Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[C:10]([Cl:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C[Si](Cl)(C)C>C(O)CCC>[Cl:11][C:10]1[C:5]2[C:4]([NH:12][CH:13]3[CH2:16][CH2:15][CH2:14]3)=[N:3][C:2]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[N:7][C:6]=2[NH:8][CH:9]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Clc1nc(NC2CCC2)c2c(Cl)c[nH]c2n1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Clc1c[nH]c2nc(Nc3ccc4cn[nH]c4c3)nc(NC3CCC3)c12
Temperature: 116 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
A mixture of 2,5-dichloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (23 mg, 0.089 mmol), 6-aminoindazole (40 mg, 0.30 mmol) and TMSCl (0.040 mL, 0.32 mmol) in nBuOH (2 mL) was stirred at 116° C. for 18 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (8 mg). MS 354.0, 356.0 (M+H, Cl pattern); UV 201.4, 246.2, 307.9 nm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]=O)[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([Mg]Br)[CH3:17].C(OCC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16]1)[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14]
Reactant: CC[Mg]Br
Reactant: CC1(C)CCN(C=O)c2ccc(Br)cc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CCN(C2CC2)c2ccc(Br)cc21
Temperature: 50 °C
Yield: 64 %

Procedure:
A stirred, cooled (0° C.) solution of 6-bromo-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-1-carbaldehyde (Intermediate 50, 21.8, 6.7 mmol) in anhydrous tetrahydrofuran (20 mL) under argon was treated with titanium tetra-iso-propoxide (2.15 mL, 7.39 mmol) followed by 3M solution of ethyl magnesium bromide in diethyl ether (5.6 mL, 16.8 mmol) and the reaction mixture was then heated at 50° C. overnight. It was then cooled in an ice-bath, quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered over celite and evaporated in vacuo to residue which was subjected to flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent to afford the title compound as an oil (1.2 g, 64%).
Reaction SMILES: [ClH:1].C([O:9][C@@H:10]1[C@H:14]([O:15]CC2C=CC=CC=2)[CH2:13][N:12]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C@:11]1([CH3:35])OCC1C=CC=CC=1)C1C=CC=CC=1.Cl.C([OH:39])C>[Pd]>[ClH:1].[CH:24]1([CH2:23][N:12]2[CH2:13][C@@H:14]([OH:15])[C@H:10]([OH:9])[C@H:11]2[CH2:35][OH:39])[CH2:25][CH2:26]1
Reactant: CCO
Reactant: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)CN1CC1CC1
Agent: [Pd]
Agent: Cl
Product: OC[C@@H]1[C@@H](O)[C@H](O)CN1CC1CC1
Reaction time: 24 h
Yield: 100 %

Procedure:
To a solution of (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxy-methyl-1-cyclopropylmethylpyrrolidine, hydrochloride (Compound 8) (0.14 g, 0.28 mmol) in 96% ethanol (15 ml) was added 10% Pd/C (50 mg) and 1M hydrochloric acid (0.1ml). The reaction mixture was hydrogenated in Parr apparatus at 40 psi for 24 hours. The mixture was filtered and concentrated in vacuo giving (2R,3R,4R)-1-cyclopropylmethyl-3,4-dihydroxy-2-hydroxymethylpyrrolidine, hydrochloride as a yellow oil (0.063 g, yield: 100%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.O=[C:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][CH:12]1[C:11]2[NH:6][C:5]3[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=3[C:15]=2[CH2:14][CH2:13]1)[CH3:21]
Reactant: CCOC(=O)CC1CCCC1=O
Reactant: Nc1ccc(F)cc1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(F)cc21
Temperature: 115 °C
Yield: 53.1 %

Procedure:
A solution of 10.00 g of 4-fluoro-2-iodoaniline, 6.57 g of ethyl 2-(2-oxocyclopentyl)acetate and 121 mg of p-toluenesulfonic acid in 100 ml of benzene was refluxed with a Dean-Stark trap under a N2 atmosphere for 24 h. After this time, the benzene was removed under distillation. Then, 60 ml of DMF was added and the solution was degassed before 19 ml of Hunig's base followed by 405 mg of Pd(OAc)2 were added successively. The solution was heated to 115° C. for 3 h, then cooled to room temperature. To quench the reaction, 300 ml of 1 N HCl and 200 ml of ethyl acetate were added and the mixture was filtered through Celite. The phases were separated and the acidic phase was extracted twice with 200 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered through Celite and concentrated. The crude material was further purified by flash chromatography eluting with 100% toluene to provide 5.36 g of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3o2)CC1

Procedure:
A mixture of 52.5 mmol 2-chlorobenzoxazol, 53.6 mmol piperazine-1-carboxylic acid tert-butyl ester and 63 mmol of potassium carbonate in 60 ml of acetonitrile was refluxed for 16 hours. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated to yield the title compounds as a slightly orange solid. MS (m/e): 304.2 (M+H+)
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1.[C:21](=[O:23])=[O:22]>C1COCC1.O>[Cl:13][C:14]1[C:19]([C:21]([OH:23])=[O:22])=[N:18][CH:17]=[C:16]([Cl:20])[N:15]=1
Reactant: Clc1cncc(Cl)n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1ncc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a solution of diisopropylamine (13.0 mL, 92.6 mmol, 2.3 eq.) in anhydrous THF (300 mL) at −78° C. under N2 was added dropwise a solution of 1.6 M nBuLi in hexanes (57.9 mL, 92.6 mmol, 2.3 eq.). After 1 hour a solution of 2,6-dichloropyrazine in anhydrous THF (6.0 g, 40.3 mmol) was added dropwise over 30 minutes. After stirring at −78° C. for 1 hour, the reaction mixture was poured onto crushed dry ice (solid carbon dioxide), and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with water (100 mL) and washed with ethyl acetate (3×100 mL). The aqueous layer was cooled to 0° C., acidified with 2N HCl until pH ˜2, and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The resultant crude was purified by column chromatography (Si-PPC, gradient 0% to 50%, methanol in dichloromethane) to give the desired product as a beige solid (3.16 g, 40.6%). 1H NMR (CDCl3, 400 MHz) δ ppm 8.60 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]([NH2:12])[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.C(N(CC)CC)C.[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29](Cl)=[O:30])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:1][C:2]1([CH3:13])[CH:11]([NH:12][C:29](=[O:30])[O:28][CH2:27][C:24]2[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)CC2(CCC1N)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1(C)CC2(CCC1NC(=O)OCc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
7,7-Dimethyl-1,4-dioxaspiro[4.5]decan-8-amine (1.3 g, 7.027 mmol, 1 eq) was dissolved in triethylamine (3.89 ml, 28.10 mmol, 4 eq) and dichloromethane (25 ml) and added dropwise at 0° C. to a 50% solution of Cbz-Cl (2.56 ml, 8.432 mmol, 1.2 eq) in toluene, and the mixture was then stirred for 2 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was diluted with dichloromethane (100 ml), washed with water (75 ml), sat. NH4Cl solution (75 ml) and sat. NaCl solution (75 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 15% ethyl acetate in hexane), the desired product was obtained in the form of a colourless, viscous oil. Yield: 34% (960 mg, 3.0 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]2[CH2:20][CH2:19]2)=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[CH3:22].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])([C:24]([O:23][CH2:21][CH3:22])=[O:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]2[CH2:20][CH2:19]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: OC1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 30 (95 mg) and triethylmethanetricarboxylate (0.140 ml) in toluene (1.5 ml) and tetrahydrofuran (1.5 ml), stirred at RT under an inert atmosphere of nitrogen, was added trimethylphosphine, 1M in toluene (0.658 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.130 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 45 mins. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere overnight. Reaction mixture concentrated in vacuo. The residue was taken up in DCM (20 ml) and washed with water (20 mL). The 2 phases were separated, the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (146 mg). LC/MS MH+503, Rt 3.37 min (5 minute run).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl-].[NH2:23][C:24]([NH2:26])=[NH2+:25].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[NH2:25][C:24]([NH2:26])=[N:23][C:4](=[O:6])[C:3]1[CH:8]=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][C:2]=1[NH2:1]
Reactant: NC(N)=[NH2+]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-c2cccnc2)cc1N
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1cc(C(=O)N=C(N)N)c(N)cc1-c1cccnc1
Reaction time: 0.25 h

Procedure:
1.0 g of methyl 2-amino-4-(3-pyridyl)-5-methylsulfonylbenzoate [obtainable by reacting methyl 2-amino-4-bromo-5-methylsulfonylbenzoate with pyridine-3-boronic acid] is dissolved in 15 ml of 1-methylpyrrolidone and the solution is stirred for 15 min. Subsequently 0.9 g of guanidinium chloride and 2.6 ml of diisopropylethylamine are added and the mixture is stirred at room temperature for one hour. Customary workup gives N-diaminomethylene-2-amino-4-(3-pyridyl)-5-methylsulfonylbenzamide.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[CH2:46]([N:53]1[CH2:58][CH2:57][N:56](C2C=CC(N)=CC=2)[CH2:55][CH2:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:46]([N:53]1[CH2:58][CH2:57][N:56]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:14]3[N:13]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]5[O:9][CH2:10][CH2:1][O:2][C:3]=5[CH:4]=4)[C:17]([F:18])=[CH:16][N:15]=3)=[CH:25][CH:24]=2)[CH2:55][CH2:54]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cnc(Nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2)nc1Nc1ccc2c(c1)OCCO2
Yield: 33 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,4-ethylendioxyphenyl)-5-fluoro-4-pyrimidineamine (50 mg, 0.18 mmol) and 4-(4-benzylpiperazino)aniline (142 mg, 0.53 mmol) resulted N2-[4-(N-benzylpiperazino)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (30 mg, 33%). 1H NMR (CDCl3): δ 2.63 (t, J=4.8 Hz, 4H), 3.16 (t, J=4.8 Hz, 4H), 3.58 (s, 2H), 4.27 (m, 4H), 6.56 (d, 1H, NH), 6.70 (br, 1H, NH), 6.82 (d, J=8.7 Hz, 1H), 6.89 (d, J=9.0 Hz, 2H), 6.96 (dd, J=2.7 and 8.7 Hz, 1H), 7.28 (d, J=2.7 Hz, 1H), 7.30-7.36 (m, 5H), 7.39 (d, J=8.7 Hz, 2H), 7.88 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ −168.94; LCMS: ret. time: 18.12 min.; purity: 98.42%; MS (m/e): 512.95 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][CH:9]1[O:14][CH:13]([CH3:15])[CH2:12][NH:11][CH2:10]1.C(N(C(C)C)CC)(C)C>C(O)C>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:11]1[CH2:10][CH:9]([CH3:8])[O:14][CH:13]([CH3:15])[CH2:12]1
Reactant: CC1CNCC(C)O1
Reactant: Clc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1CN(c2ncccn2)CC(C)O1
Yield: 76.5 %

Procedure:
In a 100 mL recovery flask, 2-chloropyrimidine (1 g, 8.73 mmol), 2,6-dimethyl morpholine (cis:trans mixture, 1.106 g, 9.60 mmol), N,N-diisopropyl-N-ethylamine (1.241 g, 9.60 mmol), and ethanol (17.46 mL) were added and refluxed for seven hours. Upon completion of the reaction, the solvent was distilled off, and saturated sodium bicarbonate was added thereto. The resulting mixture was extracted with ethyl acetate twice, and the organic phase was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→1:2) to give the title compound (1.29 g, 76%, cis:trans mixture).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][P:24](=[O:31])([O:28]CC)[O:25]CC.Br[Si](C)(C)C.O>ClCCl.CO>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][P:24](=[O:25])([OH:31])[OH:28]
Reactant: CCOP(=O)(CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O)OCC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCP(=O)(O)O
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Diethyl 12-(1,3-dioxoisoindolin-2-yl)dodecylphosphonate (2.00 g, 4.43 mmol) was dissolved in dry dichloromethane (25 mL). Bromotrimethylsilane (1.8 mL, 14.2 mmol) was added via syringe. The reaction was capped with a greased glass stopper and allowed to stir overnight. The volatiles were removed under reduced pressure to yield a yellow oil. This was dissolved in 10:1 methanol:water (20 mL) and allowed to stir overnight. After removing the solvents, recrystallization in acetonitrile yielded a white powdery solid (1.709 g, 98% yield). 1H NMR (400.14 MHz, DMSO) δ 7.84 (m, 4H), 3.54 (t, J=7.1 Hz, 2H), 1.58-1.53 (m, 2H), 1.50-1.31 (m, 4H), 1.30-1.20 (m, 16H). 13C{1H} NMR (100.62 MHz, DMSO) δ 167.9 (2C), 134.4 (2C), 131.6 (2C), 123.0 (2C), 37.36, 30.08 (d, J=15.8 Hz), 28.99, 28.95, 28.87 (2C), 28.70, 28.53, 27.85, 27.54 (d, J=136.5 Hz), 26.22, 22.73, (d, J=4.58 Hz). 31P{1H} NMR (161.97 MHz, DMSO): δ 27.74. MS (FAB, m/z): 396.2 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 396.19399 (396.19445). Analysis calculated (found) %: C, 60.75 (60.64), H, 7.65 (7.80).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:17][O:18][P:19]([O:22]C)[O:20][CH3:21]>>[CH3:17][O:18][P:19]([CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:22])[O:20][CH3:21]
Reactant: COP(OC)OC
Reactant: ClCc1c2ccccc2cc2ccccc12
Product: COP(=O)(Cc1c2ccccc2cc2ccccc12)OC
Yield: 40.5 %

Procedure:
A solution of 9-(chloromethyl)anthracene (2.5 g, 0.011 M) in trimethylphosphite (5 mL, 5.26 g, 0.042 M) is heated at reflux temperature for 72 hours. Excess trimethylphosphite is removed under reduced pressure and the residue is chromatographed over silica gel (400 g, 40-63 μm, CH2Cl2, 50 mL fractions) using CH2Cl2 (60 fractions) and 2% CH3OH in CH2Cl2 for the remaining fractions. Fractions 86-93 (2.99 g) are found to contain desired material and an impurity and are rechromatographed (400 g silica gel, 40-63 μm, CH2Cl2, 50 mL fractions) using 2.5% acetone-CH2Cl2 to elute the column. Fractions 100-160 contains compound (1.495 g, 0.00498 M, 45%) as a yellow solid. Crystallization from ethyl acetate gives the title compound (1.34 g) as yellow needles, mp 152°-153° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[Cl:52][C:53]1[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:54]=1[CH2:55][SH:56].[CH2:62]([O:64][C:65](=[O:84])[CH2:66][C:67]1[C:71]2[CH:72]=[CH:73][C:74](OS(C(F)(F)F)(=O)=O)=[CH:75][C:70]=2[S:69][CH:68]=1)[CH3:63]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:62]([O:64][C:65](=[O:84])[CH2:66][C:67]1[C:71]2[CH:72]=[CH:73][C:74]([S:56][CH2:55][C:54]3[CH:57]=[CH:58][C:59]([Cl:61])=[CH:60][C:53]=3[Cl:52])=[CH:75][C:70]=2[S:69][CH:68]=1)[CH3:63]
Reactant: CCOC(=O)Cc1csc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: SCc1ccc(Cl)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1csc2cc(SCc3ccc(Cl)cc3Cl)ccc12

Procedure:
To a solution of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15.71 mg), DIPEA (0.187 ml), 2,4-dichlorobenzyl mercaptan (0.085 mL) and ethyl(6-(((trifluoromethyl)sulfonyl)oxy)-1-benzothiophen-3-yl)acetate (200 mg) in toluene (6 mL) was added tris(dibenzylideneacetone)dipalladium(0) (24.86 mg) at room temperature. The mixture was refluxed 1.5 h. After cooling, water was poured into mixture, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (238 mg).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].C(N(CC)CC)C.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:19]1([S:25]([O:11][CH2:10][CH2:9][CH:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])[CH3:8])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)=CCC[C@@H](C)CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CCCC(C)CCOS(=O)(=O)c1ccccc1
Temperature: 0 °C
Yield: 109.6 %

Procedure:
A solution of citronellol 6 (30.0 g, 192 mmol) in 400 mL CH2Cl2 was allowed to stir at 0° C. under N2 in a 1 L round bottom flask. Triethylamine (60 mL, 430 mmol) was added in one portion, followed by DMAP (2.0 g, 1.64 mmol). Finally, benzenesulfonyl chloride (30 mL, 240 mmol) was added dropwise via syringe. After the mixture was stirred for 2 h at 0° C., it was partitioned between petroleum ether and, sequentially, 3 M aqueous HCl, water, and brine. The organic layer was dried (Na2SO4) and the solvent was removed in vacuo at 30° C. Removal of residual solvent under high vacuum yielded citronellyl benzenesulfonate (62.4 g, 110% of theoretical) as a clear yellow oil, TLC Rf(10% MTBE/petroleum ether)=0.41. 1H NMR (CDCl3) (δ): 7.92 (m, 2H), 7.66 (m, 1H), 7.56 (m, 2H), 5.03 (m, 1H), 4.09 (m, 2H), 1.91 (m, 2H), 1.68 (m, 1H), 1.67 (s, 3H), 1.57 (s, 3H), 1.52 (m, 1H), 1.44 (m, 1H), 1.24 (m, 1H), 1.11 (m, 1H), 0.81 (d, J=6.49 Hz, 3H); 13C NMR (CDCl3) (δ): u: 136.1, 131.4, 69.2, 36.6, 35.5, 25.1; d: 133.6, 129.1, 127.7, 124.2, 28.7, 25.6, 18.9, 17.5; IR (cm−1): 2914, 1449, 1360, 1188, 944.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#C[Si](C)(C)C
Product: Cc1nnc2n1-c1ccc(C#C[Si](C)(C)C)cc1C(c1ccccc1Cl)=NC2

Procedure:
This compound was similarly prepared by coupling of 6-(2-chlorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with trimethylsilylacetylene as described in Example 56. The product was isolated by chromatography and was crystallized from ethyl acetate/ hexane to give colorless crystals of the title compound with m.p. 243°-245° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[CH2:15][CH2:16][NH:17]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(NCCCC[C@H](N[CH2:51][CH2:52][CH2:53][O:54][C:55]1[CH:60]=[CH:59][C:58]([CH2:61][C:62]2[C:63]([O:70][C@@H:71]3[O:79][C@H:78]([CH2:80][OH:81])[C@@H:76]([OH:77])[C@H:74]([OH:75])[C@H:72]3[OH:73])=[N:64][NH:65][C:66]=2[CH:67]([CH3:69])[CH3:68])=[C:57]([CH3:82])[CH:56]=1)C(=O)N)=O)C1C=CC=CC=1>>[C@@H:71]1([O:70][C:63]2[C:62]([CH2:61][C:58]3[CH:59]=[CH:60][C:55]([O:54][CH2:53][CH2:52][CH2:51][NH:17][CH2:16][CH2:15][C:14]([N:11]4[CH2:10][CH2:9][N:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:13][CH2:12]4)=[O:30])=[CH:56][C:57]=3[CH3:82])=[C:66]([CH:67]([CH3:68])[CH3:69])[NH:65][N:64]=2)[O:79][C@H:78]([CH2:80][OH:81])[C@@H:76]([OH:77])[C@H:74]([OH:75])[C@H:72]1[OH:73].[C@@H:71]1([O:70][C:63]2[C:62]([CH2:61][C:58]3[CH:59]=[CH:60][C:55]([O:54][CH2:53][CH2:52][CH2:51][NH:17][CH2:16][CH2:15][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[O:30])=[CH:56][C:57]=3[CH3:82])=[C:66]([CH:67]([CH3:68])[CH3:69])[NH:65][N:64]=2)[O:79][C@H:78]([CH2:80][OH:81])[C@@H:76]([OH:77])[C@H:74]([OH:75])[C@H:72]1[OH:73]
Reactant: O=C(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])N1CCN(Cc2ccccc2)CC1
Reactant: Cc1cc(OCCCN[C@@H](CCCCNC(=O)OCc2ccccc2)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Product: Cc1cc(OCCCNCCC(=O)N2CCN(Cc3ccccc3)CC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Product: Cc1cc(OCCCNCCC(=O)N2CCNCC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
3-(β-D-Glucopyranosyloxy)-5-isopropyl-4-{[4-(3-{2-[(4-benzylpiperazin-1-yl)carbonyl]ethylamino}propoxy)-2-methylphenyl]methyl}-1H-pyrazole was prepared in a similar manner to that described in Example 51 using 4-benzyl-1-[3-(2-nitrobenzenesulfonylamino)propionyl]piperazine instead of 2-methyl-2-(2-nitrobenzenesulfonylamino)propionamide. Then the title compound was prepared in a similar manner to that described in Example 79 using this material instead of 4-[(4-{3-[(S)-5-benzyloxycarbonylamino-1-(carbamoyl)pentylamino]propoxy}-2-methylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole.