Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].Cl[P:8]1(=[S:18])[O:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[O:9]1>CO>[CH3:12][O:13][P:8]1(=[S:18])[O:4][CH2:1][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[O:9]1
Reactant: S=P1(Cl)OCc2ccccc2O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COP1(=S)OCc2ccccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
Into a reaction flask was placed 150 ml methanol, 21 g (0.15 moles) potassium carbonate, and 22 g (0.1 moles) of 2-chloro-4H-1,3,2-benzodioxaphosphorin-2-sulfide. The reaction mixture was stirred at room temperature for 2 hours, filtered, and the axcess methanol recovered via reduced pressure. The residue was dissolved in 50 ml chloroform, washed with two portions of water (total of 100 ml), dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue crystallized to yield 19.2 g (92%) of 2-methoxy-4H-1,3,2-benzodioxaphosphorin-2-sulfide having a melting point 50°-53° C. The melting point, IR and NMR spectra of this product were identical to the known insecticide, Salithion. By using corresponding alkanols instead of methanol, the corresponding 2-alkoxy derivatives are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccccc1-c1ccc(CO)c(Br)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc(-c2ccccc2C#N)cc1Br)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
To a solution of 670 mg (2.35 mmol) of 3'-bromo-4'-hydroxymethyl-1,1'-biphenyl-2-nitrile (Step F) in 5 mL of dry dimethylformamide under a nitrogen atmosphere was added 237 mg (3.49 mmol) of imidazole. The reaction mixture was cooled to 0° C. and 0.73 mL (2.8 mmol) of t-butylchlorodiphenylsilane was added dropwise by syringe over 5 minutes. The resulting solution was stirrred at 0° C. for 15 minutes then at room temperature for 2 hours. The reaction mixture was poured into 100 mL of water and extracted with ether (3×75 mL). The combined ether extracts were washed with water (75 mL), saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL). The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum to give an oil which was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (9:1), to afford 1.24 g (100%) of the product as a clear oil. 1H NMR (200 MHz, CDCl3): δ 1.13 (s, 3H), 4.80 (s, 2H), 7.30-7.50 (m, 9H), 7.55-7.80 (m, 7H), 7.86 (d, 8 Hz, 1H). FAB-MS: calculated for C30H28BrNOSi 526; found 527, 528, 271 (60%).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([C:12]2[C:17]3[S:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[N+:16]=3[CH2:15][CH2:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I-].C1(S[C:33]2[S:34][C:35]3[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=3[N+:37]=2[CH2:38][CH3:39])C=CC=CC=1.N1C=CC=CC=1>C(OCC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:38]([N:37]1[C:36]2[CH:40]=[CH:41][CH:42]=[CH:43][C:35]=2[S:34][C:33]1=[C:14]1[CH2:15][N+:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:17]=2[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:13]1)[CH3:39]
Reactant: C1=C(c2ccccc2)c2sc3ccccc3[n+]2CC1
Reactant: CC[n+]1c(Sc2ccccc2)sc2ccccc21
Agent: [I-]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCN1C(=C2C=C(c3ccccc3)c3sc4ccccc4[n+]3C2)Sc2ccccc21
Yield: 35 %

Procedure:
1,2-Dihydro-4-phenylpyrido[2,1-b]benzothiazolium perchlorate (2.0 g., 0.0055 mole), 2-phenylthio-3-ethylbenzothiazolium iodide (2.19 g., 0.0055 mole) and pyridine (30 ml.) are heated to reflux for 3 minutes, the solution is cooled, diethyl ether (30 ml.) is added and the green solution is decanted off from the oily dye. Water is added and the dye solidifies upon cooling. The solid dye is boiled out with isopropyl alcohol. The yield of dye is 1.0 g. (35% yield). The product has a melting point of 120°-128° C with an absorption maximum at 629 nm.
Reaction SMILES: Cl.[Cl:2][C:3]([O:5][CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:4].[C:14]1([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCCl>[ClH:2].[CH2:21]([N:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3](=[O:4])[O:5][CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: O=C(Cl)OC1CN2CCC1CC2
Agent: Cl
Solvent: ClCCCl
Product: O=C(OC1CN2CCC1CC2)N(Cc1ccccc1)c1ccccc1

Procedure:
To a suspension of 750 mg (2.58 mmol) of hydrochloride of 3-quinuclidyl chloroformate in 20 mL of 1,2-dichloroethane, a solution of 395 mg (2.15 mmol) of N-phenylbenzylamine in 5 mL of 1,2-dichloroethane was added dropwise. Once completed the addition, the mixture was refluxed for three hours. The reaction crude was allowed to cool down and the solvent distilled off under reduced pressure. The residue was purified by column chromatography (eluent: chloroform-methanol 10:1) yielding 720 mg (1.95 mmol) of a hygroscopic foam corresponding to the title compound. IR (KBr, cm−1): 3400-3200, 2700-2300, 1700 cm−1. 1H-RMN (δTMS, CDCl3, ppm): 12.30 (1H, s), 7.20-6.90 (10H, m), 5.10 (1H, m), 4.83 (2H, m), 3.52 (1H, m), 3.18 (4H, m), 2.80 (1H, m), 2.34 (1H, s), 1.92 (2H, m), 1.60 (2H, m).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([C:20]([OH:22])=O)[CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5]1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([CH2:25][CH2:24][NH:23][C:20]([C:15]2[CH:16]=[CH:17][C:18]3[CH2:19][CH:10]([N:7]4[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]4)[CH2:11][CH2:12][C:13]=3[CH:14]=2)=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: NCCN1CCCC1
Reactant: CN1CCN(C2CCc3cc(C(=O)O)ccc3C2)CC1
Agent: Cl
Product: CN1CCN(C2CCc3cc(C(=O)NCCN4CCCC4)ccc3C2)CC1

Procedure:
6-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide is prepared from 6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid dihydrochloride and N-(2-aminoethyl)pyrrolidine in a manner substantially analogous to Procedure B (See herein Example 8). Observed mass 371 (M++1).
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].O1CCCC1.[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(Cl)Cl>[CH3:1][S:2][CH:3]([S:4]([CH3:6])=[O:5])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSC(Cc1ccccc1)S(C)=O
Reaction time: 1 h
Yield: 64.7 %

Procedure:
590 mg of methyl methylthiomethyl sulfoxide was dissolved in 5 ml. of tetrahydrofuran, and under cooling with ice, 171 mg (1.5 equivalents) of sodium hydride was added. The mixture was stirred for 1 hour. 813 mg of benzyl chloride was added, and the mixture was stirred at room temperature for 15 hours. 50 ml of methylene chloride and 1 ml. of water were added, and the reaction mixture was dried with anhydrous sodium sulfate, and the organic layer was concentrated at reduced pressure. The residue was subjected to column chromatography (silica gel, methylene chloride and ethyl acetate) to give 659 mg of methyl 1-methylthio-2-phenylethyl sulfoxide in a conversion yield of 92.2%.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:30][CH:29]=1>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:30][CH:29]=3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCCOc3ccc(OCc4ccccc4)cc3)(CC1)CC2
Product: [Br-]
Yield: 83.1 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0479 g, 0.163 mmol) and 1-[(3-bromopropyl)oxy]-4-[(phenylmethyl)oxy]benzene (0.0730 g, 0.227 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0833 g, 83.3%). EI-MS m/z 534 (M+) Rt (2.31 min).
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[Cl:15][C:16]1[C:17]([F:26])=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])C(O)=O.CN(C=O)C>C([O-])(O)=O.[Na+].CCOC(C)=O>[Cl:15][C:16]1[C:24]([F:25])=[C:23]([CH:22]=[CH:18][C:17]=1[F:26])[C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5]
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(F)c(Cl)c1F
Temperature: 80 °C

Procedure:
A 125 mL, single-neck, round-bottomed flask was charged with di-tert-butoxy-N,N-dimethylmethanamine (48.2 ml, 201 mmol), 3-chloro-2,4-difluorobenzoic acid (9.67 g, 50.2 mmol), and DMF (50 ml). The reaction was heated to 80° C. for 48 hours. After cooling to ambient temperature, the reaction was diluted with saturated NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated NaHCO3 and brine, dried, filtered and concentrated to provide the desired product as a gold oil.
Reaction SMILES: [OH:1][C:2]([CH2:4][C:5]1([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])=[O:3].[H-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[Na+]>CS(C)=O>[CH2:28]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:4][C:2]([OH:1])=[O:3])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:6]1=[O:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1ccc(NC(=O)NC2(CC(=O)O)C(=O)Nc3ccccc32)cc1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)NC2(CC(=O)O)C(=O)N(Cc3ccccc3)c3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 0.404 g of (RS)-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 20 ml of dry dimethyl sulfoxide was added 2.5 ml of a 1M solution of sodium hydride in dry dimethyl sulfoxide at room temperature under a nitrogen atmosphere. After stirring the mixture for 15 minutes, 0.19 ml of benzyl bromide was added thereto, followed by stirring at the same temperature for 30 minutes. The reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl ether. The ethyl ether layer was dried over anhydrous magnesium sulfate and concentrated to give (RS)-1-benzyl-3-(hydroxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:17])([F:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]([NH2:15])[CH3:14])=[N:11][CH:12]=1.[CH3:18][C:19]1(C)C(C)(C)OB(C2C=CC(CC(O)=O)=CC=2)[O:20]1.C(Cl)CCl.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:17][C:4]([F:3])([F:16])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]([NH:15][C:19](=[O:20])[CH3:18])[CH3:14])=[N:11][CH:12]=1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: C[C@@H](N)c1ccc(OCC(F)(F)F)cn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)N[C@H](C)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.9 %

Procedure:
To a suspension of (R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethylamine bis-HCl (0.75 g, 2.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylacetic acid (0.67 g, 2.6 mmol), EDC (0.59 g, 3.1 mmol), and 1-hydroxy-7-azabenzotriazole (0.42 g, 3.1 mmol) in DMF (5 mL) was added diisopropylethylamine (1.8 mL, 10.2 mmol). After stirring for 90 min at room temperature, the reaction mixture was loaded directly onto a silica gel column and purified by normal phase chromatography (20-80% EtOAc/hexanes) to give 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (0.77 g, 65%) as a viscous oil that slowly solidified to a white solid. MS (Electrospray): m/z 465.1 (M+H). To a microwave vial containing 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (50 mg, 0.11 mmol), 8-bromoquinazoline (25 mg, 0.12 mmol), and bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.01 mmol) in acetonitrile (1 mL) was added aqueous 1M sodium carbonate (1 mL, 1.0 mmol) and the mixture was heated in a microwave at 150° C. for 10 min. The top organic layer was removed, loaded onto a silica gel column and purified by normal phase chromatography (30-100% EtOAc/hexanes) to give 2-(4-quinazolin-8-ylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (21 mg, 38%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 9.37 (s, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.96 (m, 2H), 7.75 (m, 1H), 7.69 (d, J=8.2 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.22 (m, 2H), 6.79 (d, J=7.2 Hz, 1H), 5.16 (m, 1H), 4.37 (q, J=8.0 Hz, 2H), 3.68 (s, 2H), 1.44 (d, J=6.8 Hz, 3H); MS (Electrospray): m/z 467.1 (M+H). FLIPR alpha1I IP=19 nM.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16]CC)=[O:15])=[C:7]2[NH:19][CH2:20][C@@H:21]([O:23][CH3:24])[CH3:22].Cl>O.O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]2[NH:19][CH2:20][C@@H:21]([O:23][CH3:24])[CH3:22]
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1NC[C@H](C)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H](C)CNc1c(C(=O)O)cnc2ccc(Br)cc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
Add a solution of sodium hydroxide (296.7 g, 7.42 mol, 6 eq.) in water (454 mL) to a solution of ethyl 6-bromo-4[[(2S)-2-methoxypropyl]amino]quinoline-3-carboxylate (454 g, 1.24 mol) in tetrahydrofuran (4.54 L) at room temperature. Heat the mixture at 50° C. overnight. After 18 hours, cool the reaction to 0° C., add 37% aq. HCl dropwise over 30 minutes until pH=6 (ca. 450 mL) with the temperature under 23° C. Filter the precipitate formed with filter paper and wash it with water (2 L), acetone (2 L) and methyl tert-butyl ether (2 L) subsequently. Dry the white solid to give the titled compound (359 g, 86%). MS (ESI) m/z (M+H)+ 338.9, 340.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:11]#[N:12])[CH2:6][C:7](=[O:10])[CH2:8][CH3:9])[CH3:2].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:11]#[N:12])[CH2:6][C:7]1([CH2:8][CH3:9])[O:16][CH2:15][CH2:14][O:10]1)[CH3:2]
Reactant: CCOC(=O)C(C#N)CC(=O)CC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)CC1(CC)OCCO1
Temperature: 25 °C

Procedure:
In a 500 mL flask equipped with a reflux condenser and Dean-Stark trap were combined 40.0 g (218 mmol) of 2-cyano-4-oxohexanoic acid ethyl ester, 20.3 g (327 mmol) of ethylene glycol, 0.83 g (4.3 mmol) of p-toluenesulfonic acid monohydrate, and 100 mL of benzene. The reaction was heated to reflux until approximately 4.5 mL of water had been collected in the trap. The reaction was cooled to ambient temperature, washed with 50 mL of water, 50 mL of saturated δsodium bicarbonate solution and dried over sodium sulfate. The mixture was then concentrated to 46.0 g (93%) of α-cyano-2-ethyl-1,3-dioxolane-2-propanoic acid ethyl ester as a light tan oil. An NMR of the crude product showed less than 10% residual ketone remained and the crude product was used without further purification. nmr (500 MHz, CDCl3) δ0.92 (t, J=7.5 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H), 1.64 (q, J=7.5 Hz, 2H), 2.29 (dd, J=6.8, 14.6 Hz, 1H), 2.41 (dd, J=6.3, 14.6 Hz, 1H), 3.59 (dd, J=6.3, 6.8 Hz, 1H), 3.59 (m, 4H), 4.24 (q, J=7.2 Hz, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH2:5][NH2:6])=[CH:14][CH:13]=1
Reactant: COc1ccc(S)cc1
Reactant: NCc1cccc(I)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: COc1ccc(Sc2cccc(CN)c2)cc1
Yield: 88.9 %

Procedure:
The general procedure in example 39 was followed. 3-Iodobenzylamine (133 μL, 1.0 mmol), 4-methoxythiophenol (123 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 3-(4-methoxyphenyl)sulfanylbenzylamine (218 mg, 89% yield) as light yellow liquid. Column chromatographic solvent (CH2Cl2 (saturated with NH3)/MeOH=30/1). Rf=0.4 (CH2Cl2 (saturated with NH3)/MeOH=30/1), (Note: same Rf value as the starting material). 1H NMR (CDCl3, 300 MHz) δ 7.40 (dt, 2 H, J=1.8 Hz, 8.7 Hz), 7.19 (t, 1 H, J=7.8 Hz), 7.06-7.13 (m, 2 H), 7.01 (dt, 1 H, J=1.5 Hz, 7.5 Hz), 6.89 (dt, 2 H, J=2.1 Hz, 8.7 Hz), 3.82 (s, 3 H), 3.79 (s, 2 H), 1.40 (brs, 2 H). 13C NMR (CDCl3, 75 MHz) δ 159.9, 144.3, 139.0, 135.6, 129.3, 126.9, 126.7, 124.8, 124.3, 115.2, 55.7, 46.6. IR (neat, cm−1) 3373 (broad), 3072, 3060, 2939, 2836. MS (EI) m/z (relative intensity) 245 (100), 106 (60). HRMS (EI), Cald. for C14H15NOS 245.0869. Found 245.0862.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>C(O)(=O)C.N1C=CC=CC=1.CN(C=O)C.[H][H].[Pd]>[O:1]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: [H][H]
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)cc1
Yield: 64.6 %

Procedure:
The photolabile linker was prepared as described by Holmes et al. in J. Org. Chem., 60: 2318-2319 (1995). 2-methoxy-4-acetylphenol was treated with Br—(CH2)3—CO2CH3 and K2CO3 in DMF and the product was reacted with excess hydroxylamine hydrochloride/pyridine/H2O. The oxime formed was reduced with H2/Pd/C in acetic acid and the resulting amine trifluoroacetylated with the anhydride in pyridine. The product was crystallized from ethanol water (80% four steps). The product was nitrated with concentrated nitrous acid in acetic acid (86%). The protecting groups were removed by reflux in NaOH/MeOH/H2O and the crude product was reacted with Fmoc chloride (81%). 4-[(tert-butyldimethylsiloxy)methyl]benzoic acid (TBDMS-HMBA) was prepared as described by Kita et al. in J. Org. Chem., 51: 4150-4158 (1986). 4-(hydroxymethyl)-benzoic acid (0.76 g, 5 mmol) was reacted with tert-butyldimethylsilyl chloride (2.29 g, 15 mmol) and imidazole (2.04 g, 30 mmol) in dry DMF (12 mL). Aqueous workup gave (0.86 g) 65% yield of the 4-[(tert-butyldimethylsiloxy)methyl]benzoic acid with melting point 157-159° C., δppm 8.06 (d, J=8 Hz); 7.39(d, J=8 Hz); 4.78 (s); 0.94 (s); 0.11 (s).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:10]=[CH:11][CH:12]=1.Cl[CH:26](SC)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>ClCCl.ClCCCl>[Br:6][C:7]1[CH:8]=[C:9]2[C:10](=[CH:11][CH:12]=1)[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:15]([S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH2:14][CH2:13]2.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:15]([S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17])[CH2:14][CH2:13]2
Reactant: O=S(=O)(NCCc1cccc(Br)c1)c1ccccc1
Reactant: CCOC(=O)C(Cl)SC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)C1c2c(Br)cccc2CCN1S(=O)(=O)c1ccccc1
Product: CCOC(=O)C1c2ccc(Br)cc2CCN1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 79 %
Yield: 19 %

Procedure:
Tin(IV)chloride (6.67 mL of a 1 M solution in dichloromethane, 6.67 mmol) was added to N-[2-(3-bromophenyl)ethyl]benzenesulfonamide (1.08 g, 3.17 mmol) and ethyl chloro(methylthio)acetate (1.07 g, 6.35 mmol) in 1,2-dichloroethane (11 mL) under argon and the reaction was heated at reflux for 3 hours. After cooling, the mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 1:4 ethyl acetate:hexanes to give 1.07 g (79%) of ethyl 6-bromo-2-(phenylsulfonyl)-1,2,3,4-tetrahydro-1-isoquinolinecarboxylate and 255.6 mg (19%) of ethyl 8-bromo-2-(phenylsulfonyl)-1,2,3,4-tetrahydro-1-isoquinolinecarboxylate as oils.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8]Cl.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: CN1CCCCC1CCl
Product: CC(=O)Cc1ccc(OCC2CCCCN2C)cc1

Procedure:
Prepared from 1-methyl-2-chloromethylpiperidine and 4-hydroxyphenylacetone by the method of Example 1 to give a mixture (50:50) of the above product and 4-([1-methyl-piperidin-2-yl]methoxy)phenyl acetone.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:3]1[C:4]2[NH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][C:2]=1[O:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CCCCCBr
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCOc1ccc2c(c1)[nH]c1ccccc12
Yield: 33 %

Procedure:
2-Hydroxycarbazole (0.5 g, 2.7 mmol), ethyl 6-bromohexanoate (0.6 g, 2.7 mmol), and potassium carbonate (0.4 g, 3.0 mmol) in dimethyl formamide (10 ml) were heated to 120° C. for 24 h. Water was added and extraction with ethyl acetate was performed. The combined organic phases were washed with water and dried (sodium sulfate). The solvent was removed i. vac. and the residue was purified by column chromatography (silica gel, ethyl acetate: heptane=1:1) to give ethyl 6-(9H-carbazol-2 yloxy)-hexanoate (290 mg, 33%) as a colorless solid. MS (M−H+)324.