Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH:16]1[C:21]([CH2:22][C:23]([NH2:25])=[NH:24])=[CH:20][C:19]([Cl:26])=[C:18]([Cl:27])[CH:17]=1>>[OH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:24]=[C:23]([CH2:22][C:21]2[CH:16]=[CH:17][C:18]([Cl:27])=[C:19]([Cl:26])[CH:20]=2)[N:25]=1
Reactant: N=C(N)Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc(Cc2ccc(Cl)c(Cl)c2)nc1O
Yield: 37 %

Procedure:
The title compound was prepared by (a) of diethyl ethoxymethylenemalonate (6 g, 27 mmol) with 3',4'-dichlorophenylacetamidine (5.5 g, 27 mmol) to afford 37% of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 15, (b) reaction of ethyl 4-hydroxy-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (2 g, 6 mmol) with POCl3 (14 g, 92 mmol) to afford 62% of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate in analogy to Example 7, (c) reaction of ethyl 4-chloro-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (1 g, 2.8 mmol) with hydrazine (0.27 g, 8.3 mmol) to afford 99% of ethyl 4-hydrazino-2-(3',4'-dichlorophenyl)pyrimidine-5-carboxylate in analogy to Example 18, (d) reaction of ethyl 4-hydrazino-2-(3',4'-dichlorobenzyl)pyrimidine-5-carboxylate (0.9 g, 2.7 mmol) with citraconic anhydride (0.49 g, 4.4 mmol) in analogy to Example 21 to afford 47% (0.3 g) of the title compound; m.p. 119-121° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F-:13].[Cs+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: [F-]
Reactant: COC(=O)c1cc(Br)cnc1Cl
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.6 %

Procedure:
To a solution of methyl 5-bromo-2-chloronicotinate (170 mg, 0.68 mmol) in 3 mL of DMSO was added CsF (152 mg, 1.0 mmol). The solution was stirred at room temperature for 2 d and then heated at 60° C. for 4 h. After cooling, the mixture was diluted with 30 mL of H2O. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, and dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by silica gel flash chromatography to give the desired product (90 mg, 57% yield). MS (ESI+) m/z 234.06, 236.09 (M+H)+.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH:10](=[O:14])[CH:11]([CH3:13])[CH3:12].[Br-].[OH-].[Na+]>C(OCC)(=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH3:12][C:11]([CH3:13])([CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH:10]=[O:14]
Reactant: BrCc1ccncc1
Reactant: CC(C)C=O
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC(C)(C=O)Cc1ccncc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 24.5 %

Procedure:
4-(Bromomethyl)pyridine hydrobromide (5.00 g, 19.8 mmol) was suspended in ethyl acetate (40 mL) and water (20 mL) and washed with 10% aq. NaHCO3 solution (35 mL) to generated the free base. The layers were partitioned and the organic portion was concentrated and redissolved in benzene (30 mL). To this solution was added tetrabutylammonium iodide (112 mg, 0.303 mmol) and isobutyraldehyde (1.10 g, 15.2 mmol). The solution of aledyde and bromide was then added via addition funnel in dropwise fashion over a period of 30 minutes to a stirred suspension of powdered NaOH (608 mg, 15.2 mmol) in benzene (90 mL) at 60° C. The reaction was stirred at 60° C. for 5 hours then cooled to ambient temperature. EtOAc (40 mL) was added and the reaction mixture was washed with water (40 mL), satd. aq. sodium bisulfite solution (2×25 mL), then brine (30 mL). The organic portion was dried (Na2SO4) and concentrated. Purification of the resulting oily residue by flash chromatography (gradient elution: hexanes then 7% EtOH/hexanes) provided the title compound (608 mg, 3.73 mmol) as a off-yellow waxy solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>C(#N)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:17])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C

Procedure:
The above prepared (2,4-dihydroxy-phenyl)-phenyl-methanone (0.775 g, 3.62 mmol) was dissolved in 15 mL of acetonitrile and treated successively at 0° C. with Cs2CO3 (1.297 g, 1.1 eq.) and iodomethane (0.242 mL, 1.08 eq.), and the mixture was then stirred over night at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, heptane/AcOEt=9/1), delivered 0.681 g of the title compound as off-white oil.
Reaction SMILES: [OH-:1].[Na+].BrC(Br)[C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)=[O:6]>O>[C:5]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)([OH:6])=[O:1]
Reactant: O=C1CCc2cc(C(=O)C(Br)Br)ccc2N1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C1CCc2cc(C(=O)O)ccc2N1
Yield: 54.5 %

Procedure:
Into 250 ml of water, 26 g sodium hydroxide was dissolved, then at a temperature of 90°-100° C. and under stirring condition, 35 g of 6-dibromoacetyl-3,4-dihydrocarbostyril was added thereinto and reacted for 3 hours. After the reaction was completed, the reaction mixture was cooled and insoluble matters formed in the mixture were removed by filtration. The mother liquor was acidified with concentrated hydrochloric acid and the crystals precipitated were collected by filtration and washed with water. The crystals thus obtained were recrystallized from ethanol twice to obtain 10.5 g of 6-carboxy-3,4-dihydrocarbostyril in the form of light yellow amorphous crystals.
Reaction SMILES: [Cl:1][CH:2]([Cl:11])[CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7].S(Cl)([Cl:14])=O>>[Cl:1][CH:2]([Cl:11])[CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([Cl:14])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CC(=O)O)CC(Cl)Cl
Product: CC(C)(CC(=O)Cl)CC(Cl)Cl
Temperature: 60 °C

Procedure:
52.25 g of 5,5-dichloro-3,3-dimethyl-pentanoic acid are reacted with 150 ml of thionyl chloride, first at room temperature and thereafter while warming at 60° C. By working up the mixture by distillation, 56.5 g of 5,5-dichloro-3,3-dimethyl-pentanoic acid-chloride of boiling point 114°-115° C./15 are obtained.
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][O:29][C:30](=[O:46])[C:31]1[CH:42]=[C:41]([N+:43]([O-:45])=[O:44])[CH:40]=[C:33]([C:34]([NH:36][CH2:37][CH:38]=[O:39])=O)[CH:32]=1.N1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH3:28][O:29][C:30](=[O:46])[C:31]1[CH:32]=[C:33]([C:34]2[O:39][CH:38]=[CH:37][N:36]=2)[CH:40]=[C:41]([N+:43]([O-:45])=[O:44])[CH:42]=1
Reactant: COC(=O)c1cc(C(=O)NCC=O)cc([N+](=O)[O-])c1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(-c2ncco2)cc([N+](=O)[O-])c1
Reaction time: 0.33 h

Procedure:
A mixture of hexachloroethane (42.7 g, 180 mmol) and 47.2 g of triphenylphosphine (180 mmol) in 1 l of acetonitrile is stirred for 20 minutes. A solution of 24 g (90.2 mmol) of 5-nitro-N-(2-oxo-ethyl)-isophthalamic acid methyl ester in 400 ml of acetonitrile is added, followed by 25.8 ml (361 mmol) of pyridine. After 18 h at rt, the mixture is diluted with 500 ml of ethyl acetate and washed with brine. The organic phase is dried over sodium sulfate and concentrated, and the residue is purified by chromatography on silica gel (EtOAc/hexane 1:3) to yield the product in the form of colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]([OH:16])C(O)=O)=[CH:10][CH:9]=1.CI.[C:21]([O:24][CH2:25]C)(=[O:23])[CH3:22]>CN(C=O)C.O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][O:16][CH2:22][C:21]([O:24][CH3:25])=[O:23])=[CH:17][CH:18]=1
Reactant: O=C(O)C(O)c1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)COCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
Cesium carbonate (6.5 g) was added to a solution of 4-fluoromandelic acid (CAS #395-33-5, 1.7 g) and methyl iodide (1.9 mL) in DMF (15 ml), and the reaction solution was stirred at room temperature for 11 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.22 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH:14]3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.C(O)C.O>C(OCC)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH:14]3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1CCc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1CNCCN1CCc1ccc2c(c1)OCCO2
Reaction time: 2 h

Procedure:
To 0.60 g of 1-tert-butyl 3-ethyl 4-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl)piperazine-1,3-dicarboxylate, 12 mL of 10 mol/L hydrogen chloride/ethanol was added, and the mixture was stirred for 2 hours, and then the solvent was removed under reduced pressure. The residue thus obtained was added with water and ethyl acetate. The aqueous layer was separated, ethyl acetate was added thereto, and the resultant solution was adjusted to pH 14 with a 5 mol/L aqueous sodium hydroxide solution. The organic layer was separated and dried over potassium carbonate, and the solvent was removed under reduced pressure to obtain 0.34 g of a brown oily substance, ethyl 1-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl)piperazine-2-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[NH:16][C:17](=[O:33])[CH2:18][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1ccc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)N=C(c1cccc(-c3cccnc3)c1)CC(=O)N2

Procedure:
The title compound was prepared from {5-methoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M51) (229 mg, 0.50 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (159 mg).
Reaction SMILES: [Cl-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=3)[CH:18]=2)[C:13](O)=[O:14])=[N:8][CH:9]=1.[CH3:26][C:27]1[N:31]=[C:30]([C@H:32]([NH2:34])[CH3:33])[O:29][N:28]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.FC(F)(F)C(O)=O>CN(C)C=O.O>[CH3:26][C:27]1[N:31]=[C:30]([C@H:32]([NH:34][C:13](=[O:14])[C:12]2[CH:16]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([CH3:25])=[N:23][CH:24]=3)[CH:18]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][N:8]=3)[CH:11]=2)[CH3:33])[O:29][N:28]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cnc(C)nc3)c2)nc1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3nc(C)no3)cc(-c3cnc(C)nc3)c2)nc1
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a solution of the sodium chloride salt of 3-(5-methylpyridin-2-yl)-5-(2-methylpyrimidin-5-yl)benzoic acid (35 mg, 0.073 mmol) in N,N-dimethylformamide (0.728 mL) was added the hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (17.5 mg, 0.087 mmol), EDC (16.8 mg, 0.087 mmol), HOBT (11.2 mg, 0.073 mmol), and triethylamine (0.041 mL, 0.291 mmol). After 16 h, water and trifluoroacetic acid were added. Purification by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (28.8 mg). HRMS 415.1880 (M+1). 1H NMR (500 MHz, CD3OD): δ 9.21 (s, 2H); 8.78 (s, 1H); 8.57-8.53 (m, 2H); 8.49 (d, J=9.5 Hz, 2H); 8.42 (d, J=8.3 Hz, 1H); 5.51 (q, J=7.2 Hz, 1H); 2.80 (s, 3H); 2.64 (s, 3H); 2.37 (s, 3H); 1.75 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[S:22][C:21]([C:23]#[N:24])=[CH:20][C:19]=1[CH3:25]>>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[S:22][C:21]([C:23]#[N:24])=[CH:20][C:19]=3[CH3:25])=[CH:8][C:7]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: Cc1cc(C#N)sc1Br
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
Prepared according to Procedure B from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 5-bromo-4-methyl-2-thiophenecarbonitrile. Off-white solid: mp 195-200° C. 1H-NMR (DMSO-d6) δ 10.2 (s, 1H), 8.32 (s, 1H), 7.41-7.44 (m, 2H), 7.01 (d, 1H, J=8.8 Hz), 2.28 (s, 3H), 1.64 (s, 6H); MS (APCI) m/z 299 [M+H]+. Anal. Calc. For C16H14N2O2S; C, 64.41; H, 4.75; N, 8.89. Found: C, 64.64; H, 4.62; N, 9.39.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].COCCON1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:3][O:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O
Agent: COCCON1C(=O)c2ccccc2C1=O
Product: CC(C)(C)OC(=O)NCCON
Yield: 58 %

Procedure:
2E was deprotected as previously described in 2A, Step 2 to give tert-butyl 2-(aminooxy)ethylcarbamate (2F, 1.26 g, 58% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 3.37 (q, J=5.31 Hz, 2H) 3.62-3.85 (m, 2H) 4.90 (br. s., 1H) 5.47 (br. s., 2H).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]12[CH:18]=[CH:17][CH:16]=[CH:15][CH:5]1[CH2:6][CH:7]2[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.BrCCCBr.CCOCC>[NH2:9][CH2:8][CH2:7][CH2:6][O:3][C:4]12[CH:18]=[CH:17][CH:16]=[CH:15][CH:5]1[CH2:6][CH:7]2[CH2:8][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: OC12C=CC=CC1CC2CN1CCCCC1
Agent: BrCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOCC
Product: NCCCOC12C=CC=CC1CC2CN1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Potassium hydroxide (1.5 g, 10%) is added over a period of 1 hour 15 min to a stirred suspension of 3-hydroxy-1-(1-piperidinylmethyl)benzocyclobutene (1.0 g), and tetrabutylammonium chloride (0.13 g) in 1,3-dibromopropane (4.6 ml) and the resulting mixture stirred at RT under nitrogen for two days. The reaction mixture is partitioned between ice-water and ether and the aqueous layer separated and extracted with ether. The combined organic extract is washed with water, ice cold 5% aqueous HCl thereby forming a precipitate which is filtered and washed with ether. The acidic layer is alkalized forming an oily precipitate which is taken up in ether. The combined ether fractions are washed with water, dried over Na2SO4, filtered and concentrated in vacuo yielding the desired product as an oil which is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:38][CH3:39])[C:22]([Cl:40])=[CH:21][N:20]=1>>[Cl:40][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[O:38][CH3:39])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield an off-white solid (65%). LCMS: m/z=551.27 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H, J=8.8 Hz), 8.04 (s, 1H), 7.79 (bs, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.25 (m, 2H), 6.53 (m, 1H), 6.41 (d, 1H, J=8.8 Hz), 3.91 (s, 3H), 3.88 (m, 4H), 3.74 (m, 2H), 3.14 (m, 4H), 2.33 (m, 2H), 2.04 (m, 2H), 1.33 (s, 6H), 1.21 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[CH3:12]/[C:13](/[CH2:17][CH2:18]/[CH:19]=[C:20](\[CH3:28])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:27])[CH2:25][CH3:26])=[CH:14]\CO>ClCCl>[Cl:1][CH2:26]/[CH:25]=[C:24](\[CH3:27])/[CH2:23][CH2:22]/[CH:21]=[C:20](\[CH3:28])/[CH2:19][CH2:18][CH:17]=[C:13]([CH3:14])[CH3:12]
Reactant: CCC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.8 %

Procedure:
(Note: all temperatures indicated are for the contents of the reaction flask). To a stirred solution of 299 mg (2.24 mmol) of N-chlorosuccinimide in 15 ml of dichloromethane at -30° C. under argon was added 0.18 ml (2.45 mmol) of distilled dimethyl sulfide over 5 minutes. After 10 minutes at -30° C., the reaction was allowed to warm to 0° C. for 10 minutes, followed by cooling to -40° C. A solution of 441.4 mg (1.99 mmol) of (E,E)-3,7,11-trimethyl-2,6,10-tridecatrien-1-ol in 5 ml of dichloromethane was added dropwise over 10 minutes. The reaction was allowed to warm gradually to 0° C. over 1 hour, and then maintained at 0° C. for 1 hour. After quenching with cold water, the mixture was extracted with hexane and the hexane extract was washed with cold water and cold brine, dried (MgSO4) and evaporated to afford 483 mg of a crude product. Rapid flash chromatography on 20 g of Merck 9385 silica gel eluted with 3:97 ethyl acetate:pet ether provided 406.5 mg (85%) of a colorless liquid. 13C NMR indicated that this material contained a trace (3%) impurity.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:13]=2[CH:12]=1.II.[Br:43]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][C:17]([Br:43])=[CH:18][CH:19]=3)[C:14]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:13]=2[CH:12]=1
Reactant: BrBr
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(-c3ccc(Br)cc3C(=O)OC)cc21
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(-c3ccc(Br)cc3C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
40 g (66 mmol) 15 is dissolved in 300 ml dichloromethane. The solution is cooled to 0° C., 1 g iodine is added and the mixture is stirred for 30 min. Then a solution of 11 g bromine in dichloromethane is slowly added by a dropping funnel. The solution is heated to reflux until the reaction is completed The reaction mixture is allowed to warm up to room temperature and of a 200 ml saturated Na2S2O3 solution is added. The organic layer is separated and the aqueous layer is extracted with dichloromethane. The unified organic layers are washed twice with 100 ml water dried over sodium sulfate, filtrated and the solvent is removed under vacuum. The residue is recystallisated from butanole to result white solid (38 g 55.6 mmol, yield: 84%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(OCC)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][N:26]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=1.C(N(CC)CC)C>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:23][CH:24]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.101 g, 0.464 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (10 mL) at 0° C. and a 1.0 M ZnCl2 solution in diethyl ether (0.530 mL, 0.530 mmol) was added cautiously over 20 minutes. After addition, the reaction was left stirring at 0° C. for 30 minutes and a solution of tert-butyl 2-(4-aminophenyl)piperidine-1-carboxylate (I36) (0.122 g, 0.441 mmol) in 1:1 t-BuOH:1,2-dichloroethane (4 mL) was added drop-wise over 15 minutes at 0° C. followed by a solution of triethylamine (0.074 μL, 0.530 mmol) in 1:1 t-BuOH:1,2-dichloroethane (4 mL) and the reaction was allowed to warm to room temperature and was stirred for 60 hours. Volatiles were evaporated in vacuo and the resulting residue was suspended in water (40 mL), the suspension was sonicated for 40 minutes and the product was collected by filtration, the solid was washed with water (5×10 mL) and dried under a high vacuum to give the title compound (I37) (0.135 g, 67% yield) as a pale pink solid. LCMS Method C: rt 6.96 min; m/z 455.2, 457.2 M−H]−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH:20]=[O:21])[CH2:15][CH2:14][CH2:13][CH2:12]1.[NH4+].[Cl-]>C1COCC1>[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:20]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[OH:21])[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Brc1ccccc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccc2)cc1OC1CCCC1
Temperature: 0 °C
Yield: 98 %

Procedure:
A Grignard complex was formed with bromobenzene (18.84 g), magnesium, turnings (2.9 g), iodine (catalytic amount) and aluminum (catalytic amount) in THF (105 ml). A solution of bromobenzene in THF (100 ml) was added dropwise, under N2 flow, to a stirs solution of magnesium, turnings and iodine in THF (5 ml). The reaction mixture was stirred and heated. After all bromobenzene was added, the reaction mixture was stirred and refluxed for 1 hour. The mixture was cooled on an ice-bath. A solution of 3-(cyclopentyloxy)-4-methoxybenzaldehyde (22.03 g) in THF (80 ml) was added dropwise at 0° C. The reaction mixture was stirred for 2 hours at RT, then cooled to 0° C. A saturated NH4Cl solution (200 ml) was added dropwise and this mixture was extracted twice with CH2Cl2 (100 ml). The separated organic layer was dried (MgSO4), filtered and the solvent evaporated, yielding 29.3 g (98%) of (±)-3-(cyclopentyloxy)-4-methoxy-α-phenylbenzenemethanol (interm. 6).