Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH3:21][CH:22]1[CH2:26][C:25](=[O:27])[O:24][C:23]1=[O:28].C1(C)C=CC=CC=1>O>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:25](=[O:27])[CH2:26][CH:22]([CH3:21])[C:23]([OH:28])=[O:24]
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CC1CC(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)C(=O)O

Procedure:
A stirred mixture of 4-(3-amino-4-fluorobenzyl)-2H-phthalazin-1-one (2.02 g, 7.5 mmol; prepared in a manner similar to that described in Example 23), 3-methyldihydrofuran-2,5-dione (0.856 g, 7.5 mmol) and toluene (100 ml) was heated under reflux for 2.5 hours (for the first 30 minutes of this period, traces of water in the mixture were removed by azeotropic distillation). The resulting solid was collected by filtration from the hot mixture, washed with toluene (20 ml) and dried in vacuo to give N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-methylsuccinamic acid (1.91 g) as an off-white solid, m.pt. 140–144° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 0.95 (d, 3H) (CH3), 2.2–2.6 (m, 3H) (—CH2CHMe-), 4.1 (s, 2H) (ArCH2—), 6.9–7.2 (m, 2H) (2×ArH), 7.6–7.9 (m, 4H) (4×ArH), 8.1 (d, 1H) (ArH), 9.55 (s, 1H) (chain CONH), 12.0 (br s, 1H) (CO2H), 12.5 (s, 1H) (ring CONH); m/z (M+H)+ 384, 100% purity.
Reaction SMILES: Br[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[C:37]=1B(O)O>>[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[C:37]=1[C:2]1[C:22]([O:23][CH3:24])=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: COc1cc2c(cc1Br)C(c1cccc(C#N)c1)=NCC(=O)N2C
Reactant: COc1cccc(OC)c1B(O)O
Agent: OB(O)c1ccccc1
Product: COc1cc2c(cc1-c1c(OC)cccc1OC)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 44 %

Procedure:
Prepared from 3-(7-bromo-8-methoxy-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 9 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2,6-dimethoxyphenyl boronic acid. The title compound (83 mg) was obtained as a pale green solid, (yield=44%).
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OC(C)C)(C)C.[OH-].[Na+]>O.O1CCCC1>[C:21]1([CH2:20][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCCOCCOCCOCCOCCOCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
To a stirred mixture of hexaethylene glycol (10 g), benzyl bromide (4.53 mL) and diisopropyl ether (25 mL) was added tetrahydrofuran (10 mL). The mixture was cooled to 15–20° C. and aqueous sodium hydroxide (10.8M, 4.92 mL) was added slowly maintaining the temperature at 15–20° C. during addition. The resulting mixture was allowed to warm to 20° C. and stirred for a further 17 hours. Water (50 mL) was then added to the reaction mixture, which was then washed with diisopropyl ether (25 mL). Sodium chloride (10 g) was added to the aqueous phase which was extracted with ethyl acetate (3×25 mL). The combined ethyl acetate extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound as a mobile oil (6.29 g). GC retention time 14.2 mins
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8](I)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].C([Li])CCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>C1COCC1>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([B:23]([OH:28])[OH:24])[CH:7]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Temperature: -75 °C
Reaction time: 4 h

Procedure:
N-Cyclopropyl-5-fluoro-3-iodo-4-methylbenzamide (Intermediate 37, 5 g) in THF (75 ml) was cooled to 0° C. and sodium hydride (60%, 1.23 g) added portionwise over 10 minutes. Once effervescence had ceased the reaction was cooled to −75° C. and n-butyl lithium (1.6M in hexanes, 20 ml) added over 25 minutes maintaining a temperature of <−70° C. Triisopropyl borate (8 ml) was added to the reaction over 10 minutes and the reaction stirred at −70° C. for 4 hours. The reaction was quenched with water (20 ml) and the mixture allowed to warm to 5° C. The reaction was concentrated under vacuum and the residue partitioned between saturated ammonium chloride and ethyl acetate. The organic phase was washed with saturated ammonium chloride, brine, dried (sodium sulphate) and reduced to dryness under vacuum. The residue was dissolved in DCM/ethyl acetate and purified by column chromatography on silica eluting with an ethyl acetate/DCM gradient (5-100% ethyl acetate) and then methanol. The product fractions were combined and the solvent evaporated under vacuum to give {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid. LCMS MH+ 238, retention time 2.19 min.
Reaction SMILES: CS(C)=O.[OH-].[K+].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)([O-:9])=[O:8].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=2)[CH:13]=[CH:14]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(ccn2Cc2ccccc2)c1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
Dry dimethylsulphoxide (20 ml) was added to potassium hydroxide (4.2 g, 0.074 mol) (crushed pellets) and the mixture was stirred under nitrogen for 5 mins. 5-Nitroindole (commercially available) (3.0 g, 0.019 mol) was then added and the red mixture stirred for 30 min at room temperature. The mixture was then cooled to −10° C., benzyl bromide (4.4 ml, 0.037 mol) was slowly added and the mixture stirred and allowed to warm to room temperature over a period of 40 mins. Water (50 ml) was then added and the mixture was extracted with diethyl ether (2×200 ml). The extracts were washed with water (4×50 ml), dried over sodium sulphate and evaporated to leave an oily solid. The excess benzyl bromide was removed by dissolving the whole in diethyl ether (50 ml), diluting this solution with 40-60 petrol (50 ml) and then gradually removing the diethyl ether in vacuo to leave a yellow solid suspended in the petrol. The solid was filtered, washed with copious amounts of 40-60 petrol and dried to give 1-benzyl-5-nitroindole (2.4 g, 51%) as a yellow solid, m.p. 102-104° C.; δH [2H6]-DMSO 8.53 (1H, s, 4-H), 8.00 (1H, d, J 9, 6-H), 7.78 (1H, s, 2-H), 7.68 (1H, d, J 9, 7-H), 7.36-7.20 (5H, m, 2′-H, 3′-H, 4′-H, 5′-H, 6′-H), 6.81 (1H, s, 3-H), 5.52 (2H, s, CH2).
Reaction SMILES: I[C:2]1[C:3]([N:8]([CH3:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH:17][C@H:18]([CH2:31][CH2:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C@H:19]([CH3:30])[O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH3:9][N:8]([CH3:10])[C:3]1[C:2]([C:24]2[CH:25]=[CH:26][C:21]([O:20][C@@H:19]([CH3:30])[C@H:18]([OH:17])[CH2:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:22][CH:23]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: CN(C)c1ncccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cccnc2N(C)C)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C

Procedure:
Prepared according to the method described in Example 21b) from 3-iodo-2-dimethylaminopyridine (Example 23a), 0.253 g), ethanol (3 ml), 2M aqueous sodium carbonate (0.5 ml), (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (Example 21a), 0.200 g), and tetrakis(triphenylphosphine)palladium(0) (0.02 g) with heating at 90° C. for 3 hours.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([Cl:10])=[C:8]([C:11]#[N:12])[CH:7]=[N:6][N:5]2[CH:13]=1.[OH:14]S(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([Cl:10])=[C:8]([C:11]([NH2:12])=[O:14])[CH:7]=[N:6][N:5]2[CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn2cc(Br)cc2c1Cl
Product: NC(=O)c1cnn2cc(Br)cc2c1Cl
Temperature: 55 °C
Yield: 89 %

Procedure:
To a 50 mL round bottom flask was added 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carbonitrile (12 g, 0.046 mol) and concentrated H2SO4 (60 mL). The reaction mixture was heated at 55° C. for 2 hours then cooled to room temperature and slowly diluted with ice water to precipitate the product which was collected by vacuum filtration, rinsed with water and dried to yield 11.2 g (89%) of the title compound as a yellow solid. HPLC (condition P): retention time=7.780 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)[CH:28]=4)[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:36]C(=O)C)[CH:10]=1>Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([C:24]4[N:25]=[N:26][N:27]([CH:29]5[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]5)[CH:28]=4)[CH:23]=[C:18]3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH2:36])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(C5CCN(C)CC5)nn4)cnc32)c1
Agent: Cl
Product: CN1CCC(n2cc(-c3cnc4c(c3)ncn4-c3cc(N)cc(-c4ccc(F)cc4F)c3)nn2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
The compound of Example 181 (0.4 g, 0.757 mmol) was added to aqueous 6 N HCl (10 ml) at 0° C. and the mixture was stirred at 70° C. for 3 h. The mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate and the residue was purified by column chromatography (60-120 silica gel, 10% methanol in DCM) to give the product in 30% yield (0.11 g). LC-MS (ESI): Calculated mass: 486.52; Observed mass: 487.3 [M+H]+ (rt: 0.22 min).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([OH:21])[CH2:19][CH2:18][C@@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1.[O:22]=[C:23]1[NH:31][C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[N:24]1[CH:32]1[CH2:37][CH2:36][N:35]([C:38](OC2C=CC([N+]([O-])=O)=CC=2)=[O:39])[CH2:34][CH2:33]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C)C=O>[O:22]=[C:23]1[NH:31][C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[N:24]1[CH:32]1[CH2:33][CH2:34][N:35]([C:38]([O:20][C@H:17]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH2:10][C@@:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])([OH:21])[CH2:19][CH2:18]2)=[O:39])[CH2:36][CH2:37]1
Reactant: O[C@@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O[C@@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100.3 %

Procedure:
In an oven-dried 100 mL round-bottom flask was dissolved (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6,9-diol (71 mg, 0.244 mmol) (azeotroped with dry benzene) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (121 mg, 0.317 mmol) in dimethylformamide (2 mL) to give a light yellow suspension under nitrogen. NaHMDS (0.926 mL, 0.926 mmol) was added dropwise. The resulting yellow suspension was stirred under nitrogen at room temperature for 3.5 h. LCMS showed complete conversion. The reaction was quenched with saturated sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (LCMS showed no product left in the aqueous phase). The combined organic layers were washed with water, brine, dried with sodium sulfate, and concentrated to give a yellow oil. Purification by FCC up to 10% methanol/methylene chloride afforded the desired product (131 mg, 100%) as a white powder. LCMS and HPLC showed >99% purity. MS(ESI)[M+H+]=536.26; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.31 (br. s., 1H) 8.35-8.50 (m, 1H) 7.97-8.11 (m, 1H) 7.31-7.60 (m, 3H) 7.02-7.18 (m, 3H) 6.98 (dd, J=7.48, 5.34 Hz, 1H) 6.03 (d, J=10.68 Hz, 1H) 4.60 (br. s., 2H) 4.40 (br. s., 1H) 3.97 (d, J=14.34 Hz, 1H) 2.80-3.20 (m, 4H) 2.67 (t, J=11.75 Hz, 2H) 2.17-2.40 (m, 2H) 2.08 (t, J=12.67 Hz, 2H) 1.89 (d, J=11.29 Hz, 2H); 19F NMR (470 MHz, CHLOROFORM-d) δ ppm −138.72 (d, J=15.15 Hz, 2F).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+:2]=[N-:3].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].C(O)(C)(C)C.[K]>O1CCCC1.C(O)(C)(C)C.O1CCCC1>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[C:5]1=[O:15])=[N+:2]=[N-:3]
Reactant: C=CC(=O)OCC
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)CCN1C(=O)C(N=[N+]=[N-])CCc2ccccc21

Procedure:
A solution of 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one [prepared as described by Watthey et al., J. Med. Chem., 28, p. 1511-15156 (1985)] in tetrahydrofuran/tert-butanol was cooled to 0° C. and treated with ethyl acrylate and 1N tert-butanol, potassium salt/tetrahydrofuran according to the procedure of Example 40 part (a) affording 3-azido-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-propanoic acid, ethyl ester as a syrup. TLC (ethyl ether:hexane, 1:1) Rf =0.45.
Reaction SMILES: [C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1.[CH2:18]([O:34][C:35]1[CH:54]=[CH:53][C:38]([C:39](O)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:37][CH:36]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([Cl:58])(=O)C>>[CH2:18]([O:34][C:35]1[CH:54]=[CH:53][C:38]([C:39]([Cl:58])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:37][CH:36]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(C(O)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Product: CCCCCCCCCCCCCCCCOc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Yield: 75 %

Procedure:
In the chemical synthesis of polynucleotide fragments by the triester procedure, chromatographic methods are important for the purification of protected intermediates and for the isolation of the unprotected final product. The chromatographic behavior of the oligomers can be varied within certain limits by protecting groups, generally producing an unspecific change in the total polarity of the molecule. For example, Gortz et al. Angew. Chem. Int. Ed. Engl., 20(8): 681-683 (1981) describe introducing 4-alkoxytrityl groups for hydrophobic protection at the 5'-end of oligonucleotides. These 4-alkoxytrityl groups contain 8, 10, 12, 14, and 16 carbon atoms. Gortz et al. synthesized 4-hexadecyloxytrityl protected thymidine by first treating 4-hexadecyloxytritanol with acetyl chloride to produce 4-hexadecyloxytrityl chloride. The 4-hexadecyloxytrityl chloride was then treated with thymidine in anhydrous pyridine in the presence of 4-dimethylaminopyridine. After various purification and separation procedures, a 75% yield was obtained. This 4-hexadecyloxytrityl protected thymidine was then condensed onto the 5'--O--position of the terminal nucleotide of a support bound oligonucleotide.
Reaction SMILES: [CH2:1]([CH:10]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=1)[N:11]1[CH:14]([CH2:15][C:16](=[O:38])[CH:17](C(OC(C)(C)C)=O)[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[CH:13]([CH:39]([O:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=2)=[O:43])[CH3:40])[C:12]1=[O:55])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:56]([CH:10]([CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[N:11]1[CH:14]([CH2:15][C:16](=[O:38])[CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])[CH:13]([CH:39]([O:41][C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]([N+:52]([O-:54])=[O:53])=[CH:50][CH:51]=2)=[O:43])[CH3:40])[C:12]1=[O:55])[C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=1
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)CC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.3 g of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-t-butoxycarbonyl-3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone was dissolved in 120 ml of dried methylene chloride, and 10 ml of trifluoroacetic acid was added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and then with water, dried over sodium sulfate and distilled off to remove the solvent. The residue was purified by silica gel chromatography to obtain 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH3:14])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CC[O:43][CH2:42]C1>ClCCl.C(O)=O>[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH3:14])[N:6]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH:42]=[O:43]
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)cc1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: O=CO
Product: COC(=O)[C@H](C)N(C=O)c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
(±)-(4-Chlorophenyl)alanine methyl ester hydrochloride (2.00 g) was suspended in dichloromethane (20 ml), and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (1.60 g), 1-hydroxybenzotriazole monohydrate (1.23 g), N-methylmorpholine (1.90 ml) and formic acid (0.30 ml) were added to stir the mixture for 15 minutes. After a process in which formic acid (0.30 ml) was additionally added to stir the mixture for 15 minutes was repeated 3 times, the reaction mixture was diluted with dichloromethane. After an ogranic layer was washed with water and then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane methanol=40:1) to obtain the title compound (1.21 g) as a yellow oil.
Reaction SMILES: [H-].[Na+].C(S)C.Cl[C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16](C2C=C(Cl)C=CC=2Cl)[C@H](C)CCCBr)(=[O:15])=[O:14])=[CH:9][CH:8]=1>O1CCCC1>[C:10]1([S:13]([NH2:16])(=[O:15])=[O:14])[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](CCCBr)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of NaH (0.025 g, 1.03 mmol) in tetrahydrofuran (2 mL) was added ethanethiol (0.096 g, 1.54 mmol), followed by 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide (0.500 g 1.03 mmol) under nitrogen at 0° C. The reaction was stirred overnight at 22° C. The mixture was quenched with H2° (3 mL), extracted with ethyl ether (2×10 mL), dried over Na2SO4, and filtered. The organic solvent was concentrated under reduced pressure. Silica gel chromatography (1:9, ethyl acetate:hexanes) afforded 0.460 g of 4-chloro-N-[2,5-dichlorophenyl}-N-[4-(ethylthio)]-1-(R)-methylbutyl]benzenesulfonamide as a yellow oil in 59% yield. LC/MS 466.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]([NH2:15])=O)[N:3]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH2:12][C:13]#[N:15])[N:3]=1
Reactant: CCCc1cc(O)nc(SCC(N)=O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CCCc1cc(Cl)nc(SCC#N)n1

Procedure:
To a suspension of 4.5 g. (0.02 mole) of 2-(4-hydroxy-6-propyl-2-pyrimidinylthio)acetamide in 50 ml of phosphorus oxychloride was added 2.98 g. of N,N-diethylaniline. The mixture was heated for ten minutes to reflux temperature. The phosphorus oxychloride was removed in a rotary evaporator and the residue was poured into 150 ml of ice-water. The water mixture was extracted with 100 ml of ether. The ether layer was dried over magnesium sulfate, filtered and evaporated in a rotary evaporator to give an oil. A small amount of the oil was dried in vacuo without purification to afford the analytical sample.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:30][CH3:31])=[CH:5][C:6]2[C:15]3[C:10](=[C:11]4[CH:19]=[C:18]5[O:20][CH2:21][O:22][C:17]5=[CH:16][C:12]4=[N:13][CH:14]=3)[N:9]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:8](=O)[C:7]=2[CH:29]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[C:4]([O:30][CH3:31])=[CH:5][C:6]2[C:15]3[C:10](=[C:11]4[CH:19]=[C:18]5[O:20][CH2:21][O:22][C:17]5=[CH:16][C:12]4=[N:13][CH:14]=3)[N:9]([CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])[CH2:8][C:7]=2[CH:29]=1
Reactant: COc1cc2c(=O)n(CCN(C)C)c3c4cc5c(cc4ncc3c2cc1OC)OCO5
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)-c1cnc3cc4c(cc3c1N(CCN(C)C)C2)OCO4
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of 8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one (160 mg, 0.38 mmol) in THF (650 mL) was added LiAlH4 (75 mg, 2.0 mmol), and the mixture was stirred under nitrogen at reflux. After 2 h, an additional 2.0 mmol of LiAlH4 was again added. The reaction was refluxed for an additional 3h, then allowed to cool to room temperature. The reaction was quenched by the sequential addition of water (5 drops), 10% NaOH (5 drops), and water (5 drops). The mixture was filtered through Celite and evaporated, and the crude mixture was chromatographed on silica in 98:2 chloroform-methanol, to give 132 mg of the reduced product, in 85% yield; mp 271-273° C. (dec.); 1H NMR (CDCl3) δ 2.24 (s, 6H), 2.58 (t, 2H, J=6.8), 3.12 (t, 2H, J=6.8), 3.97 (s, 3H), 4.02 (s, 3H), 4.27 (s, 2H), 6.13 (s, 2H), 6.79 (s, 1H), 7.38 (s, 2H), 7.61 (s, 1H), 9.05 (s, 1H); 13C NMR (CDCl3) δ 46.0, 50.6, 51.2, 56.2, 26.3, 58.4, 99.6, 101.7, 105.7, 106.6, 110.0, 120.7, 123.1, 124.8, 131.1, 144.1, 146.9, 148.0, 149.0, 149.4, 149.8, 150.2; HRMS calcd for C23H25N3O4: 407.1845; found 407.1848.