Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:21])[C:18](O)=[O:19])[CH:11]=[CH:10]2.CN(C=O)C>C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:21])[C:18]([Cl:3])=[O:19])[CH:11]=[CH:10]2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Yield: 88.7 %

Procedure:
Compound 2 was prepared from the corresponding carboxylic acid. Thionyl chloride (1.24 g, 10.42 mmoles) was added to a solution of (S)-(+)-2-(6-methoxy-naphthalen-2-yl)-propionic acid (Naproxen, 2 g, 8.69 mmoles) in 8.2 mL chloroform in a round bottom flask equipped with magnetic stirring. A drop of DMF was added and the mixture was refluxed for 3 hours. Chloroform and excess thionyl chloride were distilled from the reaction mixture while methylene chloride was added. Evaporation of residual solvent yielded (S)-2-(6-methoxy-naphthalen-2-yl)-propionyl chloride (1.918 g, 88.8% yield). Rf=0.2 (1:1 hexanes:ethyl ether). 1H NMR (400 MHz, CDCl3) δ 9.98 (br, 1H), 7.78 (t, 2H), 7.36 (d, 1H), 7.18 (d, 1H), 7.14 (m, 2H), 4.25 (q, 1H), 3.93 (s, 3H), 1.68 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:6][O:5][C:4]([C:7]2[CH:28]=[CH:27][C:10]([O:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][N:17](CC4C=CC=CC=4)[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:3]1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:29])[CH2:6][O:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:27][CH:28]=2)=[N:3]1
Reactant: [H][H]
Reactant: CC1(C)COC(c2ccc(OCCC3CCN(Cc4ccccc4)CC3)cc2)=N1
Agent: [Pd]
Solvent: CO
Product: CC1(C)COC(c2ccc(OCCC3CCNCC3)cc2)=N1
Yield: 86.4 %

Procedure:
A mixture of 5 parts of 4-[2-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenoxy]ethyl]-1-(phenylmethyl)piperidine and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 3.4 parts (86.4%) of 4-[2-[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenoxy]ethyl]piperidine as a residue (int. 75).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH3:29][C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][N:23]([S:36]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([CH3:29])[CH:31]=4)(=[O:38])=[O:37])[CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B5*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[N:8][NH:9][C:10](=O)[C:4]2=[CH:3][CH:2]=1.C(#N)C.O=P(Cl)(Cl)[Cl:17].[ClH:20]>O1CCOCC1>[ClH:17].[Cl:20][C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[N:8][N:9]=1
Reactant: O=c1[nH]ncc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Clc1nncc2ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 50 g (342 mmol) phthalazone, 1370 ml acetonitrile, 66 ml (0.72 mol) POCl3 and 85 ml 4 N HCl in dioxane is stirred for 8 h at 50° C. The resulting solution is cooled to RT, evaporated to a volume of about 0.8 l and diluted with 1.2 l DIPE. Filtration and washing with DIPE yield the title compound: FAB-MS (M+H)+=165/167.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[OH:32][CH:33]1[CH2:37][C:36](=[O:38])[CH:35]=[CH:34]1>C(Cl)Cl>[C:1]([O:38][CH:36]1[CH2:37][C:33](=[O:32])[CH:34]=[CH:35]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CC(O)C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1C=CC(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37 %

Procedure:
A solution of trityl chloride (3.44 g, 12.3 mmol) in methylene chloride (20 mL) is treated sequentially with 1,8-diazabicyclo[5.4.0]undec-7-ene (2.2 mL, 14.7 mmol, DBU) and 4-hydroxy-2-cyclopentenone (1.01 g, 10.0 mmol, in 5 mL of methylene chloride, prepared in example 1). The reaction is stirred for 3 days at room temperature and then poured onto ice (approximately 25 mL). The phases are separated and the organic phase is washed with water (25 mL). The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by column chromatography (silica gel, 10-20% ethyl acetate/hexane) to provide the title compound (1.26 g, 36 %) as a pale yellow oil; 1H NMR (CDCl3) δ 7.5 (m, 6 H), 7.3 (m, 9 H), 6.85 (dd, 1 H), 6.05 (d, 1 H), 4.8 (m, 1 H), 2.1 (m, 2 H); 13C NMR (CDCl3) δ 206.6, 162.9, 144.3, 135.2, 128.8, 128.4, 127.7, 88.2, 73.1, 43.4; IR (KBr) νmax 3061, 1719, 1491, 1449, 1352, 1181, 1107, 1053 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1cc(C)ccc1[N+](=O)[O-]
Product: CC(O)c1cc(CBr)ccc1[N+](=O)[O-]

Procedure:
Compound 2 is synthesized in two steps from 1-(5-methyl-2-nitrophenyl) ethanone (1), which can be obtained as described by Doppler et al. (1979) Helv. Chem. Acta 62:291-303. Specifically, the ring methyl group is brominated using N-bromosuccinimide and then the benzylic ketone is reduced to an alcohol. Those procedures are described below.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[N:9]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[N:11][CH:10]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:9]1[CH:14]=[C:13]([CH2:15][O:16][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)[CH:12]=[N:11][CH:10]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OCc1cncnc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2cncnc2)n1
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
Into 4 g of N,N-dimethylformamide were dissolved 304 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 200 mg of 5-pyrimidylmethyl alcohol, 97 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes. After stirring for 5 hours at room temperature, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 210 mg of 5-(5-pyrimidylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (37)).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.Cl.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[C:27]([CH3:38])[CH:26]=1>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]2[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([C:6]([CH:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:34][CH2:33]2)=[C:27]([CH3:38])[CH:26]=1
Reactant: COc1cc2ncnc(Nc3ccc(OC4CCNCC4)c(C)c3)c2cc1OC
Reactant: O=C(O)[C@H]1CCCO1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(OC4CCN(C(=O)C5CCCO5)CC4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,1′-carbonyldiimidizole (41.38 mg, 0.255 mmol) in N,N-dimethylformamide (1 mL) was added (R)-(+)-tetrahydrofuroic acid (29.6 mg, 0.255 mmol). The reaction was stirred at room temperature for 30 minutes then (6,7-dimethoxy-quinazolin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine hydrochloride was added. The reaction was stirred at room temperature overnight. The following day, the reaction was filtered through a 0.45 μm PTFE membrane filter and purified by preparatory HPLC. 1H NMR (300 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.51(d, d, J=8.71 Hz, 2H), 7.16(s, 1H), 7.05(d, J=8.4 Hz, 1H), (t, J=13.06 Hz, 7.15 Hz, 1H), 3.95(s, 3H), 3.93(s, 3H), 3.75(m, 4H), 3.44(m, 2H), 2.21(s, 3H), 2.03(m, 4H), 1.85(m, 2H), 1.70(m, 2H), LMRS (M+): 493.5, (M−): 491.5.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[O:11][C:12]([CH3:30])=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:20][CH:19]=2)[N:14]=1.[OH-].[Na+]>CO.O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[O:11][C:12]([CH3:30])=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[N:14]=1
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3cc4ccccc4s3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2cc3ccccc3s2)nc1CCOc1ccc(CCC(=O)O)cc1
Reaction time: 13 h
Yield: 97.9 %

Procedure:
Methyl 3-[4-[2-(2-(benzothiophen-2-yl)-5-methyl-4-oxazolyl)ethoxy]phenyl]propionate (1.90 g, 4.51 mmol) obtained in Example 13 was dissolved in methanol (20 ml) and tetrahydrofuran (30 ml), and 2.5N aqueous sodium hydroxide solution (2.2 ml, 5.5 mmol) was added at room temperature, which was followed by stirring for 13 hr. Then, the solvent was evaporated and water was added to the obtained residue. 1N Hydrochloric acid was added to acidify the solution and the precipitated white solid was collected by filtration, washed with water and dried to give the title compound (1.80 g, yield 98%) as a white solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:8][C:7]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:6][NH:5]1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.Cl>CN(C)C=O>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([CH2:22][N:5]2[C:4](=[O:3])[CH2:8][C:7]3([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[CH2:6]2)=[CH:24][CH:25]=1)=[O:28]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)CC2=O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Under an argon atmosphere, to an N,N-dimethylformamide (2 mL) solution of sodium hydride (60%, 94 mg), an N,N-dimethylformamide (4 mL) solution of tert-butyl 3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (514 mg) was added at 0° C. The reaction solution was stirred at 50° C. for one hour. The solution was cooled to 0° C. and then an N,N-dimethylformamide (2 mL) solution of methyl 4-(bromomethyl)benzoate (442 mg) was added. The reaction solution was stirred at 0° C. for 30 minutes. To the reaction solution, 0.5N-hydrochloric acid (20 mL) was added. The aqueous layer was extracted twice with ethyl acetate. The aqueous layer was combined with the organic layer, washed in turn with water and saturated brine, and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0→1:2) to obtain the title compound (553 mg) having the following physical properties.
Reaction SMILES: I[C@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[OH-].[Na+].[CH2:13]([OH:15])[CH3:14]>>[CH2:13]([O:15][C:6]([C@@H:5]1[CH2:4][CH2:3][C@H:2]2[C@H:8]([O:7]2)[CH2:9]1)=[O:10])[CH3:14]
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@H]2I
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)[C@@H]1CC[C@@H]2O[C@@H]2C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(1R*,4R*,5R*)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one (J. Org. Chem., vol. 61, p. 8687 (1996)) (14.3 g) was dissolved in ethanol (130 mL), and 2N aqueous sodium hydroxide (34.5 mL) was added to the solution under ice cooling, followed by stirring at room temperature for 7 hours. The solvent was distilled away under reduced pressure, and water was added to the residue. The mixture was extracted with methylene chloride, and the extract was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=83:17), to thereby give the title compound (6.54 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2].[CH3:16][C@H:17](O)[CH2:18][CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C@@H:17]([CH2:18][CH3:19])[CH3:16])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2]
Reactant: CC[C@H](C)O
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(O[C@H](C)CC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (700 mg, 3.33 mmol) in DCM (40 ml) were successively added (S)-butan-2-ol (0.37 ml, 4.0 mmol), supported PPh3 (loading of 1.52 mmol/g, 4.38 g, 6.66 mmol) and DTAD (1.15 g, 5.0 mmol). The reaction mixture was shaken at RT for 3 h, then filtered and the resin was washed with DCM. The filtrate was evaporated to dryness and the resulting residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME 95:5→1:1) to yield the title compound (818 mg, 3.07 mmol, 92%) as a colorless oil. TLC: RF=0.85 (heptane/DCM/TBME 1:1:2); HPLC: BtRet=2.46 min; API-MS: m/z 267.2 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.00 (t, J=7.5, 3H), 1.28 (t, J=7.1, 3H), 1.33 (d, J=6.1, 3H), 1.60-1.70 (m, 1H), 1.77-1.89 (m, 1H), 3.56 (s, 2H), 3.86 (s, 3H), 4.17 (q, J=7.1, 2H), 4.25 (sxt, J=6.1, 1H), 6.79 (dd, J=8.3, 2.0, 1H), 6.83-6.87 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[CH2:25]([O:27][P:28]([O:32]CC)[O:29][CH2:30][CH3:31])[CH3:26]>C(OCC)(=O)C>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P:28](=[O:32])([O:29][CH2:30][CH3:31])[O:27][CH2:25][CH3:26]
Reactant: CCOP(OCC)OCC
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCBr
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O)OCC
Temperature: 135 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
2-(12-bromododecyl)isoindoline-1,3-dione (9.30 g, 23.6 mmol) was combined with triethylphosphite (11.76 g, 70.7 mmol) in a round bottom flask and the mixture heated and stirred at 135° C. for 16 hours. The reaction mixture was then put under hi-vacuum at 90° C. for 4 hours. The product was then obtained as a clear oil after column chromatography in ethyl acetate. (8.96 g, 84% yield). 1H NMR (400.14 MHz, CDCl3) δ 7.80 (dd, J=5.43, 3.04 Hz, 2H), 7.67 (dd, J=5.47, 3.05 Hz, 2H), 4.08-4.02 (m, 4H), 3.63 (t, J=7.33 Hz, 2H), 1.73-1.45 (m, 6H), 1.32-1.11 (m, 22H). 13C{1H} NMR (100.62 MHz, CDCl3) δ 168.4 (2C), 133.7 (2C), 132.1 (2C), 123.0 (2C), 61.30 (d, J=6.5 Hz, 2C), 37.96, 30.51, (d, J=17.0 Hz), 29.41 (2C), 29.35, 29.25, 29.07, 28.98, 28.49, 26.75, 25.55 (d, J=140.1 Hz), 22.29 (d, J=5.0 Hz), 16.39 (d, J=6.1 Hz, 2C). 31P{1H} NMR (161.97 MHz, CDCl3): δ 33.38. MS (ESI, m/z): 452.235 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 452.256039 (452.254800). Analysis calculated (found) %: C, 63.84 (63.41), H, 8.48 (8.53).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[S:11])[NH:8]2)=[CH:4][N:3]=1.[OH-].[K+].I[CH3:15]>CCO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([S:11][CH3:15])=[N:8]2)=[CH:4][N:3]=1
Reactant: S=c1[nH]c2cnc(Cl)nc2[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc2nc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirring solution of 2-chloro-7H-purine-8(9H)-thione (2.00 g, 10.72 mmol) and potassium hydroxide (722 mg, 12.86 mmol) in anhydrous EtOH (66.4 mL) was added iodomethane (0.67 mL, 10.72 mmol). The reaction solution was stirred under N2 at RT for 4 h, then partitioned between EtOAc (85 mL) and 2N HCl (15 mL) and allowed to settle overnight. To the aqueous layer, which contained solid material, was added more water (60 mL). The mixture was filtered, and dried under vacuum to afford the title compound as a solid. LC-MS: calculated for C6H5ClN4S 199.99 observed m/e: 200.99 (M+H)+ (Rt 0.99/1.8 min).
Reaction SMILES: [Si:1]([O:8][C:9]([C:11]([F:35])([F:34])[C@:12](OS(C(F)(F)F)(=O)=O)([C@@H:14]([CH:16]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:17])[OH:15])O)=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:36]=[N+:37]=[N-:38].[Li+]>CN(C)C=O>[Si:1]([O:8][C:9]([C:11]([F:35])([F:34])[C@H:12]([N:36]=[N+:37]=[N-:38])[C@@H:14]([CH:16]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:17])[OH:15])=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@](O)(OS(=O)(=O)C(F)(F)F)[C@H](O)C(O)C(=O)c1ccccc1
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@H](N=[N+]=[N-])[C@H](O)C(O)C(=O)c1ccccc1
Temperature: 70 °C
Yield: 55.9 %

Procedure:
To a solution of 4.53 g (8.7 mmol) 1-t-butyldimethylsilyloxy-5-benzoyl-3-trifluoromethanesulfonyloxy-2-deoxy-2,2-difluoroxylose in dimethylformamide (50 ml) were added 1.2 g (25.2 mmol) lithium azide and the reaction mixture was heated at 70° C. for 40 minutes. The reaction mixture was then concentrated under reduced pressure and the residue dissolved in ethyl acetate. This solution was washed several times with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was redissolved in a small amount of ethyl acetate and poured over a pad of silica gel, eluting with ethyl acetate. The filtrates were concentrated under reduced pressure to give 2.09 g (58%) of the desired compound as a colorless oil. FD-MS: m/e=356, (M-57, loss of t-butyl), 357((M+1)-57, loss of t-butyl). IR(neat): 2114 cm-1, N3.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.[H+].[CH2:24](Cl)Cl>>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:24])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCO
Reactant: ClCCl
Agent: F[B-](F)(F)F
Agent: [H+]
Product: COCCCCCCCCNC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To a vigorously stirred mixture of BocNH(CH2)8OH (392 mg, 1.6 mmol) and fluoroboric acid (210 μL, 1.6 mmol) in DCM (8 mL), the TMS CHN2 (800 μL, 1.6 mmol) was added dropwise at 0° C. The solution was stirred at 0° C. and three further additions of TMS CHN2 (400 μL, 0.8 mmol and 200 μL×2, 0.4 mmol) were added at 15-minute intervals. The mixture was stirred for a further 4 hours after which starting material was still visible by t.l.c. but no further evolution of the reaction was however apparent.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[Br:15][C:16]1[CH:17]=[N:18][C:19](I)=[N:20][CH:21]=1>>[Br:15][C:16]1[CH:17]=[N:18][C:19]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:20][CH:21]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Brc1cnc(I)nc1
Product: Cc1onc(-c2ccccc2)c1C#Cc1ncc(Br)cn1
Yield: 56 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (55 mg, 0.30 mmol) was converted (using 5-bromo-2-iodo-pyrimidine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 58 mg, 56%) which was obtained as a light yellow solid. MS: m/e=341.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.Br[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:18][C:19]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[C:20]=2[C:21]([O:23][CH3:24])=[O:22])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: COc1cccc(S)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1c(CSc2cccc(OC)c2)cccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 806.2 %

Procedure:
To a solution of 3-methoxythiophenol (0.54 g, 0.48 mmol) and triethylamine (0.43 ml, 0.59 mmol) in dichloromethane (30 ml) was slowly added methyl 2-bromomethyl-6-nitrobenzoate (1.45 g, 5.3 mmol) under ice-cooling, followed by stirring for 3 hours. After the reaction was completed, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give methyl 2-(3-methoxyphenylthiomethyl)-6-nitrobenzoate (1.29 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](=O)[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C(COC)OC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](=[S:28])[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(N)=O)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(OCC(N)=S)CC1

Procedure:
A solution of 4-carbamoylmethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 13, 67.5 mg, 260 μmol) and Lawesson's reagent (116 mg, 287 μmol) in dimethoxyethane (1.5 ml) was stirred at rt for 24 h. The solvent was evaporated and the residue purified by flash chromatography (5% MeOH in CH2Cl2) to afford the title compound: δH (CDCl3) 1.50 (9H, s), 1.55-1.63 (2H, m), 1.88-1.95 (2H, m), 3.12 (2H, ddd), 3.59-3.66 (1H, m), 3.79-3.87 (2H, m), 4.40, (2H, s), 7.65 (1H, bs), 8.04 (1H, bs).