Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][CH:3]([F:31])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][CH:24]4[CH2:28][O:27]C(C)(C)[O:25]4)[CH:22]=3)[CH:12]=2)[N:5]=1.O.[OH-].[Na+]>CO>[F:31][CH:3]([F:2])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][CH:24]([OH:25])[CH2:28][OH:27])[CH:22]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)[N:5]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3COC(C)(C)O3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(O)CO)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydrochloric acid (6N, 6.6 mL, 39.7 mmol) was added to 4-(difluoromethyl)-N-(3-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-5-methylphenyl)pyrimidin-2-amine (16.5 g, 39.7 mmol) in MeOH (150 mL). The mixture heated at reflux for 2 h then cooled to RT. Water (200 mL) was added and then the pH was adjusted to 7 with NaOH (6N). The solution was seeded with crystalline product (prepared via an earlier small scale) and crystallization occurred. Additional water (150 ml) was added and the mixture was stirred for 30 min, then filtered, washed with water (2×50 mL) and dried for 14 h under a nitrogen bag to afford 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propane-1,2-diol an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:22])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.Br[CH2:24][CH2:25][CH2:26]Br>C(O)C>[CH2:24]([S:22][C:11]1[NH:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)[CH2:25][CH2:26][S:22][C:11]1[NH:12][C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: BrCCCBr
Solvent: CCO
Product: COc1ccc(-c2nc(SCCCSc3nc(-c4ccc(OC)cc4)c(-c4ccc(OC)cc4)[nH]3)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
A mixture of 4,5-bis(4-methoxyphenyl)-1H-imidazole-2-thione (15.6 g, 0.05 mol) and 1,3-dibromopropane (5 g, 0.025 mol) in ethanol (150 ml) was refluxed for three hours. After cooling, the resulting solid was removed by filtration and discarded. The solvent was removed at reduced pressure to give a yellow foam which was then treated with chloroform-ether. The resulting solid material was removed by filtration, dissolved in chloroform and washed with 10% aqueous sodium hydroxide solution. The solvent was removed at reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([N:25]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:11]=2)=[CH:5][CH:4]=1.[Br:46][C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52](Br)[CH:53]=2)[CH:48]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>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.O>[Br:46][C:47]1[CH:48]=[C:49]2[C:54](=[CH:55][CH:56]=1)[CH:53]=[C:52]([C:14]1[CH:15]=[C:10]([N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:11]=[C:12]([N:25]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=1)[CH:51]=[CH:50]2
Reactant: COc1ccc(N(c2ccccc2)c2cc(B3OC(C)(C)C(C)(C)O3)cc(N(c3ccccc3)c3ccc(OC)cc3)c2)cc1
Reactant: Brc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(c2ccccc2)c2cc(-c3ccc4cc(Br)ccc4c3)cc(N(c3ccccc3)c3ccc(OC)cc3)c2)cc1

Procedure:
13.42 g of a product (yield: 66%) was obtained in the same manner as described in the synthesis method of intermediate 2-3 except that N1,N3-bis(4-methoxyphenyl)-N1,N3-diphenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,3-diamine (17.76 g, 30 mmol), 2,6-dibromonaphthalene (9.44 g, 33 mmol), Pd(PPh3)4 (1.04 g, 0.9 mmol), K2CO3 (12.44 g, 90 mmol), THF (90 mL), and water (45 mL) were used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)=[O:19])[CH:6]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:8]=1[O:9][CH3:10].[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:28])=[O:29])=[CH:22][CH:21]=2)=[O:19])[CH:6]=[C:7]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(/C=C/C(=O)c2ccc(NS(C)(=O)=O)cc2)cc(-c2cccs2)c1OC
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(/C=C/C(=O)c2ccc(N(C)S(C)(=O)=O)cc2)cc(-c2cccs2)c1OC
Yield: 45.9 %

Procedure:
A solution of N-{4-[3E-(3,4-dimethoxy-5-thiophen-2-yl-phenyl)-acryloyl]-phenyl}-methanesulfonamide (Ex-14, 90 mg, 0.20 mmol) in anhydrous DMF was treated with potassium carbonate (56.1 mg, 0.41). Methyl iodide (126.32 uL, 2.03 mmol) was added to the reaction mixture which was then refluxed for 1.5 hours under inert conditions. The reaction was diluted with water (25 mL) and extracted with diethyl ether (2×50 mL). The organic portion was dried over sodium sulfate, filtered, and concentrated to a yellow oil. The crude material was purified by silica gel chromatography (30–50% ethyl acetate/hexanes) to give 42 mg (45%) of the title compound as a yellow solid. 1H-NMR (CDCl3) δ 8.06 (d, 2H), 7.59 (d, 1H), 7.54 (m, 4H), 7.42 (m, 2H), 7.12 (m, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.40 (s, 3H), 2.89 (s, 3H). MS m/z=457 ([M]+, 100%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Si:13](/[CH:20]=[CH:21]/[CH2:22][OH:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>ClCCl>[Si:13](/[CH:20]=[CH:21]/[CH2:22][OH:23])([C:16]([CH3:18])([CH3:19])[CH3:17])([CH3:15])[CH3:14].[CH3:8][S:9]([O-:11])(=[O:23])=[O:10]
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)[Si](C)(C)/C=C/CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)[O-]

Procedure:
As for the preparation described in Example 39, 1.6 ml (11.4 mmol) of triethylamine and 0.74 ml (9.55 mmol) of methanesulfonylchloride in 15 ml of dry dichloromethane are added to 1.3 g (7.6 mmol) of (E)-3-(t-butyldimethylsilyl)-2-propen-1-ol. [Lipshutz et al., J. Org. Chem. 54(21), 4975 (1989)] in 20 ml of dry dichloromethane to give after purification by flash chromatography on silica gel and elution with petroleum ether:ethyl acetate 9:1 1.3 g (67%) of expected (E)-3-(t-butyldimethylsilyl)-2-propen-1-ol, methanesulfonate as a colorless liquid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([N:12]3[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][S:19]([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:13]3=[O:33])[CH2:8][CH2:7]2)[CH2:5]CC[CH2:2]1.Br[CH2:35][C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:39][O:38][C:36](=[O:37])[CH2:35][N:18]([S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])[C@H:14]1[CH2:15][CH2:16][CH2:17][N:12]([CH:9]2[CH2:10][CH2:11][N:6]([CH:1]([CH3:2])[CH3:5])[CH2:7][CH2:8]2)[C:13]1=[O:33]
Reactant: O=C1[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCCN1C1CCN(C2CCCC2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN([C@H]1CCCN(C2CCN(C(C)C)CC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of the product obtained from Example 1, step d (69 mg, 0.13 mmol) in DMF (2.0 mL) at 0° C. were added methyl bromoacetate (0.05 mL) and potassium carbonate (50 mg). After stirring at 0° C. for 2 hr, the solid was filtered out, and the solvent was removed. HPLC purification (50% to 100% acetonitrile/water) gave the desired product as a solid. LC-MS found: (M+1)+=594.30.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[N:26][CH:27]=4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[CH3:36][C:37]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([C:22]4[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[N:26][CH:27]=4)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH:36]=[CH2:37])[C:3]=12
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1nn(C(C)c2cc(Cl)c(C)c(-c3ccc(C(=O)N(C)C)nc3)c2OCC)c2ncnc(N)c12
Temperature: 100 °C
Yield: 88.5 %

Procedure:
To a solution of 5-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide (130 mg, 0.21 mmol, racemic intermediate from Example 15), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (66 mg, 0.43 mmol), sodium carbonate (136 mg, 1.29 mmol) in N,N-dimethylformamide (1 mL)/water (0.64 mL) under N2 was added tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.021 mmol). The mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with water, and extracted with dichloromethane. The organic layers were concentrated and purified on silica gel (eluting with 0 to 100% EtOAc in hexanes followed by 0 to 10% MeOH in dichloromethane) to give the desired product (94 mg, 86%), LCMS calculated for C26H29ClN7O2 (M+H)+: m/z=506.2; Found: 506.2.
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[C:7](N(OC)C)=[O:8].Cl.O>O1CCCC1>[Br:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[C:7](=[O:8])[CH3:1]
Reactant: CON(C)C(=O)c1cc(Cl)ccc1Br
Reactant: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)ccc1Br
Reaction time: 1 h

Procedure:
Methylmagnesium bromide (4.26 mL of a 1.4M solution in tetrahydrofuran/toulene, 5.97 mmol) was added dropwise to a stirred solution of 2-bromo-5-chloro-N-methoxy-N-methylbenzamide (0.554 g, 1.99 mmol) in tetrahydrofuran (20 mL) at approximatately 0° C. After 1 h, 1N hydrochloric acid (5 mL) was added and the resulting biphasic mixture was stirred vigorously for about 10 min. The reaction mixture was poured into water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0–10% ethyl acetate/hexanes as eluent) provided the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[NH2:14][C:15]1([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:14][C:15]3([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17][CH2:16]3)[NH:7][C:6]=2[CH:8]=1
Reactant: NC1(CO)CCCC1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Solvent: CCO
Product: O=S1(=O)N=C(NC2(CO)CCCC2)Nc2cc(Cl)sc21
Yield: 10.7 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g, 1.95 mmol) and (1-aminocyclopentyl)-methanol (0.45 g, 3.9 mmol) in ethanol (4 ml) was stirred for 21 h at 120° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue dissolved in 1N sodium hydroxide (40 ml) followed by treatment with decolourising charcoal. After filtration, the clear solution was acidified to pH <2 with 4M hydrochloric acid and the precipitate was filtered off and recrystallised from ethanol and finally purified by chromatography (dichloromethane/methanol (19:1)) to give 70 mg (10%) of the pure title compound; mp 213-214° C.; 1H-NMR (DMSO-d6): δ1.45-2.0 (m, 8H), 3.53 (s, 2H), 5.05 (br s, 1H), 6.82 (br s, 1H) 7.11 (s, 1H), 10.8 (br s, 1H); MS: m/e 335/337 (M+), 317/319 (M—H2O)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](N)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.CC[N:15](CC)CC>>[C:2]1([NH2:1])[C:3]([NH2:15])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cccc2c(N)cccc12
Reactant: CCN(CC)CC
Product: Nc1ccc2ccccc2c1N
Yield: 76 %

Procedure:
1″,5″-[Bis-(4′-O-demethyl-4β-N-4-desoxypodophyllotoxin)] naphthalene diamine (4b) was prepared according to the method described earlier, employing 1,5-diamino naphthalene (80 mg, 0.5 mmol), Bu4N30I−(185 mg, 0.5 mmol), Et3N (150 mg, 1.5 mmol) and 4′-O-demethyl-4β-bromo-4-desoxy podophyllotoxin (462 mg, 1.0 mmol) to give the product in 76% yield. Spectral data: 1H NMR (CDCl3); 7.22-7.28 (d, 2H), 7.10-7.19 (t, 2H), 6.73 (S, 2H), 6.58 (S, 2H), 6.50 6.55 (d, 2H), 6.33 (S, 4H), 5.98 (ABq, 4H), 5.34 (S, 2H), 4.87 (br, 2H), 4.63-4.70 (d, 2H), 4.52-4.59 (d, 2H), 4.36-4.48 (t, 2H), 3.85-3.95 (d, 2H), 3.82 (3, 6H), 3.20-3.31(dd, 2H), 2.98-3.16 (m, 2H); FAB MS: m/z 922 (M+); mp. 238-240° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([O:10][CH3:9])[CH:16]=1
Reactant: Brc1ccccc1Br
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(-c2ccccc2Br)c1
Reaction time: 12 h
Yield: 69.7 %

Procedure:
20.0 g (85.52 mmol) of 1,2-dibromobenzene, 11.70 g (76.97 mmol) of 3-methoxyphenylboronic acid, 0.99 g (0.86 mmol) of Pd(PPh3)4, and 18.13 g (171.04 mmol) of sodium carbonate were put, suspended in 300 ml of toluene and 100 ml of ethanol, and refluxed and agitated for 12 hours. After the reaction was finished, extraction was performed by dichloromethane, filtering was performed by silica gel, and the column was used at a ratio of hexane:MC=4:1 (v/v) to obtain 14.12 g of 2-bromo-3′-methoxybiphenyl that was the target compound (yield 63%).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.CI.[Mg].[C:14](=[O:16])=[O:15].Cl>CCOCC.C1(C)C=CC=CC=1>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: O=C=O
Reactant: Brc1csc2ccccc12
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(O)c1csc2ccccc12
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of 3-bromobenzothiophene (0.40 mole, (D15)) and methyl iodide (25 ml, 0.40 mole) in dry ether (400 ml) was added to a stirred mixture of magnesium turnings (24 g, 1.0 mole) and dry ether (100 ml) under nitrogen, at such a rate as to maintain a steady reflux. After the addition was complete, the reaction mixture was heated under reflux for 30 minutes and then allowed to cool to room temperature. The solution was diluted with dry toluene (500 ml) and stirred vigorously as dry carbon dioxide was bubbled through over 3 hours. The thick precipitate which formed was dissolved by the addition of dilute hydrochloric acid and the organic layer was then separated. The aqueous solution was extracted with ethyl acetate (2×300 ml) and all the organic solutions were then combined and extracted with 10% sodium carbonate solution (4×300 ml). The aqueous extracts were combined, washed with ether (2×200 ml) and then acidified with dilute hydrochloric acid. The precipitate was filtered off, washed with water and then dried under vacuum to give the title compound as a white solid (31.2 g, 44%) m.p. 171°-173°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[C:44]([CH3:50])=[N:45][N:46]([CH3:49])[C:47]=2[CH3:48])=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[C:44]([CH3:50])=[N:45][N:46]([CH3:49])[C:47]=6[CH3:48])=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(-c2c(C)nn(C)c2C)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6c(C)nn(C)c6C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-1,3,5-trimethyl-pyrazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.24 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:25][B-](F)(F)F.[H+].N([O-])=O.[Na+]>O1CCOCC1.O>[F:25][C:2]1[CH:3]=[C:4]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCc1cnc(-c2ccc(CCCCC)c(N)c2)nc1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCc1cnc(-c2ccc(CCCCC)c(F)c2)nc1
Reaction time: 1 h

Procedure:
56 g of 2-(3-amino-4-n-pentylphenyl)-5-n-hexylpyrimidine (m.p. 92°, obtainable by reaction of 2-(4-n-pentylphenyl)-5-n-hexylpyrimidine (c.p. 28.5°) with nitric acid to give 2-(3-nitro-4-n-pentylphenyl)-5-n-hexylpyrimidine (m.p. 41.5°) and hydrogenation on Raney nickel) is dissolved in 150 ml of dioxane at 50° and 208 ml of 35% tetrafluoroboric acid are added dropwise, with stirring. After one hour, the resulting emulsion is cooled to 0°, whereupon crystallization occurs. A solution of 20 g of sodium nitrite in 150 ml of water is added to the suspension and the mixture is stirred for one hour. The resulting mixture diazonium tetrafluoborate is filtered off with suction, washed with ice-water and dried. 5 g of the diazonium salt is heated at 200° until the evolution of gas has ended. 2-(3-Fluoro-4-n-pentylphenyl)-5-n-hexylpyrimidine of m.p. 30° is obtained by purification by chromatography.
Reaction SMILES: C([O:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][N:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:11]1=[O:12])(=O)C.Cl.C(OCC)C>CO>[OH:4][C@H:5]([CH3:22])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][N:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]nnc2n(C)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]nnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 11020.4 %

Procedure:
To a stirring solution of (R)-1-(5-acetoxyhexyl)-3-methyl-8-azaxanthine (150 mg, 0.49 mmol) in methanol (25 ml) was added an anhydrous solution of hydrogen chloride in ethyl ether (1 M, 1.0 ml, 1.0 mmol). After stirring at room temperature for 24 hours, the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-hydroxyhexyl)-3-methyl-8-azaxanthine (CT 12463) (70 mg, 54 mmol) as a white solid.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C@@H:8]([N:11]([CH3:21])[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:6]1)(=[O:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41].O>CN(C=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([N:11]([C@@H:8]2[CH2:9][CH2:10][N:5]([C:1](=[O:4])[CH2:2][CH2:3][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])[CH2:6][C@H:7]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH3:21])=[O:20])=[CH:18][CH:17]=1
Reactant: C=CC(=O)N1CC[C@@H](N(C)C(=O)c2ccc(Cl)cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=C1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)CCN2CCCC2=O)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of the compound obtained in Example 588 (0.050 mg) in DMF (1 mL) were added potassium carbonate (0.0166 mg) and 2-pyrrolidinone (0.0093 mL), and the mixture was stirred at 110° C. for 1 hr. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 30→100% ethyl acetate/hexane) to give the title compound (37 mg, 63%) as a white powder.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(/C=C/c2c(Cc3ccccc3)sc3ccccc23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1

Procedure:
At ambient temperature, a mixture of cis and trans-2-benzyl-3-[2-(4-methoxy-phenyl)-vinyl]-benzo[b]thiophene in EtOAc and 10% palladium on carbon was stirred under H2 (atmospheric conditions). The reaction was filtered and the filtrate concentrated to give the title compound as a white solid, mp 68-70° C. 1H NMR; consistent. mass spectrum (EI) m/z 358 (M+). Anal. Calcd. for C24H22OS: C, 80.41; H, 6.19; N, 0.00. Found: C, 80.20; H, 6.18; N, 0.03.