Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC(OC)=CC=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[CH:34]=[C:33]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])[O:32][N:31]=2)=[O:28])=[C:22]([F:42])[CH:21]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:34]=[C:33]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:37])[F:38])[O:32][N:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)on2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)on2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
To a suspension of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (100 g, 170 mmol) in DCM (1 L) was added TFA (80 mL, 1077 mmol) dropwise. The mixture was stirred at 25° C. for 2 h. The mixture was then concentrated. To the residue was added H2O (500 mL) dropwise and then neutralized with saturated Na2CO3 solution to adjust pH=7.5. The precipitate was filtered, washed with H2O (350 mL×3) and dried in vacuo. To the solid was added PE/EA (3:1, v/v, 300 mL) and stirred for 0.5 h. The solid was filtered and washed with PE/EA (3:1, v/v, 100 mL×2). The solid was redissolved in DCM/MeOH (20:1, v/v, 1.5 L) and then concentrated in vacuo to a minimal amount of solvent (about 150 mL). The solid was filtered, washed with CH3CN (50 mL×2) and dried in vacuo. The residual solid was added to EtOH (2.5 L) and heated to 80° C. After the solid was dissolved completely, the mixture was concentrated in vacuo to give a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (61.4 g, 131 mmol, 77% yield): 1H NMR (400 MHz, CD3OD) δ 7.40-7.30 (m, 2H), 7.25-7.18 (m, 2H), 6.88 (s, 1H), 5.98 (s, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.37 (t, J=7.2 Hz, 3H); ES-LCMS m/z: 468 (M+H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.Cl.[NH:26]1[CH2:34][CH2:33][CH2:32][C@H:28]([C:29]([OH:31])=[O:30])[CH2:27]1.C(N(C(C)C)CC)(C)C.N1CCCC(C(O)=O)C1.[OH-].[Na+]>O>[C:11]1([C:10]2[C:5]3[C:4]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[N:3][C:2]([N:26]4[CH2:34][CH2:33][CH2:32][C@H:28]([C:29]([OH:31])=[O:30])[CH2:27]4)=[N:7][C:6]=3[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)[C@H]1CCCNC1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Agent: Cl
Agent: O=C(O)C1CCCNC1
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@H]1CCCN(c2nc(NCc3ccccn3)c3c(-c4ccccc4)csc3n2)C1
Temperature: 110 °C

Procedure:
(2-Chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine (5.9 kg, 16.7 mol) and (S)-nipecotic acid hydrochloride (4.15 kg, 25.1 mol) were dissolved in butyrolnitrile (13.9 kg). An excess of diisopropylethylamine (8.6 kg, 66.9 mol) was added and the mixture heated to 110° C. for 24 to 48 hours to complete reaction. With coupling complete (<2% nipecotic acid remaining), the reaction was cooled to room temperature and water (29 kg) was charged. The mixture pH was adjusted to ˜10 with 25% aqueous sodium hydroxide (4.5 L) and the layers separated. The product aqueous layer was extracted twice with ethyl acetate (15.9 L) then methylene chloride (23.5 kg) was added to the aqueous layer and the pH adjusted to ˜2.5 with concentrated hydrochloric acid (6.3 kg). The layers were separated and the aqueous layer re-extracted with methylene chloride (2×15.7 kg). The methylene chloride layers were combined and washed with water (18 kg) then dried over sodium sulfate (5.9 kg) and product solution was held for processing in next step (Example 16).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:10]=3[C:9]=2[C:19]([NH:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.[B-](Br)(Br)(Br)[S+](C)C>ClCCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=3[C:9]=2[C:19]([NH:21][CH3:22])=[O:20])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Agent: C[S+](C)[B-](Br)(Br)Br
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)sc2ccc(O)cc12
Temperature: 83 °C
Reaction time: 9 h

Procedure:
To a suspension containing 2-(4-fluorophenyl)-5-methoxy-N-methylbenzo[b]thiophene-3-carboxamide (0.58 g, 1.8 mmol) and DCE (18 mL), was added boron tribromide-methylsulfide complex (2.3 g, 7.4 mmol) in one portion. The mixture was stirred in a closed vessel at 83° C. for 9 h under a nitrogen atmosphere, cooled to room temperature and quenched with aqueous HCl (20 mL, 1.0 N). The mixture was concentrated to remove all solvent and water was added (50 mL). The aqueous mixture was extracted with ethyl acetate (3×20 mL), dried over MgSO4, filtered and concentrated to afford 2-(4-fluorophenyl)-5-hydroxy-N-methylbenzo[b]thiophene-3-carboxamide as a tan solid which was used without further purification. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.56 (s, 1H), 8.31 (d, J=4.58 Hz, 1H), 7.78 (d, J=8.55 Hz, 1H), 7.55-7.63 (m, 2H), 7.29-7.37 (m, 2H), 7.08 (d, J=2.14 Hz, 1H), 6.91 (dd, J=8.85, 2.44 Hz, 1H), 2.73 (d, J=4.58 Hz, 3H). LCMS: retention time: 2.137 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 302 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1(C)C=CC=CC=1.O>[C:16]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-Benzyl-4-piperidone (122.2 g, 0.645 mole) in 500 ml toluene was warmed to 45° C. Benzyl chloroformate (130 ml, 155 g, 0.915 mole) was added in a thin, steady stream, and the reaction mixture heated to reflux for 2 hours, cooled to ambient temperature, diluted with 250 ml H2O and stirred vigorously 0.5 hour. The organic layer was separated, washed 1×400 ml 6N HCl and then 1×100 ml saturated NaCl, dired (MgSO4), treated with activated carbon, and concentrated to an oil. The oil was distributed between 400 ml ethyl acetate and 400 ml of H2O containing 67.0 g NaHSO3, stirred 0.5 hour, and the aqueous layer separated, washed with 3 portions of ether, made basic with aqueous NaOH and extracted with fresh ether. The ether layer was dried and reevaporated to yield purified title product as an oil, 136.1 g.
Reaction SMILES: C([NH:8][C:9](=[N:11]C(OC(C)(C)C)=O)[NH2:10])(OC(C)(C)C)=O.C(Cl)[Cl:20].[ClH:22]>CCO>[ClH:20].[ClH:22].[NH2:10][C:9]([NH2:11])=[NH:8].[NH2:10][C:9]([NH2:11])=[NH:8]
Reactant: CC(C)(C)OC(=O)N=C(N)NC(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Solvent: CCO
Product: N=C(N)N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The N′,N″-di-BOCguanidine (0.45 g, 0.60 mmol) was dissolvedin CH2Cl2 (10 mL), diluted with dry EtOH (15 mL) and the chilled solution was saturated with dry HCl. The reaction was then kept stirring at room temperature for 3 days (drying tube), when by the product started forming a precipitate over time. After evaporating the solvent to dryness, the residue was washed with ether multiple times and was dried under vacuum at 50-60° C. over night to give whitish yellow solid of the bis-guanidine dihydrochloride; mp>300° C. 1H NMR (DMSO-d6): δ 7.85 (dd, J=1.5, 8.4 Hz, 4H), 7.92 (d, J=1.2 Hz, 4H), 8.00 (dd, J=1.5, 8.4 Hz, 4H ), 9.09 (br s, 4H), 11.25 (br s, 2H). 13C NMR (DMSO-d6): δ 155.98, 138.35, 137.32, 135.00, 127.79, 127.22, 124.79. MS (ESI) m/e (rel. int.): 344 (M+, 6), 173 (100). Anal. Calc. for C20H20N6-2.0HCl-1.0H2O-0.2C2H5OH: C %, 55.11; H %, 5.71; N %, 18.90. Found C %, 55.39; H %, 5.50; N %, 18.71.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.CS[C:13](=[NH:15])[NH2:14]>>[O:8]1[CH:9]=[CH:10][C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:13]([NH2:15])=[NH:14])=[N:7]1
Reactant: CSC(=N)N
Reactant: NCCSCc1ccon1
Product: N=C(N)NCCSCc1ccon1

Procedure:
Reaction of 3-[(2-aminoethyl)thiomethyl]isoxazole with S-methyl-isothiourea by the procedure of Example 1 gives [2-(3-isoxazolylmethylthio)ethyl]guanidine.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:5]=[CH:4][N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(F)c2)c1
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cccc(-c2nc(N)sc2-c2ccnc(NCc3ccccc3)c2)c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
A mixture of [5-(2-fluoro-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]amine (0.29 g, 1.0 mmol) and benzylamine (1.2 mL, 11 mmol) was stirred at 150° C. for 3 hrs. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=1:1) to give the title compound (0.16 g, yield 41%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:5][C:4]=2[N:3]=1.NC1N=C(C)C2C(=[N:38][OH:39])CC(C3C=CC=CC=3C3C=CC=CC=3)CC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:38][OH:39])[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:5][C:4]=2[N:3]=1
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccccc1)C2
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1-c1ccncc1)C2
Product: Cc1nc(N)nc2c1C(=NO)CC(c1ccccc1-c1ccncc1)C2

Procedure:
The title compound was prepared from 2-amino-4-methyl-7-(2-pyridin-4-yl-phenyl)-7,8-dihydro-6H-quinazolin-5-one from stage 1, following the procedure describing the synthesis of 2-amino-7-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (example 5/a stage 2—method A).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[C:6](=[O:16])[N:5]([CH3:17])[C:4]=2[N:3]=1.Cl[CH2:19][C:20]1[S:21][C:22]([CH3:25])=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Br:1][C:2]1[N:10]([CH2:19][C:20]2[S:21][C:22]([CH3:25])=[CH:23][N:24]=2)[C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][OH:15])[C:6](=[O:16])[N:5]([CH3:17])[C:4]=2[N:3]=1
Reactant: Cc1cnc(CCl)s1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2[nH]c(Br)nc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1cnc(Cn2c(Br)nc3c2c(=O)n(CCCO)c(=O)n3C)s1
Temperature: 60 °C
Yield: 58.5 %

Procedure:
To a solution of 8-bromo-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.5 g, 1.65 mmol) in DMF (50 mL) was added 2-(chloromethyl)-5-methylthiazole (0.27 g, 1.81 mmol, intermediate 4), potassium carbonate (0.34 g, 2.48 mmol) and TBAI (2 mg, 0.02 mmol). The mixture was heated at 60° C. for 3 h. The mixture was cooled; then partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by a column chromatography eluting with DCM/methanol (60:1 to 30:1) to give 8-bromo-1-(3-hydroxypropyl)-3-methyl-7-((5-methylthiazol-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione (0.4 g, 58.4%) as a yellow oil which was used without further purification. LCMS MH+ 416.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][N:23]5[CH:27]=[CH:26][N:25]=[N:24]5)[O:19][C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7][CH2:6]2)[O:4]CC1>C(O)(=O)C.O>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][N:23]4[CH:27]=[CH:26][N:25]=[N:24]4)[O:19][C:18]3=[O:28])=[CH:13][C:12]=2[F:29])[CH2:9][CH2:10]1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1
Yield: 68.3 %

Procedure:
(5R)-3-(4-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (1.47 g, 3.65 mM) was dissolved in a mixture of glacial acetic acid (30 ml) and water (30 ml), and heated at 50° for 18 hours. Solvent was evaporated, the residue azeotroped with toluene (50 ml), then partitioned between ethyl acetate (150 ml) and water (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution (2×100 ml), water (100 ml), dried (magnesium sulfate) and evaporated to give product (894 mg), of sufficient quality for use without purification.
Reaction SMILES: [BH4-].[Na+].CO.[Cl:5][C:6]1[C:24]([Cl:25])=[CH:23][C:9]2[N:10]([CH2:18][C:19](=[O:22])[CH2:20][CH3:21])[C:11]([CH2:13][C:14]([F:17])([F:16])[F:15])=[N:12][C:8]=2[CH:7]=1>O>[Cl:5][C:6]1[C:24]([Cl:25])=[CH:23][C:9]2[N:10]([CH2:18][CH:19]([OH:22])[CH2:20][CH3:21])[C:11]([CH2:13][C:14]([F:15])([F:16])[F:17])=[N:12][C:8]=2[CH:7]=1
Reactant: CCC(=O)Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(O)Cn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (11.16 mg, 0.2949 mmol) was added into methanol (5 mL). After the bubbling ceased, 1-[5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-benzoimidazol-1-yl]-butan-2-one (19170-168) (100 mg, 0.2949 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was poured into water and then extracted with EtOAc. The organic layer was dried over anhydrous MgSO4. The solvent was distilled out under reduced pressure to yield the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[C:36]([F:39])([F:38])[F:37])[NH:32][CH2:31][CH2:30]2>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:32]2[C:33]3[C:29](=[CH:28][C:27]([O:26][CH3:25])=[C:35]([C:36]([F:38])([F:39])[F:37])[CH:34]=3)[CH2:30][CH2:31]2)=[O:17])=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: Cc1ccncc1-c1cc(NC(=O)Oc2ccccc2)ccc1C
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(C)c(-c3cnccc3C)c1)CC2
Temperature: 100 °C
Yield: 46.2 %

Procedure:
Phenyl N-(4-Methyl-3-(4-methylpyrid-3-yl)phenyl)carbamate (D69) (0.5 g, 0.0016 mole) in dry dimethylformamide (20 ml) was treated with 5-methoxy-6-trifluoromethylindoline (D11) (0.34 g, 0.0016 mole) under argon and heated to 100° C. for 6 hrs. The mixture was allowed to cool and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and the solution washed with 10% aqueous sodium hydroxide solution (2×20 ml) and then with saturated aqueous sodium chloride solution (30 ml). The organic phase was then dried (Na2SO4) filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with 1% methanol/dichloromethane. Trituration of the resulting residue with diethyl ether gave the title compound (E28) (0.326 g, 47%) m.p. 138-140° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Br)([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[C:11]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)Br
Reactant: O=C(O)c1ccc(Br)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 4-bromobenzoic acid (100 g, 0.5 mol) in dry CH2Cl2 (1.5 L) was added silver carbonate (275 g, 1 mol) and molecular sieves (4A, 100 g). The reaction mixture was cooled to 0° C. and then tert-butyl bromide (115 mL) was added dropwise over a period of 45 min. The reaction mixture was allowed to stir at Rt for 20 h and filtered off the solid. The filtrate was washed with an aqueous solution of NaHCO3 (10%), water, brine and dried. The solvent was removed under vacuum to the title compound (100 g, 79%) as colorless liquid.
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1.BrC1C(Cl)=NC=NC=1>>[Br:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[NH:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=4)[N:18]=3)[CH2:12][CH2:13]2)=[N:6][CH:5]=[N:4][CH:3]=1
Reactant: Nc1ncnc(N2CCC(c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)c1Br
Agent: Clc1ncncc1Br
Product: FC(F)(F)c1cccc(-c2c[nH]c(C3CCN(c4ncncc4Br)CC3)n2)c1

Procedure:
The title compound was prepared in an analogous manner as 5-Bromo-6-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 5-bromo-4-chloropyrimidine instead of 5-bromo-6-chloropyrimidin-4-amine. LC-MS: (M+1=452, obsd.=452).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCCOc1ccnc(CO)c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COCCCCOc1ccnc(CCl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
5.6 g of crude 2-hydroxymethyl-4(4-methoxybutoxy)pyridine was dissolved in 80 ml of chloroform to obtain a solution. A solution of 3.8 g of thionyl chloride in 10 ml of chloroform was dropwise added to this solution at 0° C. The obtained mixture was stirred at 0° C. for one hour. After the completion of the reaction, the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with 200 ml of chloroform twice. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The obtained residue was dried in a vacuum to obtain 5.09 g of the title compound as a crude oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:15][O:1][C:2]1[C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c1oc1ccccc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2c1oc1ccccc12
Temperature: 40 °C
Yield: 98 %

Procedure:
4-hydroxy-dibenzofuran (5.19 g, 28.2 mmoles) is dissolved in acetone (175 mL) under nitrogen atmosphere. Solid K2CO3 (5.85 g, 42.3 mmoles) and iodomethane (7.9 mL, 126.9 mmoles) are added and the resulting mixture is vigorously stirred to reflux (40° C.) to complete conversion of the starting material (7h). The reaction mixture is evaporated to dryness, the crude is then dissolved in water and extracted with DCM; the combined organic layers are washed again with water and brine, dried over sodium sulphate and evaporated to dryness to give the desired product as a white solid (5.48 g) which is employed in the next step without further purification.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:8][CH:9]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[O:8][CH:9]=[C:5]([CH2:4][NH2:1])[N:6]=2)=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1coc(-c2ccc(F)cc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
A solution of 4-(azidomethyl)-2-(4-fluorophenyl)oxazole (0.5 g, 2.3 mmol) in THF—H2O (15 mL, 8:2 v/v) was cooled to 0° C. and triphenylphosphine (892 mg, 3.4 mmol) was added. The reaction mixture was allowed to warm up to room temperature and then stirred for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with 1.5N HCl. The aqueous layer was washed with CH2Cl2 and then the pH of the aqueous layer was adjusted to ˜8-9 using 10% NaOH solution. The organic product was extracted with CH2Cl2 and organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford (2-(4-fluorophenyl)oxazol-4-yl)methanamine (330 mg, yield 75%) as a pale yellow liquid, which was carried through without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.01-7.98 (m, 2H), 7.94 (s, 1H), 7.38-7.34 (m, 2H), 3.65 (d, J=1.1 Hz, 2H). MS (ESI) m/z: Calculated for C10H9FN2O: 192.07. found: 193.2 (M+H)+.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.O.ON1C2C=CC=CC=2N=N1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[N:29]2[CH:30]=[C:31]([C:34]3[C:35]([C:58]4[CH:66]=[CH:65][C:61]([C:62](O)=[O:63])=[CH:60][CH:59]=4)=[N:36][N:37]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:38]=3)[CH:32]=[CH:33][C:28]2=[N:27][CH:26]=1.N1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>O.C(OCC)(=O)C.CN(C)C=O>[O:5]1[CH2:6][CH2:7][N:2]([C:62]([C:61]2[CH:60]=[CH:59][C:58]([C:35]3[C:34]([C:31]4[CH:32]=[CH:33][C:28]5[N:29]([C:25]([C:20]6[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=6)=[CH:26][N:27]=5)[CH:30]=4)=[CH:38][N:37]([C:39]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:36]=3)=[CH:66][CH:65]=2)=[O:63])[CH2:3][CH2:4]1
Reactant: CN1CCOCC1
Reactant: O=C(O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1)N1CCOCC1
Yield: 93.6 %

Procedure:
17 mg N-methyl morpholine and 13 mg 1-hydroxy-1H-benzotriazole monohydrate were added in this order at room temperature to a mixture of 50 mg 4-{4-[3-(2-pyridyl)imidazo[1,2-a]pyridin-6-yl]-1-trityl-1H-3-pyrazolyl} benzoic acid obtained in Example 46, 7.7 mg morpholine, 17 mg 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 8 mL N,N-dimethylformamide. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated, washed twice with water and then with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was evaporated, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) to give 52 mg of the title compound as a colorless amorphous.