Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2F)([OH:16])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.O>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OC1(Cc2cc(F)ccc2F)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Fc1ccc2c(c1)CC1(CCN(Cc3ccccc3)CC1)O2
Temperature: 110 °C

Procedure:
To a suspension of magnesium strip (763 mg) in diethyl ether (7 mL) was added iodine (one crystal) followed by 0.4 mL of 2-(bromomethyl)-1,4-difluorobenzene under nitrogen. The reaction was initiated with a heat gun and 2-(bromomethyl)-1,4-difluorobenzene (5.0 g, 24.25 mmol) in diethyl ether (7 mL) was added slowly. After addition was completed the reaction mixture was refluxed for 100 minutes, cooled to room temperature. To this is reaction mixture a solution of 1-benzylpiperidin-4-one (4.57 g, 24.24 mmol) in diethyl ether (12 mL) was added dropwise with vigorous stirring. After addition was completed the mixture was left at room temperature over night. Saturated aqueous NH4Cl solution (excess) was added and stirred at room temperature until hydrolysis was completed and the mixture was extracted with diethyl ether. The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane, 0.2% NH4OH) to give intermediate 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol (2.74 g) containg large quantities of unknown impurities. To a suspension of NaH (55%, 1.12 g, 26.0 mmol) in toluene (10 mL) was added slowly a solution of 1-benzyl-4-(2,5-difluorobenzyl)piperidin-4-ol in toluene (15 mL). After addition was completed the reaction mixture was stirred at 110° C. (in a pre heated oil bath), after 5 minutes, DMF (9 mL) was added and the mixture was refluxed for 2 hours. The reaction mixture was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-1.5% methanol in dichloromethane, 0.2% NH4OH) to give sub title compound (190 mg). 1H-NMR (CDCl3, 400 MHz): δ 7.39-7.26 (m, 5H); 6.88-6.76 (m, 2H); 6.67 (dd, J=4.2, 8.7 Hz, 1H); 3.59 (s, 2H); 2.99 (s, 2H); 2.68-2.47 (m, 4H); 2.03-1.94 (m, 2H); 1.86-1.76 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[OH:29])=[O:18].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:29][C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: CC(=O)c1c(O)ccc2ccccc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccc4ccccc4c3C(C)=O)c2cc1OC
Temperature: 160 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-1-acetonaphthone (250 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 160° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (100 mg, yield 60%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([OH:16])=O)([O-:3])=[O:2].[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:14]([C:9]2[C:10]3[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:7][CH:8]=2)=[O:16])=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)c1cccc2c([N+](=O)[O-])cccc12
Reactant: CC(C)(C)c1ccc(CN)cc1
Product: CC(C)(C)c1ccc(CNC(=O)c2cccc3c([N+](=O)[O-])cccc23)cc1
Yield: 42.6 %

Procedure:
Using 5-nitronaphthalene-1-carboxylic acid (197 mg, 0.907 mmol) and 4-tert-butylbenzylamine (107 mg, 0.998 mmol), the same operation as the Example 104(2) gave the title compound as a light yellow solid (140 mg, 42.6%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)(Cl)Cl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: NCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)NCCCn1c(CCCOc2ccccc2)nc2c(N)nc3ccccc3c21

Procedure:
Using the general method of Example 242, except that chloroform was used in place of dichloromethane, 1-(3-aminopropyl)-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.32 mmol) was reacted with methanesulfonyl chloride (3+ g) to provide 1.38 g of N-{3-[4-amino-2-(3-phenoxypropyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}methanesulfonamide as a solid, m.p. 176-178° C. Analysis: Calculated for C23H27N5O3S: % C, 60.91; % H, 6.00; % N, 15.44; Found: % C, 60.71; % H, 5.98; % N, 15.45.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[N:31]=[N:32][C:33]([CH3:38])=[CH:34][C:35]=1[CH2:36]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:36][C:35]2[CH:34]=[C:33]([CH3:38])[N:32]=[N:31][C:30]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: Cc1cc(CCl)c(Cl)nn1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)c(Cl)nn1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with 3-chloro-4-chloromethyl-6-methyl-pyridazine (prepared by U.S. Pat. No. 3,453,277) gave the title compound. ES-MS m/e (%): 539.1(M+H+).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[C:13](Cl)=[N:14][CH:15]=[C:16]([CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18].[C:33](#[N:37])[CH:34]([CH3:36])[CH3:35]>C1COCC1>[Br:11][C:12]1[C:13]([C:34]([C:33]#[N:37])([CH3:36])[CH3:35])=[N:14][CH:15]=[C:16]([CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18]
Reactant: CC(C)C#N
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Temperature: -70 °C
Reaction time: 1 h

Procedure:
KHMDS 1 M in THF (1.517 mL) was added dropwise to a mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 200 mg, 0.506 mmol) and isobutyronitrile (52 mg, 0.758 mmol) in THF (5 mL) at −78° C. under a nitrogen atmosphere. The RM was stirred at −70° C. for 1 h, and allowed to warm to RT overnight. The RM was quenched with water and extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure. The residue was purified by flash chromatography (RediSep® Silica gel column, 24 g, EtOAc/n-hexane, isocratic 1:3) to afford 5-bromo-6-(2-cyanopropan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, of which (122 mg, 0.285 mmol) together with pyrimidine-5-boronic acid (53 mg, 0.427 mmol), Na2CO3 (0.427 mL, 0.855 mmol), PdCl2(dppf) (11 mg, 0.014 mmol) and dioxane (1.6 mL) were added to a vial, which was sealed, evacuated/purged with argon. The RM was stirred at 90° C. for 3 h, cooled to RT, treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 24 g, MeOH/DCM, isocratic 5:95) to afford the title product as a yellow solid. UPLC-MS (Condition 2) tR=1.05 min, m/z=428.0 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.72 (s, 6H) 7.38 (d, J=8.99 Hz, 2H) 7.80-7.91 (m, 2H) 8.26 (d, J=1.96 Hz, 1H) 8.96 (d, J=0.78 Hz, 2H) 9.18 (d, J=1.95 Hz, 1H) 9.30 (s, 1H) 10.64 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C([OH:25])C.OO.O>[OH-].[Na+]>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]2[NH:2][C:1](=[O:25])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][C:4]=3[N:9]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCO
Reactant: N#Cc1cccnc1NC(=O)CCCCCc1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(CCCCCc2ccccc2)nc2ncccc12

Procedure:
To 6-phenyl-hexanoic acid (3-cyano-pyridin-2-yl)-amide (360 mg, 1.2 mmol) in sodium hydroxide (6 ml, 5M) was added ethanol (0.1 ml) and hydrogen peroxide (3% in H2O, 1.5 ml). The reaction mixture was heated to reflux for 3 hours. Water was added, the solution was acidified (pH 5) and extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over Na2SO4, filtrated and concentrated in vacuo. Column chromatography on silica gel with CH2Cl2:MeOH 9:1 as eluent, followed by trituration from diethyl ether yielded 2-(5-phenyl-pentyl)-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid, MS (m/e): 294.3 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]([OH:14])=[O:13])=[CH:5]2.[H-].[Na+].C1(C)C=CC(S(O[CH2:27][CH2:28][O:29][C@@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([O:36][CH2:37][C:38]3[N:39]=[C:40]([C:44]4[CH:45]=[C:46]([CH3:50])[CH:47]=[CH:48][CH:49]=4)[O:41][C:42]=3[CH3:43])[CH2:31]2)(=O)=O)=CC=1.C(O)(C(F)(F)F)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:27][CH2:28][O:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][C@H:32]([O:36][CH2:37][C:38]3[N:39]=[C:40]([C:44]4[CH:45]=[C:46]([CH3:50])[CH:47]=[CH:48][CH:49]=4)[O:41][C:42]=3[CH3:43])[CH2:31]1)[C:6]([C:12]([OH:14])=[O:13])=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CCC[C@H](OCc3nc(-c4cccc(C)c4)oc3C)C2)cc1
Reactant: O=C(O)c1cc2cc(F)cc(F)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCn4c(C(=O)O)cc5cc(F)cc(F)c54)C3)c(C)o2)c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
79 mg of 5,7-difluoroindolecarboxylic acid are dissolved in 2 ml of dried DMF, and 34 mg of 60 percent strength sodium hydride suspension are added. After 30 min at room temperature, 100 mg of ((1R,3S)-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy)ethyl toluene-4-sulfonate, dissolved in 2 ml of DMF, are added. The mixture is stirred at 65° C. until the reaction has gone to completion (monitored by LC-MS). 50 μl of TFA are added, the mixture is filtered and the residue is purified by RP-HPLC. This gives 40 mg of (1R,3S)-5,7-difluoro-1-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethyl}-1H-indole-2-carboxylic acid as a colorless oil. C29H30F2N2O5 (524.56), MS (ESI): 525 (M+H+).
Reaction SMILES: Cl.[CH2:2]([NH2:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S-:11][C:12]#[N:13].[NH4+]>BrC1C=CC=CC=1.O>[CH2:2]([NH:10][C:12]([NH2:13])=[S:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#C[S-]
Reactant: NCCc1ccccc1
Agent: Cl
Agent: [NH4+]
Solvent: Brc1ccccc1
Solvent: O
Product: NC(=S)NCCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
Phenethylamine hydrochloride (257 grams, 1.63 moles) and ammonium thiocyanate (123.6 grams, 1.63 moles) were heated to 160° C. in 340 ml bromobenzene under nitrogen. After heating for 90 minutes, the mixture was cooled to room temperature and then to 5° C. This procedure was repeated with a further batch of 257 grams of phenethylamine hydrochloride. The combined solids obtained in the above reaction were stirred in 1.5 l water and filtered. Recrystallization from isopropyl alcohol yielded 261.5 grams (45%) N-phenethylthiourea, m.p. 132°-134°.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(C=CC(O)=CC=1)O.[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30](Cl)=[C:29]([Cl:35])[C:28]=1[OH:36].IC1C=C(C=C(I)C=1O)C#N>>[Cl:26][C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[C:29]([Cl:35])[C:28]=1[OH:36].[CH:1]1[CH:2]=[CH:3][C:4]([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Oc1c(Cl)c(Cl)cc(Cl)c1Cl
Agent: N#Cc1cc(I)c(O)c(I)c1
Agent: O=S(=O)(Oc1ccc(Cl)cc1)c1ccccc1
Agent: Oc1ccc(O)cc1
Product: Oc1c(Cl)ccc(Cl)c1Cl

Procedure:
In all cases examined, PcpB converted the substituted phenol to the corresponding hydroquinone. PCP and 2,3,5,6-tetrachlorophenol were converted to a compound with the same HPLC retention time as that of TeCH (Xun and Orser, 1991c). TeCH was confirmed as the end-product by GC/MS (data not shown). PcpB oxidized 2,4,6-triiodophenol (TIP) to a product with a retention time of 7.75 min. by GC analysis and mass spectrum consistent with that expected for 2,6-diiodo-p-hydroquinone (DIHQ, molecular formula of C6H4I2O2). The base peak was at M/Z 362 (M+), and major fragments were found at M/Z 235 (loss of I from 362), 207 (loss of CO from 235), and 108 (loss of 2 I from 362). The end product of 3,5-diiodo-4-hydroxylbenzonitrile was also identified as DIHQ because it shared the same retention time with DIHQ produced from TIP by HPLC analysis. Incubation of 2,3,6-trichlorophenol with PcpB yielded a product with a retention time of 4.65 min. by GC analysis and a mass spectrum consistent with that expected for 2,3,6-trichloro-p-hydroquinone (molecular formula of C6H3Cl3O2). The relative intensities of the peaks at M/Z 212 (base peak, M+), 214 (M+2), and 216 (M+4) are characteristic of a molecule containing 3 chlorine atoms, although the peak expected at M/Z 218 (M+6) was not observable. Major peaks were observed at M/Z 178 (loss of H35Cl from 214), M/Z 176 (loss of H35Cl from 212, H37Cl from 214), M/Z 150 (loss of CO from 178), and M/Z 148 (loss of CO from 1976).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[N:7][CH:8]=1.Br[C:16]1[N:21]=[C:20]2[N:22]([C@H:27]3[CH2:32][CH2:31][C@H:30]([O:33][CH3:34])[CH2:29][CH2:28]3)[C:23](=[O:26])[CH2:24][NH:25][C:19]2=[N:18][CH:17]=1>CN(C)C=O>[OH:12][C:9]([C:6]1[N:7]=[CH:8][C:3]([C:16]2[N:21]=[C:20]3[N:22]([C@H:27]4[CH2:32][CH2:31][C@H:30]([O:33][CH3:34])[CH2:29][CH2:28]4)[C:23](=[O:26])[CH2:24][NH:25][C:19]3=[N:18][CH:17]=2)=[CH:4][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Reactant: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(Br)nc32)CC1
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(-c4ccc(C(C)(C)O)nc4)nc32)CC1
Temperature: 120 °C

Procedure:
2-(5-(Trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example 5.E) (9.43 g, 31.4 mmol), 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (10.02 g, 29.4 mmol), [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II) dichloromethane adduct (2.398 g, 2.94 mmol) and N,N-dimethylformamide (25 mL) were combined in a round-bottom flask with a stirbar. The atmosphere in the vessel was removed under vacuum and replaced with nitrogen gas three times. The resulting mixture was stirred vigorously and heated at 120° C. under nitrogen for 35 min. The resulting mixture was purified using flash chromatography, split into 4 separate columns, (2-15% methanol in dichloromethane). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. The resulting mixture was purified using reverse-phase preparatory HPLC (20-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min), split into 6 runs. Fractions containing the desired product were combined and all of the acetonitrile and some of the water were removed under reduced pressure at 25° C. The remaining yellow solution was loaded onto 50 g of Strata X—C ion exchange resin from Phenomenex. The column was washed successively with water, acetonitrile, methanol and then 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol wash and was concentrated under reduced pressure and dried under high vacuum to give the desired product (4.85 g, 12.20 mmol, 42% yield) as a pink foam-solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.03 (d, J=1.56 Hz, 1H), 8.28 (s, 1H), 8.24 (dd, J=2.34, 8.20 Hz, 1H), 7.74 (d, J=7.81 Hz, 1H), 7.61 (s, 1H), 5.26 (s, 1H), 4.90 (tt, J=3.71, 12.10 Hz, 1H), 4.13 (s, 2H), 3.28 (s, 3H), 3.20 (tt, J=4.00, 10.84 Hz, 1H), 2.58 (qd, J=2.93, 12.82 Hz, 2H), 2.14 (d, J=10.15 Hz, 2H), 1.68 (d, J=10.93 Hz, 2H), 1.47 (s, 6H), 1.17-1.35 (m, 2H); MS (ESI) m/z 398.3 [M+1]+; mp 196-198° C. (uncorrected).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:43][O:44][C:45]1[CH:64]=[CH:63][C:48]([C:49]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([C:59]([O:61][CH3:62])=[O:60])[CH:52]=2)=O)=[CH:47][C:46]=1[C:65]([O:67][CH3:68])=[O:66]>C1COCC1>[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[C:49]([C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[C:53]([C:59]([O:61][CH3:62])=[O:60])[CH:52]=1)[C:48]1[CH:63]=[CH:64][C:45]([O:44][CH3:43])=[C:46]([C:65]([O:67][CH3:68])=[O:66])[CH:47]=1
Reactant: CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C(=O)c2ccc(OC)c(C(=O)OC)c2)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCCCCC=C(c1ccc(OC)c(C(=O)OC)c1)c1ccc(OC)c(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
n-Hexyltriphenylphosphonium bromide (0.427 g, 1 mmol) was dried by azeotropic distillation from a benzene solution and then stirred in dry THF (10 mL) under nitrogen atmosphere. Sodium bis(trimethylsilyl)amide (1 M in THF, 1 mL, 1 mmol) was added and the ylide produced was stirred under nitrogen at 0° C. for 30 min. Intermediate 35 (0.276 g, 0.77 mmol) was added as a solution in THF (10 mL) under nitrogen. The mixture was stirred at rt overnight and partitioned between 1 N HCl (100 mL) and ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, and evaporated to afford an oil which was chromatographed on SiO2 (230-400 mesh, 50 g), eluting with hexanes/ethyl acetate (4:1) to give the product (36) (0.15 g, 46%) as an oil: 1H NMR (CDCl3, 300 MHz) δ 7.63 (d, J=2.3 Hz, 1H), 7.56 (d, J=2.2 Hz, 1H), 7.20 (dt, J=2.3 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 6.82 (d, J=8.7H, 1H), 5.96 (t, J=7.5 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.83 (s, 6H), 2.05 (q, J=7.3 Hz, 2H), 1.39 (t, J=7.2 Hz, 2H), 1.22 (m, J=1.9 Hz, 2H), 0.83 (t, J=6.7 Hz, 3H); IR (neat) 2927, 2853, 1732, 1606, 1500, 1435, 1263 cm−1. Anal. (C25H30O6) C, H.
Reaction SMILES: [Cl:1]CCN(CCCl)P(N(CCCl)CCCl)(=O)OCCSCCN(C(C)C)C(C)C.FC(F)(F)C(O)=O.C(OO)(=O)C.[Cl:42][CH2:43][CH2:44][N:45]([CH2:70][CH2:71][Cl:72])[P:46]([N:63]([CH2:67][CH2:68][Cl:69])[CH2:64][CH2:65][Cl:66])(=[O:62])[O:47][CH2:48][CH2:49][S:50]([CH2:53][CH2:54][N:55]([CH:59]([CH3:61])[CH3:60])[CH:56]([CH3:58])[CH3:57])(=[O:52])=[O:51]>CN(C)C=O.C(O)(=O)C.C(OCC)(=O)C>[ClH:1].[Cl:66][CH2:65][CH2:64][N:63]([CH2:67][CH2:68][Cl:69])[P:46]([N:45]([CH2:44][CH2:43][Cl:42])[CH2:70][CH2:71][Cl:72])(=[O:62])[O:47][CH2:48][CH2:49][S:50]([CH2:53][CH2:54][N:55]([CH:59]([CH3:60])[CH3:61])[CH:56]([CH3:58])[CH3:57])(=[O:52])=[O:51]
Reactant: CC(C)N(CCSCCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)C(C)C
Agent: CC(=O)OO
Agent: CC(C)N(CCS(=O)(=O)CCOP(=O)(N(CCCl)CCCl)N(CCCl)CCCl)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-{[2-(diisopropylamino)ethyl]thio}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate (2.3 g, 4.3 mmol) in dimethylformamide (30 mL) at 0° C. was treated with trifluoroacetic acid (1.6 mL, 21.5 mmol, 5.0 eq.) and stirred at 0° C. for an additional 10 minutes. Peracetic acid (726 μL of a 32%/wt solution in acetic acid, 10.8 mmol, 2.5 eq.) was added over 5 minutes, then the mixture was allowed to warm to room temperature. Stirring was continued until analysis of an aliquot by LC/MS indicated complete conversion of 2-{[2-(diisopropylamino)ethyl]thio}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate to 2-{[2-(diisopropylamino)ethyl]sulfonyl}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)phosphorodiamidate (typically about 2 hours). The reaction mixture was diluted with ethyl acetate (800 mL) and washed with a 1:1 mixture of 0.2M aqueous Na2S2O4 and saturated aqueous NaHCO3 (2×800 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and treated with excess hydrochloric acid (4.0M in dioxane). The resulting hazy solution was concentrated under vacuum to give 2-{[2-(diisopropylamino)ethyl]sulfonyl}ethyl N,N,N′,N′-tetrakis(2-chloroethyl)-phosphorodiamidate hydrochloride as a clear oil (2.53 g, 100% yield). MS (ES+): m/z=564 [C18H39Cl4N3O4PS+H]; 1H NMR (CD3OD): δ=1.44 (t, J=6.3 Hz, 12H), 3.41-3.52 (m, 8H), 3.64-3.87 (m, 16H), 4.53 (q, J=5.5 Hz, 2H); 31P NMR (CD3OD): δ=18.01.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[N+:2]=[N-:3].[CH2:16]([Sn:20]([C:29]#[CH:30])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C1COCC1>[CH2:25]([Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:16][CH2:17][CH2:18][CH3:19])[C:29]1[N:3]=[N:2][N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:30]=1)[CH2:26][CH2:27][CH3:28]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: [N-]=[N+]=NCCCCCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(CCCCCCCCCC(=O)O)nn1
Reaction time: 24 h
Yield: 8.4 %

Procedure:
10-Azidodecanoic acid (2.0 g, 9.5 mmol) in THF (50 mL) is treated with tributylstannyl acetylene (2.99 g, 9.5 mmol) copper(I)iodide (90 mg 0.47 mmol) and triethylamine (256 mg, 2.54 mmol) at room temperature with constant stirring for 24 h. The reaction is then filtered through celite and concentrated in vacuo to a gum, and then chromatographed on silica in a gradient of 10-40% ethyl acetate in petrol. The main fraction is collected and concentrated in vacuo to give 10-(4-tributylstannyl-[1,2,3]triazol-1-yl)-decanoic acid (3.22 g, 0.8 mmol).