Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.COCCOC.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[C:20]([F:21])[CH:19]=[C:18]2[C:14]=1[CH:15]=[N:16][N:17]2[CH3:22]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: ClCCl
Product: Cn1cc(-c2ccc3ncc(Cc4c(F)cc5c(cnn5C)c4F)n3n2)cn1
Reaction time: 0.5 h

Procedure:
In a microwave vial were introduced under argon 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (23 mg, 0.112 mmol) and 6-chloro-3-(4,6-difluoro-1-methyl-1H-indazol-5-ylmethyl)-imidazo[1,2-b]pyridazine (Stage 284.1, 25 mg, 0.075 mmol) with 0.3 mL DME. The solution was degassed with argon, before adding PdCl2(PPh3)2 (1.5 mg) and 2 M K2CO3 (0.101 mL). The RM was then stirred at 80°-90° C. for 30 min. Additional 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (10 mg, 0.048 mmol) and PdCl2(PPh3)2 (1.5 mg) were added. The RM was then diluted with DCM and washed with sat. aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered, evaporated to dryness and the residue was purified (CombiFlash® Companion System®, with RediSep® silica gel column, EtOAc/MeOH=100:0->80:20) to afford the title compound as a beige crystalline powder (tR 3.91 min (conditions 3), MH+=380.2, 1H-NMR in DMSO-d6: 8.36 (s, 1H); 8.18 (s, 1H); 8.05 (s, 1H); 8.02 (d, 1H); 7.50 (m, 2H); 7.45 (s, 1H); 4.40 (s, 2H); 3.97 (s, 3H); 3.90 (s, 3H)).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:15][C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccnc1N1CCNCC1
Reactant: ClCc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cccnc1N1CCN(Cc2nc3ccccc3[nH]2)CC1
Reaction time: 1.25 h
Yield: 36.2 %

Procedure:
The product of Example 28B(0.50 g, 2.76 mmol), 2-chloromethyl-1H-benzimidazole (0.48 g, 2.90 mmol), and cesium carbonate (1.8 g, 5.52 mmol) were combined in N,N-dimethylformamide (28 mL) at 23° C. and stirred for 1.25 hours. The mixture was concentrated under reduced pressure and rinsed with 10% methanol/dichloromethane. The solid was filtered off and the filtrate concentrated under reduced pressure. The residue was impregnated onto flash silica gel and chromatographed on flash silica gel (10% methanol/dichloromethane) to afford 311 mg (36% yield) of the title compound. mp 210-212° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H), 3.43 (m, 4H), 3.78 (s, 2H), 6.87 (m, 1H), 7.14 (m, 2H), 7.50 (m, 3H), 8.00 (m, 1H); MS (APCI) m/e 312 (M+H)+; Anal. calcd for C17H18FN5 0.4 H2O: C, 64.10; H, 5.95; N, 21.98. Found: C, 64.16; H, 5.86; N, 21.95
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.[NH2:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:5]([NH:32][CH2:33][C:34]1[C:35]([OH:42])=[N:36][C:37]([CH3:41])=[CH:38][C:39]=1[CH3:40])=[O:7]
Reactant: CC(Oc1ccccc1)c1ccc(C(=O)O)cc1Cl
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccccc3)c(Cl)c2)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 87.6 %

Procedure:
To a solution of 3-chloro-4-(1-phenoxyethyl)benzoic acid (262 mg, 1.0 mmol), 1-hydroxybenzotriozole (202 mg, 1.5 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (288 mg, 1.5 mmol) triethylamine (0.4 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide as a white solid (360 mg, 88%). LRMS (M+H+) m/z: 410.14. found 410. HPLC Purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), δ 8.33 (d, J=5.1, 1H), 7.47 (s, 1H), 7.34 (m, 2H), 67.20 (m, 2H), 6.88 (m, 3H), 5.84 (s, 1H), δ 5.54 (q, J=6, 1H), 4.25 (d, J=4.5, 2H), 2.17 (s, 3H), 2.13 (s, 3H), 3.06 (d, J=6, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:17])[C:9]=2[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18]([O:20][C:21](=[O:26])[C:22](Br)([CH3:24])[CH3:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:26])[C:22]([CH3:24])([O:17][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[C:2]([CH3:1])[NH:3]2)[CH3:23])[CH3:19]
Reactant: Cc1[nH]c2cccc(O)c2c1-c1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1cccc2[nH]c(C)c(-c3ccccc3)c12

Procedure:
The above compound was prepared from 2-methyl-3-phenyl-1H-indole-4-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:17]=[CH:16][C:12]2[NH:13][CH:14]=[N:15][C:11]=2[CH:10]=1)[CH2:3][CH2:4][C:5]([O:7]C)=[O:6].[OH-].[Li+].O>O1CCCC1>[O:1]=[C:2]([C:9]1[CH:17]=[CH:16][C:12]2[NH:13][CH:14]=[N:15][C:11]=2[CH:10]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CCC(=O)c1ccc2[nH]cnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1ccc2[nH]cnc2c1
Yield: 78 %

Procedure:
Prepared analogously to Example 5 from methyl γ-oxo-1H-benzimidazol-5-butanoate, lithium hydroxide and water in the presence of tetrahydrofuran in a yield of 78% of theoretical. Colourless crystals, m.p. 251–255° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH3:2].[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CCOC(=O)CCc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(C(=O)CCC(=O)O)ccc1OC
Yield: 77.6 %

Procedure:
Starting with a mixture of 3.12 g (15.0 mmol) of 2-methoxybenzenepropanoic acid ethyl ester, 1.53 g (15.3 mmol) of succinic anhydride, 4.46 (33.5 mmol) of aluminum chloride and 20 mL of methylene chloride, the title compound (3.59 g, 77.7%) was obtained as a white solid, mp 128°-129° C. (recrystallized from ethanol), using the procedure of example 139.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:30][O:31][C:32](=[O:39])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][NH2:38]>C(Cl)Cl>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@@H:9]([C:11]([NH:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][C:32]([O:31][CH3:30])=[O:39])=[O:13])[CH3:10]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CCCCCN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CCCCCNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 25 h

Procedure:
Boc-(D)-alanine (5.1 g, 26.9 mmol) in 100 ml of methylene chloride (CH2Cl2) was cooled to 0° C. and 5.9 ml (53.8 mmol) of N-methylmorpholine (NMM) were added. After cooling this vigorously stirred solution to -78° C., 3.5 ml (26.9 mmol) of isobutylchloroformate (IBCF) were added to this reaction which was run entirely under an Ar atmosphere. The mixture was allowed to warm slowly to 20° before it was again cooled to -78° C. and 4.9 g (26.9 mmol) of 6-aminohexanoic acid methylester hydrochloride were added in a single portion. Following warming this mixture to room temperature, it was allowed to stir 25 hour (h). Precipitated N-methylmorpholine hydrochloride was filtered off and the filtrate, after diluting with CH2Cl2 (200 ml), was washed 3×100 ml of 0.5N potassium bisulfate (KHSO4). The combined aqueous washes were extracted with a 100 ml portion of CH2Cl2 and the combined organics were washed 1×75 ml of brine, dried over Na2SO4 (anhy.), and stripped of all solvent under reduced pressure. By thin layer chromatography (10% ethanol (EtOH)/chloroform (CHCl3)) the yellow liquid title product was essentially one spot and used in subsequent reactions without further purification. Optical rotation [α]D +21.5° and +93.7° (365 nm) CHCl3. NMR shift of the (D)Ala methyl=1.34δ (CDCl3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:10]([O:12][C@@H:20]1[CH:21]2[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]2)[CH2:19]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccs1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)-2-(thiophen-2-yl)acetic acid (710 mg, 2.76 mmol), (R)-quinuclidin-3-ol (421 mg, 3.31 mmol), DCC (683 mg, 3.31 mmol), HOBT (507 mg, 3.31 mmol) in THF (20 ml) was stirred at RT overnight. THF was evaporated, and the crude was portioned between EtOAc and 1M K2CO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=98/2) to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(thiophen-2-yl)acetate (509 mg, 50.3% yield).
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[SH:24])([CH3:17])([CH3:16])[CH3:15].[Li]C(CC)C.[Br:30]C(F)(F)C(F)(F)Br>C1CCCCC1.C1COCC1>[Br:30][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:19]=1[SH:24]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: CC(C)(C)c1ccccc1S
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(Br)c1S
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of tetramethylethylenediamine (198.4 mmol, 30 mL) in cyclohexane (140 mL) is slowly added n-BuLi (198.4 mmol, 99.2 mL; 2M solution in cyclohexane) at 23° C. The resulting solution is cooled to 0° C. A solution of 2-tert-butylthiophenol (15.0 g, 90.2 mmol) in cyclohexane (40 mL) is then added at a rate such that the temperature stays below 10° C. The reaction is then stirred at 0° C. for 5 h and is then allowed to warm to 23° C. overnight. To the resulting yellow solution at 23° C. is added sec-BuLi (90.2 mmol, 69.4 mL of 1.3M solution in cyclohexane) over 0.5 h. The resulting solution gradually turns orange. After 1.5 h, the orange, cloudy reaction mixture is cannulated into a stirring solution of 1,2-dibromotetrafluoroethane (180.4 mmol, 21.5 mL) in THF (50 mL) over 1 h. After addition is complete, the resulting reaction mixture is quenched with 1N HCl (80 mL), and extracted with hexanes (3×100 mL). The hexanes are dried (MgSO4) and evaporated to a dark oil (29.48 g). This oil is taken up in 1N NaOH (100 mL), and extracted with CH2 Cl2 (3×50 mL). The organic phase is discarded, and the aqueous phase is acidified with 12N HCl, and extracted with CH2Cl2 (3×100 mL). The organic phase is dried (MgSO4) and evaporated to provide the title compound as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18]([CH3:20])[CH3:19])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:28](I)[CH3:29]>CC(C)=O>[CH2:28]([O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18]([CH3:19])[CH3:20])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[CH3:29]
Reactant: CN(C)C=C1C(=O)N(c2cccc(O)c2)c2ccccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1cccc(N2C(=O)C(=CN(C)C)c3ccccc32)c1

Procedure:
Title product of Example D1 (0.28 g, 1.0 mmole ) in 2 ml of acetone was stirred under N2 with Na2CO3 (0.21 g, 2 mmoles) for 1 hour. Ethyl iodide (2.28 ml) and 0.5 g Na2CO3 were then added. The mixture was refluxed for 11 hours, cooled, salts removed by filtration and the filtrate stripped of solvent in vacuo. The residue was chromatographed on silica gel (15 cm×3.5 cm), eluting with 1:1 ethyl acetate:hexane. The resulting oil was crystallized from toluene/pentane to yield purified title product; 51.5 mg; 17%; m.p. 99°-102°.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: C1=COCCC1
Reactant: OC1CCCc2sccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: c1cc2c(s1)CCCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 19.0 g (0.123 mol) of product from Step A, 15.53 g (0.185 mol) of dihydropyran, 2.56 g (0.010 mol) of pyridinium-4-toluenesulfonate, and 700 ml CH2Cl2 was stirred at ambient temperature for 5 hours. The reaction mixture was washed twice with half saturated NaCl solution, dried (Na2SO4), filtered, and evaporated. The residual colorless oil was distilled (112° C., 0.05 mm Hg) yielding a quantitative amount of product.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18].II>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]1[S:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: O=Cc1cc(Br)ccc1Br
Reactant: Nc1ccccc1S
Agent: II
Solvent: CN(C)C=O
Product: Brc1ccc(Br)c(-c2nc3ccccc3s2)c1

Procedure:
5 g (18.5 mmol) of 2,5-dibromobenzaldehyde, 3 mL (27.7 mmol) of 2-aminothiophenol, and 2.35 g (9.25 mmol) of iodine (I2) were dissolved in 100 mL of DMF. The solution was reacted at 100° C. for 1 hour. The acquired reactant was purified through a column, obtaining 4.64 g (Y=68%) of a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([N:28]=1)[C:24]1[CH:23]=[C:22]([OH:25])[CH:21]=[C:20]([F:26])[C:19]=1[O:18][C:17]1[C:12]2=[CH:13][C:14](Br)=[CH:15][CH:16]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>CN(C=O)C.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>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([N:28]=1)[C:24]1[CH:23]=[C:22]([OH:25])[CH:21]=[C:20]([F:26])[C:19]=1[O:18][C:17]1[C:12]2=[CH:13][C:14]([C:35]2[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:15][CH:16]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: OB(O)c1cccnc1F
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: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Temperature: 85 °C

Procedure:
Sodium carbonate (saturated, 2 mL), Pd(PPh3)4 (0.237 g, 0.205 mmol), (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (0.75 g, 2.054 mmol), and 2-fluoropyridine-3-boronic acid (310 mg, 2.18 mmol) were combined in DMF (5 mL). The solution was heated at 85° C. overnight before being cooled to rt. The solution was diluted with water (25 ml) and filtered. The solids were triturated with MeOH and dried under vacuum to afford (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a tan solid. MS m/z=382.0 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH3:9])[CH:7]=1
Reactant: C[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A solution of 3,5-dibromopyridine (32, 20 g, 84.4 mmol) in DMF (200 mL) was stirred at RT under nitrogen atmosphere and 21.3 mL of sodium methoxide (25% by wt. in methanol, 92.8 mmol) was added slowly. The reaction mixture was stirred overnight at 70° C. under N2. The reaction was cooled to RT and quenched with water (200 mL) and extracted with Et2O (2×200 mL). The combined organic extracts was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude 3-bromo-5-methoxypyridine (33, 14.8 g, 93% theory) afforded a colorless oil after flash chromatography on silica gel (EtOAc:hexane 1:10).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([O:11][C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2cccc3c2CCCC3)ccn1
Yield: 97.6 %

Procedure:
Using the method of Example 3, Step A, 5,6,7,8-tetrahydronaphthalen-1-ol (935 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(5,6,7,8-tetrahydronaphthalen-1-yloxy)pyridine (1.60 g, 98% yield) as an oil. 1H NMR (CDCl3) δ 8.19 (d, 1H), 7.15 (t, 1H), 7.03 (d, 1H), 6.82 (d, 1H), 6.71-6.75 (m, 2H), 2.82 (t, 2H), 2.52 (t, 2H), 1.71-1.81 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:8]([O:9][CH3:10])[CH2:7][CH2:6][CH:5]([CH2:11][CH2:12][N:13]=[C:14]=[O:15])[CH2:4]1.[F:16][C:17]1[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=1>N1C=CC=CC=1>[CH3:1][O:2][CH:3]1[CH:8]([O:9][CH3:10])[CH2:7][CH2:6][CH:5]([CH2:11][CH2:12][NH:13][C:14]([N:21]2[CH:22]=[C:17]([F:16])[C:18](=[O:24])[NH:19][C:20]2=[O:23])=[O:15])[CH2:4]1
Reactant: COC1CCC(CCN=C=O)CC1OC
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Product: COC1CCC(CCNC(=O)n2cc(F)c(=O)[nH]c2=O)CC1OC
Temperature: 90 °C
Yield: 48.3 %

Procedure:
A mixture of 2.12 g of 2-(3, 4-dimethoxycyclohexyl) ethylisocyanate, 1.5 g of 5-fluorouracil and 50 ml of pyridine was heated at 90° C. for 2 hr. The solution was cooled to 50° C. and pyridine was evaporated under reduced pressure. The residue was shaked in a mixture of 80 ml of dichloromethane and 100 ml of hydrochloric acid water, and the lower layer of the solution was dried and evaporated. The residue was chromatographed on silica gel and 1.65 g of 1-(3, 4-dimethoxycyclohexylethylcarbamoyl)-5-fluorouracil (melting point: 129° C.) was obtained (Compound No. 8). NMR: 0.73-2.27 (9H b CH2) 2.77-3.40 (2H b CH2 --NH) 3.30-3.57 (H b CHOCH3) 3.35 (6H s OCH3) 3.50-3.77 (H b CHOCH3) 8.42 (H d C6 --H) 9.20 (H b NH CO).
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]([B:25]5[O:29]C(C)(C)C(C)(C)[O:26]5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1>CC(C)=O.O>[F:24][C:22]1[CH:21]=[CH:20][C:19]([B:25]([OH:29])[OH:26])=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([O:2][CH3:1])=[O:34])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B(O)O)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
{(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 (3.00 g) is dissolved in acetone (20 mL) and water (10 mL). NaIO4 (5.90 g) and NH4O2CCH3 (2.85 g) are added. The mixture is stirred at room temperature for 36 h. Water is added and the resulting mixture is extracted with ethyl acetate. The combined extract is dried (Na2SO4) and concentrated to give the title compound LC (method 12): tR=1.02 min; Mass spectrum (ESI+): m/z=387 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]([CH2:20][C:21]([O:23]CC)=[O:22])[C:7]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[CH3:19])C.[OH-].[Na+]>CO.O1CCCC1>[CH3:19][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)=[CH:12][C:7]=1[N:6]([CH2:5][C:4]([OH:26])=[O:3])[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2noc(C)n2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(C)c(N(CC(=O)O)CC(=O)O)c2)no1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
The compound (10.32 g, 28.56 mmol) obtained in step A was dissolved in a methanol (100 ml)-tetrahydrofuran (40 ml) mixed solvent. 1N sodium hydroxide (110 ml) was added with stirring at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (150 ml) was added, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (8.64 g, yield 99%) as a colorless solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]2[CH:17]=[C:18]([CH2:20]Cl)[N:19]=[C:11]2[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:8][C:9]1[N:14]=[C:13]([S:15][CH3:16])[N:12]2[CH:17]=[C:18]([CH2:20][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:19]=[C:11]2[CH:10]=1
Reactant: Oc1ccccc1
Reactant: CSc1nc(Cl)cc2nc(CCl)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1nc(Cl)cc2nc(COc3ccccc3)cn12
Temperature: 50 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
Phenol (0.050 g, 0.53 mmol) was added to a suspension of 7-chloro-2-chloromethyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidine (0.15 g, 0.53 mmol) and K2CO3 (0.21 g, 1.58 mmol) in ACN (2 mL). The mixture was stirred at 50° C. for 18 hours and then the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with diethyl ether and the solid thus obtained, filtered and dried in vacuo to yield 7-chloro-5-methylsulfanyl-2-phenoxymethyl-imidazo[1,2-c]pyrimidine (0.085 g, 53% yield) as a white solid.