]2[CH2:10][C@@:11]3([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)[C@H:16]([CH2:17][C:8]=2[C:7]=1[CH3:27])[CH2:15][N:14]([CH2:35][C:31]1[O:30][CH:34]=[CH:33][CH:32]=1)[CH2:13][CH2:12]3)=[O:5])[CH3:29]
Reactant: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@H]1CNCC[C@@]1(c1cccc(OC)c1)C2
Reactant: O=Cc1ccco1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1[nH]c2c(c1C)C[C@@H]1CN(Cc3ccco3)CC[C@@]1(c1cccc(OC)c1)C2
Temperature: 0 °C
Reaction time: 15 h

Procedure:
1.3 g (3.3 mmol) of (±)-trans-2-diethylaminocarbonyl-8a-(3-methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g]isoquinoline, 0.28 ml (4.95 mmol) of acetic acid, 0.33 ml (3.96 mmol) of 2-furaldehyde were dissolved in 50 ml of MeOH under nitrogen atmosphere. 0.415 g (6.6 mmol) of sodium cyanoborohydride were added and the solution stirred for 15 h. Additional acetic acid (0.1 ml), 2-furaldehyde (0.3 ml) and sodium cyanoborohydride (0.2 g) were added. After two hours of stirring the reaction mixture was cooled to 0° C. and 50 ml of 5N hydrochloric acid were added. The solvent was removed in vacuo, the aqueous solution was extracted with Et2O, the pH was adjusted to 8 with 20% NaOH and then extracted with AcOEt. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude product was dissolved in acetone/MeOH and the solution brought to acidic pH with HCl/Et2O . The precipitate was filtered, yielding 1.7 g of the title compound. M.p.=105° C. dec.
Reaction SMILES: [N:1]([CH:4]1[CH:8]([O:9][CH2:10][CH3:11])[O:7][C:6](=[O:12])[CH2:5]1)=[N+]=[N-].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25](O)=[O:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>[Pd].C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:25](=[O:26])[NH:1][CH:4]1[CH2:5][C:6](=[O:12])[O:7][CH:8]1[O:9][CH2:10][CH3:11])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC1OC(=O)CC1N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1OC(=O)CC1NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A mixture of 4-azido-5-ethoxy-dihydrofuran-2-one (1.06 g, 6.2 mmol), (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.33 g, 6.2 mmol), and 10% palladium on carbon (0.50 g) in ethyl acetate previously degassed with N2 (50 mL) was stirred under 1 atm hydrogen at room temperature for 1 h. The mixture was diluted with dichloromethane, filtered (Celite) and evaporated. The crude mixture was dissolved in dichloromethane (100 mL), was treated with diisopropylethylamine (5.4 mL, 30.8 mmol), EDC (1.48 g, 7.71 mmol), and HOBT (1.04 g, 7.71 mmol) and was stirred at room temperature under nitrogen for 24 h. The reaction was diluted with ethyl acetate, was washed with 10% sodium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate:hexanes provided (R)-2-(2-ethoxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.19 g, 56% yield) as a very viscous, pale yellow oil. 1H-NMR (500 MHz, CDCl3) δ 7.61 (br, 0.6H), 5.29 (s, 0.6H), 5.25 (br s, 0.4H), 4.29 (br, 1.2H), 4.20 (br s, 0.8H), 3.78 (m, 1H), 3.57 (m, 1H), 3.34 (br, 1.4H), 3.25 (br, 0.6H), 2.94 (br dd, J=14.9, 3.8 Hz, 1H), 2.31 (dd, J=18.0, 1.4 Hz, 1H), 2.1-2.3 (br 1H), 1.82 (br s, 1H), 1.39 (s, 9H), 1.17 (m, 3H) ppm. MS (ES+): m/e=343 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[C:29]([O-])(O)=O.[Na+].BrN1[C:41](C)(C)[C:39](=[O:40])N(Br)C1=O.N1CC(=O)NC1=O>C(Cl)(Cl)(Cl)Cl>[C:39]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH:14]=[C:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][C:2]([CH3:29])([CH3:1])[CH3:3])[CH2:17]1)(=[O:40])[CH3:41]
Reactant: O=C([O-])O
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C1CNC(=O)N1
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@H](C)CCCC(C)(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C

Procedure:
Cholesterol derivative 12 (1 mmole) in 40 ml of CCl4 is treated with 600 mg NaHCO3 and 170 mg of 1,3-dibromo-5,5-dimethyl hydantoin, and the mixture is refluxed under N2 for 3 hours. After cooling to 0° C. the solid hydantoin is removed by filtration. The filtrate is evaporated, the residue is redissolved in 5 ml xylene at 140° C. After 1.5 hours under N2 at this temperature the mixture is cooled to room temperature, diluted with benzene, and washed with 5% HCl, 4% NaHCO3 and saturated NaCl solution. After drying (using Na2SO4) the solvent is evaporated and the residue is chromatographed on AgNO3 -impregnated thin layer plates developed with ethyl acetate/Skellysolve B (1:4). This yields pure 5,7-diene (13) of molecular weight 440 and exhibiting the typical 5,7-diene ultraviolet spectrum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([I:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH3:22]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:21]([CH3:22])[CH3:20])[C:11]([I:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1I

Procedure:
The title compound was prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B1) (399 mg, 1 mmol) and dimethylamine (5.6 N in EtOH, 0.36 mL, 2 mmol) in THF (3 mL) at 65° C. for 18 h in a sealed tube according to the general procedure C. Obtained as a yellow solid (386 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]=[CH2:21])=[CH:12][CH:11]=2)[CH:3]=1.[Zn](CC)[CH2:23]C.ICI>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][O:19][CH:20]3[CH2:23][CH2:21]3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: C=COCCCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: CCOCC
Product: Clc1ccc(Br)cc1Cc1ccc(CCCOC2CC2)cc1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-bromo-1-chloro-2-(4-(3-(vinyloxy)propyl)benzyl)benzene (0.75 g, 2.04 mmol) and Et2Zn (5.11 mL, 5.11 mmol, 1.0 M in hexane) in dry ethyl ether (10 mL) was added diiodomethane (0.41 mL, 5.11 mmol) dropwise during 20 min at room temperature under argon. After stirring overnight, the reaction mixture was poured slowly into ice cold dilute hydrochloride solution with stirring. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and then with brine (20 mL), and then dried over sodium sulfate. The residue was concentrated and purified by preparative TLC (eluent EA:PE=1:40) to obtain intermediate DH (0.64 g) as a light yellow oil. 1H NMR (CDCl3, 400 MHz): δ 7.32˜7.25 (m, 3H), 7.15 (d, 2H), 7.11 (d, 2H), 4.05 (s, 2H), 3.53 (t, J=6.4 Hz, 2H), 3.31˜3.26 (m, 1H), 2.68 (t, J=7.2 Hz, 2H), 1.93˜1.86 (m, 2H), 0.61˜0.45 (m, 4H).
Reaction SMILES: [Zn:1].[F:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C@@H:9]([OH:29])/[CH:10]=[CH:11]/[C:12]#[C:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17]/[C@@H:18]([OH:28])[C@@H:19]([OH:27])[CH2:20][O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:5][CH:4]=1.O>CO>[Zn:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C@@H:9]([OH:29])/[CH:10]=[CH:11]/[CH:12]=[CH:13]\[CH:14]=[CH:15]\[CH:16]=[CH:17]\[C@@H:18]([OH:28])[C@@H:19]([OH:27])[CH2:20][O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:30][CH:31]=1
Reactant: COC(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C#C/C=C/[C@H](O)COc1ccc(F)cc1
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COC(=O)COC[C@H](O)[C@H](O)/C=C/C=C/C=C\C=C\[C@H](O)COc1ccc(F)cc1
Reaction time: 42 h
Yield: 10.8 %

Procedure:
Activated zinc was prepared from 10 g of zinc and the reduction carried out using the procedure described in Helv. Chim. Acta (1987), Vol. 70, p. 1025). A solution of (5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, methyl ester, (0.8 g, 1.2 mmol) in methanol (4 mL) was added to a slurry of activated zinc in 1:1 methanol:water (45 mL). The flask was stirred vigorously under nitrogen for 24-60 hours. The mixture was filtered through a pad of Celite 545 and rinsed with methanol (3×25 mL). Purification by chromatography on a reverse phase semi-prep column using a gradient of acetonitrile and water afforded 55 mg of (5S,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxa-7,9,11,13-hexadecatetraenoic acid, methyl ester, as an oil; 1H-NMR (400 mHz, methanol-d4) δ 3.62 (m, 2H), 3.75 (s, 3H), 3.93 (m, 2H), 4.13 (m, 3H), 4.58 (m, 1H), 5.85 (m, 2H), 6.14 (m, 2H), 6.36 (m, 2H), 6.77 (m, 1H), 6.96 (m, 5H) ppm.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CC(=O)CC>[Cl:19][CH2:18][CH2:17][CH2:16][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: ClCCCOc1ccc(I)cc1
Temperature: 25 °C

Procedure:
A mixture of p-iodophenol (20 g, 91 mmol), potassium carbonate (25.2 g, 182 mmol) and 1-bromo-3-chloropropane (commercially available, for example, from Aldrich) (18 g, 114 mmol) in anhydrous 2-butanone (300 ml) was heated at reflux for 72 h, cooled to room temperature, filtered and evaporated to dryness. The resulting residue was purified by SPE filtration (70 g silica cartridge, eluting with 20:1 cyclohexane-ethyl acetate) to afford the title compound (24.9 g); 1H NMR (CDCl3) δ 7.5 (2H, d), 6.7 (2H, d), 4.1 (2H, t), 3.8 (2H, t), 2.2 (2H, q).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:53][CH2:54][N:55]1[CH2:59][CH2:58][CH2:57][CH2:56]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7](=[O:14])[C:6]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=1)=[C:5]2[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:53][CH2:54][N:55]2[CH2:59][CH2:58][CH2:57][CH2:56]2)=[CH:30][CH:31]=1
Reactant: OCCN1CCCC1
Reactant: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(O)cc3)c2cc1Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OCCN4CCCC4)cc3)c2cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a solution of 6-bromo-4-(4-hydroxy-benzyl)-7-methoxy-3-(4-trifluoromethyl-phenyl)-chromen-2-one (0.70 g, 1.4 mmol) and triphenylphosphine (0.73 g, 2.8 mmol) in THF (40 mL) were sequentially added 1-(2-hydroxylethyl)pyrrolidine (0.65 mL, 5.6 mmol) and diisoproyl azodicaroxylate (0.55 mL, 2.8 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. Organic extracts were combined and washed with water and saturated sodium chloride in succession, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification using silica gel flash column chromatography (10% methanol in CH2Cl2) provided the title compound as a solid (0.44 g, 53%). MS (ESI) m/z 602.3 (M+1)+, 604.3 (M+1+2)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OC)=O.[NH2:30][C:31]1[CH:47]=[CH:46][C:34]([CH2:35][S:36]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(=[O:38])=[O:37])=[CH:33][CH:32]=1>C(Cl)Cl.O>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:35][S:36]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])(=[O:38])=[O:37])=[CH:46][CH:47]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)CCS(=O)(=O)Cc1ccc(N)cc1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CS(=O)(=O)CCC(=O)OCC)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of 6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 0.2 g; 0.85 mmol) in DCM (5 ml) was treated with triethylamine (0.13 ml; 0.93 mmol) and methyl chloroformate (0.085 ml; 1.1 mmol). After stirring at 0° C. for 30 minutes, ethyl 3-(4-aminobenzylsulfonyl)propanoate (Intermediate 42, 230 mg; 0.85 mmol) was added. After stirring at 0° C. for 5 minutes and RT for 1 hour water was added and the mixture passed through a hydrophobic frit. The solvent was removed in vacuo and the residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.