Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([Cl:16])[CH:5]=[CH:6]3)[CH:2]=1)=O.[OH-].[Na+].[NH2:19][CH2:20][C:21]([OH:23])=[O:22].Cl>>[Cl:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:15])[N:19]([CH2:20][C:21]([OH:23])=[O:22])[C:11](=[O:13])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: NCC(=O)O
Reactant: O=C1OC(=O)c2ccc(Cl)c3cccc1c23
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Yield: 74.3 %

Procedure:
4-Chloro-1,8-naphthalic anhydride (20.0 g, 0.086 mole; commercial material purified by crystallization from toluene) was suspended in an aqueous 1 N sodium hydroxide solution (95 ml) of glycine (3.8 g, 0.095 mole). The mixture was stirred and refluxed for one hr, after which time a clear solution had resulted. The mixture was rendered acidic with conc hydrochloric acid. The resulting precipitate was collected and dried. Crystallization of the precipitate from anhydrous ethanol afforded 18.5 g of 6-chloro-1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid, mp 260° C.; UV (MeOH) 235,339 and 352 nm, ε=41,310, 15,190 and 13,700, respectively; IR (CHCl3) 1725, 1705 and 1670 cm-1 ; NMR (DMSO-d6) δ4.6 (s, 2H), 6.0 (m, 1H), 7.9 (m, 2H), 8.45 (m, 3H); Anal. Calc'd.: C, 58.05%; H, 2.78%; N, 4.83%; Found: C, 58.16%; H, 2.74%; N, 4.69%.
Reaction SMILES: CN(C)[CH:3]=[O:4].C(Cl)(=O)C(Cl)=O.[CH3:12][C:13]1[N:14]([Si](C(C)C)(C(C)C)C(C)C)[CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl>[CH:3]([C:16]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]([CH3:12])[NH:14][CH:15]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(C=O)c[nH]c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
N,N-dimethylformamide (5.5 mL, 71 mmol) in dichloromethane (126 mL) at 0° C. was treated dropwise with oxalyl dichloride (6 mL, 71 mmol). The mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 1 hour. The mixture was again cooled to 0° C. and treated with a mixture of Example 1a (20 g, 64.6 mmol) in dichloromethane (126 mL). The reaction mixture was stirred at 0° C. for 2 hours and then at ambient temperature for 48 hours. The reaction mixture was again cooled to 0° C. and slowly quenched with 4 N aqueous sodium hydroxide solution. The mixture was then extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was triturated with a mixture of 9:1 hexanes/ethyl acetate, filtered, and dried under high vacuum to give 8.67 g (74%) of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20](F)[CH:19]=1>CN(C)C=O>[CH3:9][C:8]([O:7][C:6](=[O:12])[N:5]([CH2:4][CH2:3][CH:2]([O:1][C:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[N+:24]([O-:26])=[O:25])[CH2:14][CH2:15][CH3:16])[CH3:13])([CH3:10])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxyhexyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2-fluoronitrobenzene in N,N-dimethylformamide.
Reaction SMILES: N1C(=O)C=[CH:3]N1.[C:7]1([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][NH:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[CH3:3][N:14]1[CH:15]=[CH:16][C:17](=[O:18])[N:13]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=c1cc[nH][nH]1
Reactant: O=c1cc[nH]n1-c1ccccc1
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: Cn1ccc(=O)n1-c1ccccc1
Temperature: 50 °C

Procedure:
The pyrazolinone prepared as described above in (a) (1.153 g, 7.2 mmol) in dry toluene (3 ml) was treated with dimethyl sulphate (8 mmol, 750 μl) and the whole refluxed under nitrogen for 5 hours. The reaction mixture was then allowed to cool and in doing so separated into two phases. The upper consisting mainly of toluene was carefully pipetted off and discarded. The remaining layer was then treated with water (1 ml), the whole warmed with stirring to 50° C. and then treated with 40% sodium hydroxide solution (1 ml) and stirred at 50° C. for a further 30 minutes. The resultant solution was subsequently extracted with three portions of benzene. The first two extracts were found to contain two products which has spectral properties consistent with 2-methyl-1-phenyl-3-pyrazolin-5-one and 2,4-dimethyl-1-phenyl-3-pyrazolin-5-one. These were separated by chromatography on silica (ethyl acetate) to give 2-methyl-1-phenyl-3-pyrazolin-5-one (95 mg). The third extracton (above) consisted solely of 2-methyl-1-phenyl-3-pyrazolin-5-one (208 mg) (Total yield, 24%). νmax (CHCl3) 1655, 1595, 1550, 1495 cm-1. δ(D6Acetone) 3.11 (3H, s, --NMe), 5.44 (1H, d, J4 Hz, C4 proton), 7.47 (5H, m, phenyl protons), 7.83 (1H, d, J4 Hz, C3 proton). Found: M+ 174.0798; C10H10N2O requires M; 174.0794.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[C:23]([NH:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][CH:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cc1cccc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(NC(C)=O)n1
Reaction time: 1 h

Procedure:
To the solution of ethyl 2-(6-aminopyridin-2-yl)acetate (50 mg, 0.28 mmol) and N-ethyl-N-isopropylpropan-2-amine (71.0 mg, 0.55 mmol) in DCM was added acetyl chloride (43.2 mg, 0.55 mmol) dropwise at room temperature. The mixture was continued to stir for 1 h, washed with brine and evaporated in vacuum to dryness. The residue was purified by a standard method to afford desired compound. LC-MS: m/z (M+H)=222.4
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[CH3:15][O:16][C:17](=O)[C@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:19][CH:20]=O>C(Cl)(Cl)Cl>[CH2:22]([C:18]1[N:19]=[CH:20][S:2][C:17]=1[O:16][CH3:15])[CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)[C@H](CC(C)C)NC=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: ClC(Cl)Cl
Product: COc1scnc1CC(C)C
Temperature: 25 °C

Procedure:
A 500 ml flask equipped with heating mantle, condenser, and drying tube is charged with 27.25 g (0.125 mole) of phosphorus pentasulfide, 17.3 g (0.1 mole) of N-formylleucine methyl ester, and 250 ml of chloroform, and the contents are refluxed for 24 hours. The reaction mixture is thereupon cooled to room temperature, washed with 250 ml of 10% potassium hydroxide, and then washed with 250 ml of distilled water.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:13]=1)[CH2:9]Br)([CH3:5])[CH3:4])#[N:2].[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:4][C:3]([C:6]1[CH:7]=[C:8]([CH2:9][N:19]2[N:20]=[CH:21][N:22]=[CH:23]2)[CH:11]=[C:12]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:13]=1)([C:1]#[N:2])[CH3:5]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C#N)c1cc(CBr)cc(C(C)(C)C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: CC(C)(C#N)c1cc(Cn2cncn2)cc(C(C)(C)C#N)c1

Procedure:
In yet another embodiment of the present invention, the purified bromo compound (formula (III)) is alkylated with 1,2,4-triazole in a suitable solvent using a suitable base in the presence of a phase transfer catalyst such as tetrabutyl ammonium bromide to obtain anastrozole, which is further purified using column chromatography, followed by precipitation/crystallization using ethyl acetate and diisopropyl ether to obtain pure anastrozole in high yield.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=4[O:23][CH:24]([CH2:28][CH2:29][CH3:30])[C:25]([OH:27])=O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O[N:36]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=4[O:23][CH:24]([CH2:28][CH2:29][CH3:30])[C:25]([NH2:36])=[O:27])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(N)=O
Yield: 102.2 %

Procedure:
To a solution of 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanoic acid (500 mg) and 1-hydroxybenzotriazole (141 mg) in dimethylformamide (5 ml) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (200 mg) at room temperature. The solution was stirred for an hour at the same temperature and was ice-cooled. Then concentrated solution of ammonia (0.3 ml) was added into the solution and the resulting mixture was stirred further for an hour. The mixture was diluted with water and was extracted with ethyl acetate. The organic layer was separated and was washed successively with sodium hydrogen carbonate solution and brine, and was dried over magnesium sulfate. Concentration gave 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}-pentanamide (510 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10]C(=O)C)[C:7]([CH3:14])=[N:6][C:5]=1[C:15](=O)[NH:16][C:17]([C:22](=[O:24])[NH2:23])([CH3:21])[CH:18]([CH3:20])[CH3:19].P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O=P(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:14])=[N:6][C:5]=1[C:15]1[NH:23][C:22](=[O:24])[C:17]([CH:18]([CH3:20])[CH3:19])([CH3:21])[N:16]=1
Reactant: COC(=O)c1cc(OC(C)=O)c(C)nc1C(=O)NC(C)(C(N)=O)C(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(O)c(C)nc1C1=NC(C)(C(C)C)C(=O)N1

Procedure:
A solution of 47 g (0.129 mol) 5-acetoxy-2-(1-carbamoyl-1,2-dimethylpropyl-carbamoyl)-6-methyl-nicotinic acid methyl ester and 93.8 g phosphorus pentachloride in 470 ml phosphoroxychloride is stirred 12 hours at room temperature. The solution is then hydrolysed with ice and neutralized with sodium carbonate. The product is extracted with ethyl acetate, the extract is then dried across magnesium sulfate and compressed. The crude product is recrystallized from ethyl acetate/isopropyl ester.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][CH:29]=1>O1CCCC1>[C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:34]([OH:35])[C:31]3[CH:32]=[CH:33][C:28]([CH3:36])=[CH:29][CH:30]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Reactant: Cc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccc(C)cc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 75 g. (0.348 mole) of 3-phenyl-5,N-dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran is cooled to -65° C. and 478 ml. of 1.6M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° and -70° C. After the addition is complete, the orange suspension is stirred for 11/2 hours at -60° to -70° C., and then 37.2 g. (0.350 mole) of p-tolualdehyde in 375 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete the mixture is stirred for 11/2 hrs. at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with a 50:50 mixture of ether:petroleum ether, filtered and washed with cold ether to give 3-phenyl-5-(4-methyl-β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide; m.p. 148° to 150° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[I:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:17]([CH:20]=1)[CH2:18]Br>>[CH3:2][O:3][C:4](=[O:11])[CH:5]([CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH2:18][C:17]1[CH:20]=[C:13]([I:12])[CH:14]=[CH:15][C:16]=1[O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]
Reactant: COC(=O)C[C@H]1CCCN1
Reactant: COCCOCOc1ccc(I)cc1CBr
Agent: Cl
Product: COCCOCOc1ccc(I)cc1CC(C(=O)OC)C1CCCN1

Procedure:
(R)-Pyrrolidin-2-yl-acetic acid methyl ester hydrochloride (0.78 g, 4.4 mmol) is alkylated with 5-Iodo-2-(2-methoxyethoxymethoxy)benzyl bromide (1.5 g, 3.7 mmol) as described in EXAMPLE 12B to yield 3-[5-Iodo-2-(2-methoxyethoxymethoxy)phenyl]-2-pyrrolidin-2-yl propionic acid methyl ester. This material is treated with triethylamine (0.52 mL, 3.74 mmol) and Boc anhydride (0.82 g, 3.74 mmol) in methylene chloride (25 mL) at 0° C. The reaction mixture is warmed to ambient temperature over 3 h. The solvent is removed under vacuo and the residue is partitioned between ethyl acetate and bicarbonate solution. The organic layer is separated, washed with water and brine, dried over MgSO4 and concentrated to a tan oil. This material is chromatographed (25% ethyl acetate/hexane) to give the title compound as an oil (1.66 g, 3.6 mmol). 1H NMR (CDCl3, 300 MHz) □ 7.43-7.38(m, 2H), 6.88(d, 1H), 5.23(s, 2H), 4.23-4.06(m, 1H), 3.83-3.76(m, 2H), 3.57(s, 3H), 3.56-3.48(m, 2H), 3.37(s, 3H), 3.36-3.26(m, 3H), 2.94-2.78(m, 1H), 2.76-2.61(m, 1H), 2.03-1.75(m, 4H), 1.45(s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:17].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:17][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28]
Reactant: CC(C)=CCBr
Reactant: COc1ccnc(Nc2ccc(Cl)c(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccnc(Nc2ccc(Cl)c(OCC=C(C)C)c2)n1
Yield: 51 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 2-chloro-5-(4-methoxypyrimidin-2-ylamino)phenol (54 mg, 0.22 mmol) and Cs2CO3 (70 mg, 0.22 mmol) in acetone (3 mL) was treated with 4-bromo-2-methyl-2-butene (25 μL, 0.22 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 8/2) in 51% yield (35 mg).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C@@H:12]2[CH2:16][NH:15][C:14](=[O:17])[CH2:13]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[Cl:8].N([O-])=O.[Na+].O>OS(O)(=O)=O>[Cl:8][C:7]1[CH:2]=[CH:3][C:4]([C@@H:12]2[CH2:16][NH:15][C:14](=[O:17])[CH2:13]2)=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Nc1cc([C@@H]2CNC(=O)C2)c([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1C[C@H](c2ccc(Cl)cc2[N+](=O)[O-])CN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
A solution of (4R)-4-(3-amino-4-chloro-6-nitrophenyl)pyrrolidin-2-one (3.5 g, 13.7 mmol) in 12.6 mL of conc. H2SO4 was heated to 55° C. Sodium nitrite (16.94 mmol) was added in small portions. The reaction mixture turned from yellow to red, then dark red. After the mixture was stirred for additional 30 min at this temperature, the mixture was cooled to room temperature and water was added. The mixture was then extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water and brine, and dried over Na2SO4. The solvent was removed in vacuo to afford the title compound (2.5 g, 80% yield). 1H-NMR (400 MHz, CD3OD): δ 2.45-2.51 (dd, J=17.2, 6.8 Hz, 1H), 2.77-2.84 (dd, J=17.2, 9.2 Hz, 1H), 3.41-3.44 (m, 1H), 3.80-3.85 (dd, J=10.4, 8.0 Hz, 1H), 4.03-4.05 (m, 1H), 7.61-7.63 (d, J=8.4 Hz, 1H), 7.67-7.70 (dd, J=8.4, 2.0 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H); MS (ESI) m/z 241.01 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18].[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)Cl>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:21](=[O:23])[CH3:22])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:16][C:17]([F:18])([F:20])[F:19]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Oc2ccc(N)cn2)cc1OC(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccc(C)c(OC(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-[4-methyl-3-(trifluoromethoxy)phenoxy]pyridin-3-amine (Intermediate 31, 475 mg, 1.67 mmol) and TEA (0.28 mL) in 5 mL of dry DCM under nitrogen at 0° C., acetyl chloride (0.13 mL) dissolved in 2 mL of dry DCM was added drop wise. The ice bath was then removed and the resulting solution was allowed to stir at room temperature for 30 minutes until complete conversion. Water was added and phases were separated. The organic phase was then washed with an aqueous 15% solution of NaHCO3, dried over Na2SO4, filtered and concentrated to give the title compound (502 mg) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Product: OCc1cnc(N2CCNCC2)c(Cl)c1

Procedure:
A mixture of 5,6-dichloro-3-pyridinemethanol (0.71 g, 4 mmol, TCI-US), piperazine (0.52 g, 6 mmol) and N,N-diisopropylethylamine (1 mL, 5.8 mmol, Aldrich) was reacted under the conditions of Example 43a to give the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 228 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[C:9]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][C:20]([CH2:22][N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:21][C:15]=4[N:14]=3)=[N:10][NH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:29]1COCC1>>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[C:9]([C:13]3[NH:14][C:15]4[CH:21]=[CH:29][C:19]([CH2:20][CH2:22][N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:18][C:16]=4[N:17]=3)=[N:10][NH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: C1CCOC1
Reactant: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CCN3CCOCC3)ccc2[nH]1)NC1CC1
Reaction time: 8 h

Procedure:
A sample of crude 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea free base was dissolved in THF and then concentrated in vacuo to a minimum volume (˜4 volumes). To the solution was added water dropwise (2-4 volumes) until the solution became turbid. A small amount of THF was added to re-establish solution clarity and the mixture left to stand overnight to give a crystalline material which was air-dried to give 1-cyclopropyl-3-[3-(5-morpholin-4-ylethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea free base dihydrate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:12])[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8].[Br-:13].[Br-].O1CCOCC1>O1CCOCC1>[Br:13][CH:10]([CH3:11])[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)=[O:12]
Reactant: CCC(=O)c1ccc(F)c(F)c1
Reactant: [Br-]
Solvent: C1COCCO1
Product: CC(Br)C(=O)c1ccc(F)c(F)c1
Yield: 98.9 %

Procedure:
To 3',4'-difluoropropiophenone (Alfa Products, Danvers, Mass. 01923) (90.5 g, 0.53 mole) was added a solution of dioxane dibromide (131.4 g, 0.53 mole) in dioxane (500 ml). The reaction was worked up as in Example 1 to yield crude 2-bromo-3',4'-difluoropropiophenone (130.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: C[C@H](C(=O)O)c1ccc(F)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Solvent: CO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)[C@@H](C)c2ccc(F)cc2)CC1

Procedure:
Example 168 was prepared from (2S)-2-(4-fluorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D=+13.5° (C=1.02, MeOH): 1H NMR (400 MHz, CDCl3) δ 7.58–7.49 (m, 2 H), 7.37–7.29 (m, 2 H), 7.26–7.19 (m, 1 H), 7.06 (d, 1 H, J=8.0 Hz), 7.04–6.92 (m, 3 H), 3.56 (t, 1 H, J=6.8 Hz), 3.43–3.23 (m, 2 H), 2.95 (ABq, 2 H), 2.63–2.59 (m, 1 H), 2.59–2.45 (m, 1 H), 2.37 (t, 2 H, J=6.0 Hz), 2.27 (s, 3 H), 2.07–1.90 (m, 2 H), 1.82–1.57 (m, 6 H), 1.50 (d, 3 H, J=7.2 Hz), 1.22 (d, 6 H, J=7.2 Hz); ESMS m/e: 468.3 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:15]1([CH3:23])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Mg]Br>C(OCC)C.C(=O)=O.CC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccccc1[Mg]Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cc1ccccc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 5 h
Yield: 112.6 %

Procedure:
N-Boc-4-piperidone (Boc-29.155) (200 mg, 11.0 mmol) was dissolved in 5 ml of anhydrous ethyl ether, cooled in dry ice/acetone bath. 2-Tolylmagnesium bromide (550 μl, 2M in ethyl ether, 1.1 mmol) was added dropwise over 5 min. White precipitate was formed. After 5 h, remove the dry ice/acetone bath and rise to room temperature gradually. After 2 h, cooled in ice bath, 8 ml of saturated NH4Cl and 2 ml of H2O were added. The organic phase was separated and aqueous phase was extracted with 4×10 ml of Et2O. Combined with organic phase and washed with 8 ml of H2O and 10 ml of brine, dried over MgSO4. Concentrated and dried to obtain 361 mg of colorless oil. Separated by silica gel to obtain 4f (229.7 mg, 79% yield) as colorless oil. 1H NMR (CDCl3, 200 MHz) δ 1.47 (s, 9H), 1.93 (m, 4H), 2.60 (s, 3H), 3.27 (t, 2H, J=13.0 Hz), 3.96 (d, 2H, J=12.2 Hz), 7.15 (m, 3H), 7.35 (m, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.[I:17]I>C1COCC1.CCOC(C)=O>[F:9][C:10]1[C:15]([I:17])=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1
Reactant: Fc1cccc(F)n1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(I)c(F)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of lithium diisopropylamide (4.34 mL, 8.69 mmol, 2.0 M solution in heptane/THF/ethylbenzene) in THF (20 mL) at −78° C. under a nitrogen atmosphere was added 2,6-difluoropyridine (0.79 mL, 8.69 mmol). The mixture was stirred at −78° C. for 45 min before iodine (2.21 g, 8.69 mmol) in THF (10 mL) was added via syringe. The reaction was stirred for an additional 30 min at −78° C. The reaction mixture was diluted with EtOAc and washed with 10% aqueous sodium sulfite. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give 2,6-difluoro-3-iodopyridine.