Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C@@H:3]2[C@H:4]([OH:22])[CH2:5][C:6]3[C@:19]([CH3:20])([C@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([OH:21])[CH2:12][CH2:11]2)[CH2:8][CH:7]=3.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]1[C@@H:3]2[C:4](=[O:22])[CH:5]=[C:6]3[C@:19]([CH3:20])([C@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C:13](=[O:21])[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)[C@H]5C[C@H]5[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@@]12C(=CC(=O)[C@H]3C[C@H]31)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C

Procedure:
The 1β,2β-methylene-5-androstene-3β,17β-diol is dissolved in acetone and Jones reagent added until a persistent yellow-orange color appears. After stirring at room temperature for ten minutes the mixture is poured onto ice-water and the precipitate is collected by filtration. The precipitate is dissolved in a solution of sodium methoxide in methanol and stirred for a period of 30 minutes at room temperature. The methanol is removed and the residue triturated with water. The solid which results is filtered and crystallized from acetone to yield 1β,2β-methylene-4-androstene-3,17-dione.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(Cl)Cl>C1COCC1>[OH:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@@H](/C=C/CCO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude (4) (12.0 g, 24.3 mmol) in THF (200 mL) at 0° C. was added TBAF (1.0 M in THF, 1.25 eq, 30.4 mL, 30.4 mmol) and the reaction was warmed to RT and stirred for 2 h. The reaction was quenched with sat. aq. NH4Cl, organic layer washed with brine, dried (MgSO4), filtered and concentrated. The crude residue was purified by chromatography on SiO2 (3:7, EtOAc:hexanes) to yield 5.51 g (88%, 2 steps) as a colorless oil. [α]D −12.7 (c 1.0, CH2Cl2); 1H NMR δ 5.56 (dt, 1H, J=15.3, 6.9 Hz), 5.41 (dd, 1H, J=15.4, 6.4 Hz), 4.41 (bs, 1H), 4.06 (bm, 1H), 3.65 (appbq, 2H, J=5.7 Hz), 2.29 (q, 2H, J=6.3 Hz), 1.76 (bs, 1H), 1.68 (m, 1H), 1.44 (s, 9H), 1.33 (m, 2H), 0.92 (m, 6H); 13C NMR δ 155.4, 134.3, 126.9, 79.2, 61.5, 50.9, 44.5, 35.6, 28.3, 24.6, 22.5; EIMS m/z 257 ([M]+, 10), 227 (55), 171 (65); HRMS (EI) m/z calcd for C14H27NO3 257.1991, found 257.1994.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[N:10]=1)[C:5]([OH:7])=O.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH2:21][CH2:20]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[C:4]([C:5]([N:22]2[C:23]3[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=3)[CH2:20][CH2:21]2)=[O:7])[CH:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: CS(=O)(=O)Nc1cc(C(=O)O)cc(Cl)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.28 g (1.1 mmol) 2-chloro-6-methanesulphonylamino-isonicotinic acid, 0.16 g (1.1 mmol) 5-fluoro-2,3-dihydro-1H-indole, 0.31 mL (2.2 mmol) TEA in 4.0 mL DMF were mixed with 0.39 g (1.2 mmol) TBTU and stirred for 2 h at RT. The reaction mixture was purified by HPLC. The product fractions were combined and evaporated down.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:38]O)[C:22]1[CH:36]=[CH:35][C:25]([O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([F:37])[CH:23]=1>>[F:37][C:24]1[CH:23]=[C:22]([C:21]2[N:38]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:20]=2)[CH:36]=[CH:35][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)CCCOc1ccc(C(N)=NO)cc1F
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: CCOC(=O)CCCOc1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(COC)c3)n2)cc1F

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 28 (192.22 mg; 0.75 mmol) and Intermediate 66 (234.54 mg; 0.83 mmol). The reaction mixture was filtered through a SPE NH2 column (2×2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2×2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.41 (d, J=1.4 Hz, 1H), 8.15 (dd, J=7.8, 1.9 Hz, 1H), 7.95-7.90 (m, 2H), 7.36-7.23 (m, 4H), 7.14-7.05 (m, 2H), 4.27-4.13 (m, 6H), 3.33 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.19 (quint., J=6.6 Hz, 2H), 2.08 (s, 3H), 1.27 (t, J=7.2 Hz, 3H). LC/MS (Method B): 505.3 (M+H)+. HPLC (Method A) Rt 6.24 min (Purity: 98.9%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=5)[N:21]([CH3:29])[N:20]=4)[N:17]=3)[N:12]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:11]=2)=[O:9])[CH2:2]1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([N:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=5)[N:21]([CH3:29])[N:20]=4)[N:17]=3)[N:12]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:11]=2)=[O:9])[CH2:2]1)(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCCNC2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCCN(S(C)(=O)=O)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (R)-piperidin-3-ylamide (104 mg, 0.19 mmol) in dichloromethane (1.5 ml) at 0° C. was added triethylamine (0.04 ml, 0.29 mmol) followed by methanesulfonyl chloride (0.02 ml, 0.26 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with dichloromethane (2×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-4% MeOH) then triturated with ethyl acetate to afford 106 mg (89%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methanesulfonyl-piperidin-3-yl)-amide as a light yellow solid.
Reaction SMILES: ClC1N=C(N[C@H](C)CSC2SC3C=CC=CC=3N=2)C2N=CN(C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.NC1N=C2C(N=CN2[C@@H]2O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H]2OC(=O)C)=C(Cl)N=1.C([O:66][C@@H:67]1[C@H:71]([O:72]C(=O)C)[C@@H:70]([CH2:76][O:77]C(=O)C)[O:69][C@H:68]1[N:81]1[C:103]2[N:102]=[C:101]([NH2:104])[N:100]=[C:85]([NH:86][C@H:87]([CH3:99])[CH2:88][S:89][C:90]3[S:91][C:92]4[CH:98]=[CH:97][CH:96]=[CH:95][C:93]=4[N:94]=3)[C:84]=2[N:83]=[CH:82]1)(=O)C.C[O-].[Na+]>CO>[NH2:104][C:101]1[N:100]=[C:85]([NH:86][C@H:87]([CH3:99])[CH2:88][S:89][C:90]2[S:91][C:92]3[CH:98]=[CH:97][CH:96]=[CH:95][C:93]=3[N:94]=2)[C:84]2[N:83]=[CH:82][N:81]([C:103]=2[N:102]=1)[C@@H:68]1[O:69][C@H:70]([CH2:76][OH:77])[C@@H:71]([OH:72])[C@H:67]1[OH:66]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H](C)CSc4nc5ccccc5s4)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: C[O-]
Solvent: CO
Product: C[C@H](CSc1nc2ccccc2s1)Nc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 19 %

Procedure:
The title compound was prepared according to general method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride (prepared as described in Example 5) (7.13 g, 24 mmol) with 2-amino-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-9H-purine (Nucleic Acid Chemistry, Townsend L. B. and Tipson, R. S., eds., John Wiley and Sons Inc., 1986, 3, 144) (8.56 g, 20 mmol) followed by deacylation of a portion of the purified 2',3',5'-tri-O-acetyl-2-amino-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosine using sodium methoxide in methanol to provide the title 2-amino-N-[(R)-1-(2-benzothiazolyl)thio2-propyl]adenosine (0.71 g, 19%) as a foam (following column chromatography) 1H NMR (DMSO-d6) δ 1.34 (3H, d, --CHCH3), 3.50-3.73 (4H, m, H-5'a and H-5'b and --CH2 --), 3.90 (1H, q, H- 4'), 4.10 (1H, d, H-3'), 4.51 (1H, q, H-2'), 5.11, 5.37 (2H, 2d, 2'- and 3'-OH), 5.40 (1H, t, 5'-OH), 5.73 (1H, d, H-1'), 5.79 (1H, br, --NH2), 7.36, 7.47 (2H, 2t, Ar-H), 7.92 (1H, s, H-8), 8.0 (1H, d, N--H). HPLC retention time 13.5 min [gradient elution, 20-80% acetonitrile/water (containing 0. 1% TFA)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=O.[CH3:21][S:22]([CH2:25][C:26](=O)[CH3:27])(=[O:24])=[O:23].[Na]>C(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:26]([CH3:27])[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[C:9]2[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)CS(C)(=O)=O
Agent: [Na]
Solvent: CCO
Product: Cc1nc2ccc(Br)cc2c(-c2ccc(C(F)(F)F)cc2)c1S(C)(=O)=O
Yield: 29.1 %

Procedure:
(2-Amino-5-bromo-phenyl)-(4-trifluoromethyl-phenyl)-methanone (compound of example A.3) (4 g, 11.6 mmol), methanesulfonylacetone (2.37 g, 17.4 mmol) and sodium tetrachloroaureate(III) dihydrate (0.23 g, 0.58 mmol) were heated at reflux in ethanol (50 ml) for 4 days. The resulting mixture was evaporated to dryness and the residue extracted with dichloromethane (2×), NaOH (2×) and NaCl (1×). The crude product was purified by chromatography on silica gel in heptane/ethyl acetate 70:30. One obtained a light yellow solid (1.5 g, 29%). MS: m/z=444 (M).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[C:12](/[CH3:28])=[CH:13]/[CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:31]=1>>[C:22]1([C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[C:12](\[CH3:28])/[C:11]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[O:10])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1cccnc1
Product: C/C(=C\C=C(c1ccccc1)c1ccccc1)C(=O)NCCCCc1cccnc1
Yield: 86.3 %

Procedure:
As in Example 134, (E)-5,5-diphenyl-2-methyl-2,4-pentadienoic acid 4-nitrophenyl ester (1.6 g) was reacted with 3-pyridinebutanamine (0.63 g) for 18 hours at 25° C. The crude amide obtained from the usual work up was purified by HPLC (ethyl acetate) and then crystallized from ether to provide 1.42 g of (E)-5,5-diphenyl-2-methyl-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 93°-94° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].Cl.[F:9][C:10]([F:27])([S:23]([O-:26])(=[O:25])=[O:24])[CH:11]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]([F:15])([F:14])[F:13].[Na+].ClCCl>O.C(OCC)C>[F:27][C:10]([F:9])([S:23]([O-:26])(=[O:24])=[O:25])[CH:11]([O:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])[C:12]([F:13])([F:15])[F:14].[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC[NH+](CC)CC

Procedure:
Triethylamine was dissolved in cold water, and hydrochloric acid was added thereto to adjust the pH of the reaction liquid to fall within a range of 1 to 3. Then sodium 1,1,3,3,3-pentafluoro-2-(pivaloyloxy)propanesulfonate and dichloromethane were added thereto and stirred. The separated organic layer was washed with water, and dichloromethane was removed under reduced pressure from the washed organic layer. To the residue thus obtained, diethyl ether was added for recrystallization. The resultant was filtrated and dried to obtain a desired product at a yield of 75%. The structure of the obtained product was identified using 1H-NMR, IR and TOFMS spectra.
Reaction SMILES: Br[C:2]1[S:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9][CH2:8]2)=[CH:5][N:6]=1.Br[C:17]1[S:18][C:19]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[C:24]([C@H:33]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:34]([O:36][CH3:37])=[O:35])[C:23]([CH3:43])=[CH:22][C:20]=2[N:21]=1>C1(C)C=CC=CC=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.[Cu]I>[C:39]([O:38][C@@H:33]([C:24]1[C:23]([CH3:43])=[CH:22][C:20]2[N:21]=[C:17]([C:2]3[S:3][C:4]([N:7]4[CH2:12][CH2:11][N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9][CH2:8]4)=[CH:5][N:6]=3)[S:18][C:19]=2[C:25]=1[C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)[C:34]([O:36][CH3:37])=[O:35])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CC(C)N1CCN(c2cnc(Br)s2)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ncc(N4CCN(C(C)C)CC4)s3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
A 5 mL microwave reaction tube was charged with 2-bromo-5-(4-isopropylpiperazin-1-yl)thiazole (12 mg, 0.041 mmol), Pd(PPh3)4 (7 mg, 15 mol %), CuI (4 mg, 30 mol %) and (SnBu3)2 (48 mg, 2 eq.) and toluene (0.5 mL). The reaction was heated to 110° C. in oil bath. (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (20 mg, 1.1 eq.) in toluene (4 mL) was added slowly (over 1.5 hours). The reaction was heated at 110° C. in oil bath for 2 hours. The reaction crude was partitioned between ethyl acetate and brine. The organic layer were concentrated and purified by reverse phase column chromatography (5-100% ACN/H2O+0.1% TFA) to give desired product. LCMS-ESI+: calc'd for C31H38ClN4O3S2: 613.2 (M+H+); Found: 613.2 (M+H+).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)S(O[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1[C:30]([O:32][CH3:33])=[O:31])(=O)=O.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12

Procedure:
Diphenylphosphine (0.55 mL, 3.16 mmol, 1 eq) was added to a stirred solution of methyl 2-trifluoromethanesulfonyloxy-1-naphthoate (1.047 g, 3.13 mmol, 1 eq), triethylamine (0. 5 mL, 3.59 mmol, 1.1 eq), 1,4-bis(diphenylphosphino)butane (dppb) (0.03 g, 0.07 mmol, 0.02 eq) and palladium acetate (0.005 g, 0.02 mmol, 0.006 eq) in degassed MeCN (10 mL) instantly giving a red coloration. The solution was heated at reflux under nitrogen for 17 hours. The blood-red solution was allowed to cool and an aliquot taken for NMR analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([OH:25])=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[OH:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][NH:32][CH2:33]2>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][CH:36]=[CH:37][C:28]=4[OH:27])[CH2:33]3)=[O:25])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: Oc1cccc2c1CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(-c2nc(C(=O)N3CCc4c(O)cccc4C3)c3ccccc3n2)cc(OC)c1OC
Yield: 18.8 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 93 (18.8% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.74 and 2.87 (2t, 2H), 3.54 and 4.05 (2t, 2H), 3.76-3.78 (2s, 3H), 3.86 and 3.92 (2s, 6H), 4.46 and 4.96 (2s, 2H), 6.30-7.08 (m, 3H), 7.64-8.17 (m, 6H), 9.50 and 9.53 (2s, 1H); MS (ESI) m/z 472 ([M+H]+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH3:18].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:14]2[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([Cl:9])[C:15]=2[Cl:16])=[O:7])=[CH:2]1
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1ccoc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)c2ccoc2)c(Cl)c1Cl

Procedure:
3-Furoyl chloride (18.0 g) and 2,3-dichloro anisole (24.7 g) are dissolved in 125 ml of CS2 and treated with AlCl3 (18.7 g), first at 5° C. and then at room temperature. After five hours the reaction is quenched with ice/HCl and extracted with CH2Cl2. Drying and evaporation gives a crystalline product that is triturated with hexane to yield 4-(3-furoyl)-2,3-dichloroanisole, mp 118°-122° C.
Reaction SMILES: [Cl-:1].[Cl-].[CH:3]1([Zr+2:8][C:9]2([CH2:14][CH2:15][CH2:16][O:17][Si](C)(C)C)[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:7]=[CH:6][CH:5]=[CH:4]1>C1(C)C=CC=CC=1>[Cl-:1].[Cl-:1].[CH:3]1([Zr+2:8][C:9]2([CH2:14][CH2:15][CH2:16][OH:17])[CH:10]=[CH:11][CH:12]=[CH:13]2)[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: C[Si](C)(C)OCCCC1([Zr+2]C2C=CC=C2)C=CC=C1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: OCCCC1([Zr+2]C2C=CC=C2)C=CC=C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39 %

Procedure:
0.5 g (1.18 mmol) of (cyclopentadienyl)(trimethylsiloxypropyl-cyclopentadienyl) zirconium dichloride was added to a suspension of 1.1 g of Silica XPO 2407 in 75 ml of dry toluene at room temperature; the suspension immediately acquired a greenish-yellow color. The sample was maintained under continuous magnetic stirring at room temperature for two days. Then it was filtered, separating the solution from the insoluble product. The resulting colorless solution was brought to dryness. In this way it was possible to isolate a dusty white solid product. (0.16 g Yield: 39%) 1H-NMR: (Cl3CD): 1.45 (m,1 H), 1.87 (t,2H), 2.72 (t,2H),3.80 (t,2H), 6.10 (m,2H), 6.28 (m,2H), 6.28 (m,2H), 6.45 (s,5H). Mass spectrum: M+ -36.45 (312):55%.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]3)[CH:19]=[CH:18][N:17]=1)[CH2:12]2)=O)(C)(C)C.Cl.CO>O1CCOCC1>[CH3:31][S:28]([N:25]1[CH2:26][CH2:27][N:22]([C:20]2[CH:19]=[CH:18][N:17]=[C:16]([N:11]3[CH2:12][CH:13]4[NH:8][CH:9]([CH2:15][CH2:14]4)[CH2:10]3)[CH:21]=2)[CH2:23][CH2:24]1)(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1cc(N3CCN(S(C)(=O)=O)CC3)ccn1)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCN(c2ccnc(N3CC4CCC(C3)N4)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.1 %

Procedure:
3-[4-(4-Methanesulfonylpiperazin-1-yl)pyridyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.75 g, 1.66 mmol) is solubilized in 16 ml of dioxane. 4N HCl in dioxane (4.3 ml, 17.5 mmol) is then added, followed by approximately 3 ml of methanol. After stirring for 16 h at ambient temperature, the reaction medium is concentrated, and taken up with water. After extraction with diethyl ether, the pH of the aqueous phase is brought to pH 10 with K2CO3 in the presence of dichloromethane. After extraction with dichloromethane, the organic phase is washed with a saturated aqueous sodium chloride solution, and dried over MgSO4, and then concentrated to dryness. 0.59 g of expected 3-[4-(4-methane-sulfonylpiperazin-1-yl)pyridyl]-3,8-diazabicyclo[3.2.1]octane is obtained, which is subsequently used as it is.
Reaction SMILES: C(NCC(O)=O)(OC(C)(C)C)=O.Cl.C(OC(=O)[C@@H]1CCCN1)C1C=CC=CC=1.[CH2:29]([O:36][C:37]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:44](=[O:60])[C@H:45]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])C1C=CC=CC=1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]([C@@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[C:44](=[O:60])[CH2:45][NH:52][C:53]([O:55][C:56]([CH3:58])([CH3:57])[CH3:59])=[O:54])=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1

Procedure:
Compound 26 was synthesized from N-Boc-glycine and L-proline benzyl ester hydrochloride, following the procedure as described for compound 2a, as a white crystallized solid. MS (ESI, EI+) m/z=363 (MH+).