Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([I:19])[CH:14]=2)[N:3]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C[Si](N[Si](C)(C)C)(C)C.CC(O[C@@H:40]1[O:44][C@H:43]([CH2:45][O:46][C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:48])[C@H:42]([O:55][C:56]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:57])[CH:41]1[O:64][C:65]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:66])=O.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>ClC(Cl)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:40]2[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:48])[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C@@H:42]([O:55][C:56](=[O:57])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C@H:41]2[O:64][C:65](=[O:66])[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([I:19])[CH:14]=2)[N:3]=1
Reactant: Clc1nc(NCc2cccc(I)c2)c2[nH]cnc2n1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
A mixture of 2-chloro-N6 -(3-iodobenzyl)adenine (0.84 g, 2.18 mmol), ammonium sulfate (catalytic amount), and HMDS (20 ml) was refluxed for 5 h under nitrogen to provide the silylated derivative. The clear solution was concentrated to dryness in vacuo with exclusion of moisture and the residue was dissolved in dry dichloroethane (6 ml). A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranoside (Janssen Chimica Chemical Co., 1 g, 1.98 mmol) in dry dichloroethane (12 ml) and TMSOTf (0.42 ml, 2.18 mmol) was added, and the reaction mixture was stirred for 20 min at room temperature and refluxed for 14 h under nitrogen. After a workup similar to that for the compound of Example 55, the residue was purified on a silica gel column chromatography (Hx-EtOAc, 2:1) to yield 2-chloro-N6 -(3-iodobenzyl)-9-[2,3,5-tri-O-benzoyl-β-D-ribofuranosyl]-adenine [Rf =0.11 (Hx-EtOAc, 3:1), 1.495 g, 91%] as a colorless foam. 1 H NMR (CDCl3) d 4.69-4.92 (m, 5H, CH2, H-4', H-5'), 6.15 (m, 3H, H-2', H-3', NH), 6.45 (d, J=4.3 Hz, 1H, H-1'), 7.07 (pseudo t, 1H, Bn), 7.31-8.10 (m, 20H, Ar).
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:24][C@@H:25]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=2)(=[O:32])=[O:31])[CH2:26]1)(C)(C)C>>[Cl:46][C:45]1[C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:30]([N:27]2[CH2:28][CH2:29][C@@H:25]([OH:24])[CH2:26]2)(=[O:31])=[O:32])=[N:41][C:42]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:43][CH:44]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@@H](O)C3)n1)CCN(C[C@@H](C)O)CC2
Yield: 29 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (R)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and {2-[(R)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. The product was isolated as a white solid (35 mg, 29%). mp: 197-199° C., MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.58-7.52 (m, 2H), 7.25 (t, J=8 Hz, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.88 (m, 4H), 3.42 (m, 3H), 3.31 (d, 1H), 2.91-2.52 (m, 10H), 2.27 (m, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[OH:19])[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]([O:15][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 9.4 %

Procedure:
Benzyl bromide (1.50 cm3, 2.16 g, 12.6 mmol) was added to a stirred suspension of 3,4-dihydroxybenzoic acid (1.00 g, 6.49 mmol), potassium carbonate (1.97 g, 14.3 mmol) and a catalytic amount of tetrabutylammonium iodide in N,N-dimethylformamide (50 cm3). The suspension was stirred under nitrogen overnight then water (500 cm3) and 5% hydrochloric acid (50 cm3) were added, and the mixture was extracted with diethyl ether (3×100 cm3). The combined extracts were washed with water (3×100 cm3) and brine (100 cm3), then dried (Na2SO4) and evaporated to an orange oil. Flash column chromatography (eluent: 10-20% ethyl acetate in light petroleum) gave first benzyl 3,4-dibenzyloxybenzoate (168 mg, 6%), identical to that prepared above. Further elution then gave benzyl 4-benzyloxy-3-hydroxybenzoate (1.312 g, 60%) as a pale yellow oil. The position of the benzyloxy group was deduced from an n.O.e. observed between the proton at position 5 and the methylene protons of the benzyloxy group at position 4.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[CH2:8]Cl.II.[CH2:15]([N:22]1[CH2:27][CH2:26][O:25][CH:24]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(OCC)C>[CH2:15]([N:22]1[CH2:27][CH2:26][O:25][CH:24]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([OH:29])[CH2:8][C:7]2[CH:10]=[C:3]([F:2])[CH:4]=[CH:5][C:6]=2[O:11][CH3:12])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(F)cc1CCl
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(F)cc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Yield: 106.8 %

Procedure:
Alternatively, the following method may be used. Magnesium turnings (21.6 g, 0.888 mole, 2 eq.) and diethyl ether (300 ml) were loaded in a reactor under N2. A solution of 5-fluoro-2-methoxybenzyl chloride (116 g, 0.664 mole, 1.5 eq.) in diethyl ether (200 ml) was loaded in an addition funnel. Iodine crystals and a small amount of the 5-fluoro-2-methoxybenzyl chloride solution were added and the reaction mixture was stirred to initiate the reaction. The remainder of the 5-fluoro-2 methoxybenzyl chloride solution was then added drop-wise maintaining the temperature of the reaction mixture below 28° C. The mixture was stirred for another 5 minutes at 19° C. after completion of the addition and a white suspension was formed. A solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (125 g, 0.444 mole) in diethyl ether (1.8 L) was added drop-wise, maintaining the temperature of the reaction mixture below 25° C. The suspension obtained was stirred for 2 hours. The reaction mixture was quenched through the addition of a saturated aqueous NaHCO3 solution (625 ml) and water (500 ml), maintaining the temperature below 20° C. The mixture was stirred for 30 minutes and the solids were filtered, washed with water (125 ml) and diethyl ether (200 ml). The filtrates were loaded into a separation funnel and the layers were separated. The aqueous layer was extracted with diethyl ether (1 L). The organic layers were combined and dried over MgSO4, filtered and the filter cake was washed with diethyl ether (100 ml). The filtrates were concentrated under vacuum. The yield of title compound was 201 g as a yellow solid (107%). Title compound (200 g, 0.474 mole) was then suspended in isopropanol (400 ml) under N2. The suspension was heated under reflux until all solids were dissolved. The solution is allowed to cool to 20° C. over 4 hours under stirring. The solid is filtered, washed with isopropanol (100 ml) and dried at 40° C. under vacuum. The yield of pure title compound is 158 g (79%). 1H-NMR (CDCl3): 6.99-7.26 ppm, 10H, mp; 6.60-6.71 ppm, 1H, dt; 6.49-6.60 ppm, 1H, dd; 6.31-6.44 ppm, 1H, dd; 3.92-4.01 ppm, 1H, dt; 3.80-3.90 ppm, 1H, dd; 3.64-3.73 ppm, 1H, dd; 3.59-3.64 ppm, 1H, d; 3.52-3.59 ppm, 3+1 H, 2s; 3.37-3.45 ppm, 1H, d; 3.07-3.17 ppm, 1H, d; 2.84-2.92 ppm, 1H, d; 2.43-2.53 ppm, 1H, d; 2.20-2.28 ppm, 1H, d; 1.98-2.11 ppm, 2H, mp.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]3[N:22]4[C@@H:23]([CH:27]([CH3:29])[CH3:28])[CH2:24][O:25][CH2:26][C:21]4=[N:20][C:14]=3[C:15]([NH2:19])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.[Pd]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]3[CH2:26][O:25][CH2:24][C@H:23]([CH:27]([CH3:28])[CH3:29])[N:22]3[C:13]=2[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[N:16]=1
Reactant: CC(C)[C@H]1COCc2nc3c(N)nc4cc(OCc5ccccc5)ccc4c3n21
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)[C@H]1COCc2nc3c(N)nc4cc(O)ccc4c3n21
Reaction time: 8 h
Yield: 60.5 %

Procedure:
(11S)-3-(Benzyloxy)-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (800 mg, 2.05 mmol) was dissolved in 260 mL of ethanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 460 mg) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa) overnight. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with 1:1 CH2Cl2/ethanol and the combined filtrates were concentrated under reduced pressure to give an off-white solid. Chromatography (SiO2, 20-40% CMA/CHCl3) gave the desired product (370 mg) as an off-white solid, mp 210-215° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[CH3:16])[CH3:2]>C(OCC)(=O)C.[Ni]>[CH2:17]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[CH3:16])[CH3:18]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1C
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(N)cc1C
Reaction time: 36 h

Procedure:
3.10 g (12.3 mmol) diethyl-[2-(2-methyl-4-nitro-phenoxy)-ethyl]-amine were dissolved in 250 mL ethyl acetate, 0.55 g Raney nickel was added and the mixture was hydrogenated for 36 hours at 50 psi and ambient temperature. The catalyst was filtered off and the filtrate evaporated down i. vac.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:32]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:11]=2[O:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[Cl:21])[C:5]([O:7][CH3:8])=[O:6])(=[O:44])=[O:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.13 g of methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in a mixture of toluene/pyridine (20 ml/30 ml) treated dropwise while cooling with ice with a solution of 1.05 g of 4-tert.butyl-benzenesulphonyl chloride in toluene (30 ml) and subsequently stirred at RT for 24 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was dried over magnesium sulphate. After removing the solvent there was obtained methyl 3-(4-tert-butyl-benzenesulphonylamino)-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:46]>CN(C=O)C.C(OCC)(=O)C>[Br:46][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[S:18]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])=[O:19])=[CH:5][CH:4]=1
Reactant: CC(C)Cc1cc(-c2ccc(CO)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc(-c2ccc(CBr)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
3-(4-Hydroxymethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (280 mg, 0.734 mmol, see step (a) above) was dissolved in DMF (10 mL). PPh3 (459.2 mg, 1.75 mmol) and CBr4 (580.3, 1.75 mmol) were added to the resultant solution. The mixture was stirred for 24 h at room temperature and then diluted with ethyl acetate. The organic phase was washed with water (50 mL) and brine (50 mL) and then dried over MgSO4. After removing the solvents, the residue was purified by column chromatography using hexane:acetone (5:1) as eluent to give the sub-title compound (314.9 mg, 0.709 mmol, 76% yield).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:16](I)[CH2:17][CH3:18].C([O-])(=O)C([O-])=O>CCOC(C)=O>[CH2:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)[CH2:17][CH3:18]
Reactant: CCCI
Reactant: CC(=O)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])C(=O)[O-]
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2cccc(C(C)=O)c2)CC1

Procedure:
Beginning with 1-(3-piperazin-1-yl-phenyl)-ethanone and n-Pr-I: m.p. 119° C. (oxalate), MS m/z (rel. intensity, 70 eV) 246 (M+, 10), 217 (33), 132 (18), 70 (bp), 56 (41); Rf 0.23 (EtOAc).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2([NH:14][C:15]([C:17]3[C:18]4[CH:19]=[N:20][N:21]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:22]=4[CH:23]=[C:24](Br)[CH:25]=3)=[O:16])[CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3].CS([C:38]1C=C(C2(NC(C3C4C=NN(C5C=CC(F)=CC=5)C=4C=C(I)C=3)=O)CC2)C=C[N:39]=1)(=O)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2([NH:14][C:15]([C:17]3[C:18]4[CH:19]=[N:20][N:21]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:22]=4[CH:23]=[C:24]([C:38]#[N:39])[CH:25]=3)=[O:16])[CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(C2(NC(=O)c3cc(Br)cc4c3cnn4-c3ccc(F)cc3)CC2)ccn1
Reactant: CS(=O)(=O)c1cc(C2(NC(=O)c3cc(I)cc4c3cnn4-c3ccc(F)cc3)CC2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C2(NC(=O)c3cc(C#N)cc4c3cnn4-c3ccc(F)cc3)CC2)ccn1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 6-bromo-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid [1-(2-methanesulfonyl-pyridin-4-yl)-cyclopropyl]-amide, and 1-(4-fluoro-phenyl)-6-iodo-1H-indazole-4-carboxylic acid [1-(2-methanesulfonyl-pyridin-4-yl)-cyclopropyl]-amide (150 mg) in DMF (1.0 mL, degassed and anhydrous) is added tetrakis(triphenylphosphine)palladium (33 mg, 0.028 mmol) and zinc cyanide (40 mg, 0.34 mmol). The solution is evacuated and purged with Argon (3 times) and warmed to 120° C. After 3 hours, the reaction is cooled to room temperature, diluted with saturated aqueous ammonium chloride (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic layers are washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified on SiO2 using a gradient of 50-100% ethyl acetate in heptane to give a solid, which is triturated with ethyl ether to afford the title product.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:14])[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=1[NH2:10])(=[O:3])[CH3:2].[CH2:15](OC(OCCCC)N(C)C)CCC>CN(C=O)C>[OH:3][C:1]1[C:4]2[C:5](=[O:14])[N:6]([CH3:13])[C:7](=[O:12])[N:8]([CH3:11])[C:9]=2[N:10]=[CH:15][CH:2]=1
Reactant: CC(=O)c1c(N)n(C)c(=O)n(C)c1=O
Reactant: CCCCOC(OCCCC)N(C)C
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(O)ccnc2n(C)c1=O
Temperature: 80 °C
Yield: 70.2 %

Procedure:
0.8 g of 5-acetyl-6-amino-1,3-dimethyluracil was dissolved in DMF and 4 ml of dimethylformamide dibutylacetal was added thereto. The solution was heated for 8 hr at 80° C. and distilled under reduced pressure. After purification by silica gel column chromatography, the crude product was recrystallized from ethanol to give 0.59 g of 5-hydroxy1,3-dimethylpyrido[2,3-d]pyrimidine-2,4-dione (Compound 14).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH3:17][CH2:18][O:19][CH2:20][CH3:21]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C:6]1([CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[CH2:7][C:8]2=[O:11]
Reactant: CCOCC
Reactant: O=C1CCc2ccc(Br)cc21
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: O=C1CC2(CCOCC2)c2ccc(Br)cc21
Temperature: -25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-1-indanone (0.50 g, 2.35 mmol) in anhydrous THF (40 mL) under N2 atmosphere at −78° C. was added a solution of NHMDS (1 M in THF, 2.5 mL, 2.5 mmol) within 30 min, followed by TMSCl (0.281 g, 0.327 mL 2.59 mmol) after stirred 30 min. To this reaction mixture was added NHMDS (1 M in THF, 6.0 mL, 6.0 mmol) within 30 min at this temperature. The temperature was allowed to warm to −30 to −20° C., after stirred another 30 min, 2,2-eichlorodiethyl ether (336 mg, 0.275 mL, 2.35 mmol) was added. Then the reaction temperature was allowed to warm to room temperature without removing cooling bath, and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl, and extracted with EA two times. The combined organic phases were washed with 1 M HCl, H2O, brine successively, and dried over anhydrous Na2SO4, and filtered, and concentrated to give black oil. It was purified by flash chromatography on silica gel yield 103 mg of the desired product. MS ESI+ve m/z 281 (M+H)+.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:30])[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=1.[Cl:31][C:32]1[N:37]=[C:36]([Cl:38])[C:35]([CH2:39]I)=[CH:34][N:33]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:30])[CH:19]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:39][C:35]1[C:36]([Cl:38])=[N:37][C:32]([Cl:31])=[N:33][CH:34]=1
Reactant: COC(=O)Cc1cc(OC)cc(OC)c1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(OC)cc(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 3,5-dimethoxy-phenyl-acetic acid methyl ester (2.05 g, 9.76 mmol) (from Example 3a supra) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To this reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-(3,5-dimethoxy-phenyl)-propionic acid methyl ester as a colorless oil. (Yield 1.45 g, 78.0%).
Reaction SMILES: CCN(CC)CC.[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:21][C:22]1[S:26][C:25]([NH:27][C:28]([CH:30]([C:38]2[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)[CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:29])=[N:24][CH:23]=1>CC(N(C)C)=O>[Cl:21][C:22]1[S:26][C:25]([NH:27][C:28]([CH:30]([C:38]2[CH:39]=[CH:40][C:41]([S:44]([N:11]3[CH2:12][CH2:13][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:10]3)(=[O:46])=[O:45])=[CH:42][CH:43]=2)[CH2:31][CH:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:29])=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Nc1ncc(Cl)s1)C(CC1CCOCC1)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(CC3CCOCC3)C(=O)Nc3ncc(Cl)s3)cc2)CC1
Reaction time: 16 h

Procedure:
NEt3 (278 μL, 2.0 mmol) and tert-butyl piperazine-1-carboxylate (373 mg, 2.0 mmol) were added to a stirred solution of 4-[1-(5-chlorothiazol-2-ylcarbamoyl)-2-(tetrahydropyran-4-yl)ethyl]benzenesulfonyl chloride (Preparation 60, 449 mg, 1.0 mmol) in anhydrous DMAc (4 mL). The mixture was stirred for 16 h, then the solvents were removed in vacuo. The residue was dissolved in EtOAc (50 mL) to give a solution that was washed with H2O (15 mL), saturated aqueous Na2CO3 (15 mL), and brine (15 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH-EtOAc, 7:3 to 1:1) gave tert-butyl 4-{4-[1-(5-chlorothiazol-2-ylcarbamoyl)-2-(tetrahydropyran-4-yl)ethyl]benzenesulfonyl}piperazine-1-carboxylate: m/z (ES+)=599.5 [M+H]+. A solution of this compound (189 mg, 316 μmol) in CH2Cl2-TFA (1:1, 7 mL) was stirred for 1 h. The solvents were evaporated off under reduced pressure, then the residue was triturated with Et2O. The product was collected, washed with Et2O, and air-dried to furnish the trifluoroacetate salt of the title compound: RTA=2.64 min; m/z (ES+)=499.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:5][C:3]=1[OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:33]([C:35](C)=O)[CH3:34].C(Br)C=C>O>[CH2:35]([O:4][C:3]1[CH:5]=[C:6]([C:10](=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:7]([OH:9])=[CH:8][C:2]=1[CH3:1])[CH:33]=[CH2:34]
Reactant: CCCCCCCCCCCCCCCC(=O)c1cc(O)c(C)cc1O
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Product: C=CCOc1cc(C(=O)CCCCCCCCCCCCCCC)c(O)cc1C

Procedure:
Under nitrogen atmosphere a mixture of 17.5 g of the keto-compound of step 1, 10.2 g of potassium carbonate and 200 ml of methyl ethyl ketone was refluxed with stirring together with 6.9 g of allyl bromide for 1 hour. After a total refluxing time of 9 h the reaction mixture was mixed with 100 ml of water. The methyl ethyl ketone layer is separated, shaken twice with a 20% by weight sodium chloride solution and dried with sodium sulphate. The residue left after evaporation of the solvent was stirred with methanol, whereupon the precipitate formed was filtered with suction and recrystallized from methanol.