Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][Cl:7])[CH3:3].[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-:26].[K+].[K+]>C(O)(C)C>[C:10]([NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:3][CH2:2][N:4]([CH2:8][CH3:9])[CH2:5][CH3:6])[CH2:21][CH2:20]1)(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1.[OH2:26].[ClH:7].[ClH:1].[ClH:7].[ClH:7]
Reactant: O=C([O-])[O-]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Product: CCN(CC)CCN1CCC(NC(=O)c2ccccc2)CC1
Product: O

Procedure:
Equimolar amounts of 2-diethylaminoethyl chloride, hydrochloride and 4-benzamidopiperidine were stirred under reflux in isopropanol with 2.5 molar equivalents of anhydrous potassium carbonate for 18 hours. The hot suspension was filtered and the filtrate was treated with ethereal HCl to give the title compound as a dihydrochloride, hemihydrate, m.p. >220° (with decomp.)
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.[F:13][C:14]([F:41])([F:40])[S:15]([O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[C:22]([CH:29](O)[CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:23]=[CH:24][CH:25]=2)[N:20]=1)(=[O:17])=[O:16].O>C(OCC)C>[F:41][C:14]([F:40])([F:13])[S:15]([O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[C:22]([CH:29]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH:23]=[CH:24][CH:25]=2)[N:20]=1)(=[O:17])=[O:16]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCC(O)c1cccc2ccc(OS(=O)(=O)C(F)(F)F)nc12
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: O
Product: CCN(CC)C(CO[Si](C)(C)C(C)(C)C)c1cccc2ccc(OS(=O)(=O)C(F)(F)F)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
13.21 ml of triethylamine and 7 ml of methanesulfonyl chloride are successively added to a solution, cooled to 0° C. with an ice bath, of 13.8 g (30.53 mmol) of 2-trifluoromethanesulfonyloxy-8-(1′-hydroxy-2′-tert-butyldimethylsilyloxyethyl)quinoline in 300 ml of ethyl ether. The mixture is stirred for 30 min at 0° C. and then for 10 min at ambient temperature and is hydrolyzed by the addition of 300 ml of water. Extraction is carried out with ethyl acetate (3×250 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is dissolved in 200 ml of chloroform and 45 ml of diethylamine and the mixture is brought to reflux for 16 h. 200 ml of water are added and extraction is carried out with ethyl acetate (3×150 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica chromatographic column (eluent: cyclohexane/ethyl acetate 8/2) to provide 14 g of 2-trifluoromethane sulfonyloxy-8-(1-diethylamino-2-tert-butyldimethylsilyloxyethyl)quinoline in the form of a yellow oil. (Yield: 90%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.[C:16](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:16])[C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCc2[nH]c3ccc(F)cc3c21
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1c2c(c3cc(F)ccc31)C(=O)CCC2
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
The product of Stage (ii) (7.28 g), potassium carbonate (9.90 g), acetone (70 ml), and dimethylsulphate (5.1 ml) were vigorously stirred at room temperature overnight under nitrogen. The mixture was concentrated to one half of its volume and then stirred with water (350 ml) for 30 min. The mixture was filtered off, washed with water (50 ml), air-dried for 1 h, and dried in vacuo over phosphorus pentoxide to give the title compound as needles (7.59 g), m.p. 157.5°-158.5°.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[NH2:21][C:22]([NH2:24])=[S:23]>>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]2[N:21]=[C:22]([SH:23])[NH:24][C:11]=2[C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=[CH:2][CH:3]=1
Reactant: NC(N)=S
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nc(S)[nH]c2-c2ccc(OC)cc2)cc1

Procedure:
27.23 g (0.1 mol) of p-anisoin and 10.8 g (0.15 mol) of thiourea were reacted as in example 10. The yield was 20 g.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)=[CH:6][CH:5]=1.[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[CH3:18][C:14]1[N:13]=[C:12]([CH2:11][O:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([N:28]3[CH2:29][CH2:30][CH2:31][C@H:27]3[CH2:26][N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[CH3:20])=[O:19])=[CH:9][CH:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: COC(=O)c1ccc(OCc2cccc(C)n2)cc1
Product: Cc1cccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCC[C@H]3C)cc2)n1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 4-(6-Methyl-pyridin-2-ylmethoxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 412.3
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.F[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[CH3:1][S:2][C:3]1[C:4]2[C:5](=[CH:9][N:10]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[N:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: CSc1ncnc2cn[nH]c12
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc(-n2cc3ncnc(SC)c3n2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 49.8 %

Procedure:
To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (100 mg) and methyl 4-fluorobenzoate (102 mg) in 1-methyl-2-pyrrolidone (2 mL) was added potassium carbonate (125 mg), and the mixture was stirred at 120° C. for 3 hrs. After the completion of the reaction, water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant solid was collected by filtration, washed with diisopropyl ether and dried to give the title compound (90 mg) as yellow crystals.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[CH2:21])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]=[CH2:21])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C=CCOc1ccc(C[C@H](NC(C)=O)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOc1ccc(C[C@H](NC(C)=O)C(=O)O)cc1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 15 (2.90 g, 9.98 mmol) in THF/water, (3:1, 80 mL) was added lithium hydroxide monohydrate (838 mg, 20.0 mmol) and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed by evaporation. The aqueous layer was extracted with DCM (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined organic fractions were dried and evaporated to yield the title compound (2.62 g, 9.98 mmol, 100%) as white needles, which had spectral data in agreement with that reported.122 Mp 170-172° C. (lit 200° C.)122 1H NMR (D6 acetone, 300 MHz): δ 7.09 (s, 1H, NH); 7.04 (d, J=8.4 Hz, 2H, ArH2′ and ArH6′); 6.73 (d, J=8.4 Hz, 2H, ArH3′ and ArH5′); 5.94 (m, 1H, H2″); 5.27 (dd J=1.3 Hz, 17.3 Hz, 1H, H3a″); 5.10 (dd J=1.3, 10.5 Hz, 1H, H3b″); 4.52 (m, 1H, H2); 4.41 (d J=5.5 Hz, 2H, H1″); 2.98 (dd, J=5.7, 14.1 Hz, 2H, H3a); 2.79 (dd, J=8.1, 14.1 Hz, 2H, H3b); 1.75 (s, 3H, NCOCH3). Mass Spectrum (CI, +ve) m/z 264 (100%) [MH+]. HRMS calcd for C14H18NO4 264.1236, found 264.1246.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.[C:13]([OH:19])(=[O:18])[CH2:14]C(O)=O.C([O-])(=O)C.[NH4+:24].[ClH:25]>C(O)C>[ClH:25].[NH2:24][CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)[CH2:14][C:13]([OH:19])=[O:18]
Reactant: [NH4+]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCO
Product: NC(CC(=O)O)c1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
The method described in J. Am. Chem. Soc., 1936, 58, 299 is used. 15.5 g of 2-formylnaphthalene, 10.4 g of malonic acid and 15.4 g of ammonium acetate in 150 ml of ethanol are mixed together and refluxed for 6 hours. After cooling to RT, the product is drained, washed with EtOH and dried. The product obtained is dissolved in a sufficient amount of 2N HCl and the insoluble material is then filtered off. The acidic solution is concentrated by evaporating under vacuum and the solid thus formed is recrystallized from 20 ml of an AcOH/H2O mixture (1/1; v/v). 3.8 g of the expected product are obtained.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[C:22]([OH:23])=[CH:21][C:20]([N:24]2[C:29](=[O:30])[C:28]([F:31])=[C:27]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[N:26]=[C:25]2[O:39][CH3:40])=[C:19]([F:41])[CH:18]=1.[C:42](O)(=[O:47])[CH2:43][CH2:44][C:45]#[CH:46].N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[C:42]([O:23][C:22]1[CH:21]=[C:20]([N:24]2[C:29](=[O:30])[C:28]([F:31])=[C:27]([C:32]([F:37])([F:38])[C:33]([F:34])([F:36])[F:35])[N:26]=[C:25]2[O:39][CH3:40])[C:19]([F:41])=[CH:18][C:17]=1[Cl:16])(=[O:47])[CH2:43][CH2:44][C:45]#[CH:46]
Reactant: C#CCCC(=O)O
Reactant: COc1nc(C(F)(F)C(F)(F)F)c(F)c(=O)n1-c1cc(O)c(Cl)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: C#CCCC(=O)Oc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.74 g of N,N'-dicyclohexylcarbodiimide is added while stirring at room temperature to a solution of 1.60 g of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-5-fluoro-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone, 0.30 g of 4-pentynoic acid and 0.05 g of 4-pyrrolidino-pyridine in 50 ml of methylene chloride and the mixture is stirred at room temperature for 5 hours. Insoluble constituents are subsequently filtered off under suction and the filtrate is evaporated to dryness. The residue is purified by chromatography on a silica gel column using n-hexane/diethyl ether (3:1) as the eluent. The product is recrystallized from n-hexane/diethyl ether. There is obtained 2-chloro-4-fluoro-5-[5-fluoro-2 -methoxy-6-oxo-4-pentafluoroethyl-1(6H)-pyrimidinyl]-phenyl 4-pentynoate, m.p. 107°-109° C.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]([F:31])([F:30])[C:8]([F:29])([F:28])[C:9]([F:27])([F:26])[C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:38]([O:42][C:43](=[O:46])[CH2:44]Br)([CH3:41])([CH3:40])[CH3:39]>CC(C)=O>[C:38]([O:42][C:43](=[O:46])[CH2:44][N:3]([CH2:1][CH3:2])[S:4]([C:7]([F:30])([F:31])[C:8]([F:28])([F:29])[C:9]([F:26])([F:27])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:6])=[O:5])([CH3:41])([CH3:40])[CH3:39]
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC(=O)OC(C)(C)C)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
20 g (37.94 mmol) of N-ethylperfluorooctylsulfonamide and 15.73 g (113.8 mmol) of potassium carbonate are suspended in 200 ml of acetone, and 14.80 g (75.87 mmol) of bromoacetic acid-tert-butyl ester is added in drops at 60° C. It is stirred for 3 hours at 60° C. The salts are filtered out, and the filtrate is evaporated to dryness in a vacuum. The residue is chromatographed on silica gel (mobile solvent: hexane/dichloromethane/acetone=10/10/1). After the product-containing fractions are concentrated by evaporation, the residue is recrystallized from methanol/ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]=[C:10]=[S:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][NH2:13]>C1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[C:3]([NH:9][C:10]([NH:13][CH3:12])=[S:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCO
Product: CNC(=S)Nc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3,5 dichloro-2-pyridylisothiocyanate (5.13 g.) in benzene (20 ml.) was added to a solution of methylamine in ethanol (5 ml., 33%) and the mixture was stirred for 18 hours at ambient temperature. Petroleum ether (60°-80° C., 30 ml.) was added and the resulting precipitate was filtered off and recrystallised from benzene-light petroleum to give colourless microcrystals of 1-(3,5-dichloro-2-pyridyl)-3-methyl-2-thiourea (4.18 g.) m.pt. 105°-109° C.
Reaction SMILES: C1COC2(N)N(C(NC3C=CC4OC(CO)=CC=4C=3)=NC=C2F)O1.[Cl:25][C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][CH2:39][C:40]3=[O:43])=[CH:35][CH:34]=2)[C:29]([F:44])=[CH:28][N:27]=1.CC(C[Al]CC(C)C)C>>[Cl:25][C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][CH2:38][CH2:39][CH:40]3[OH:43])=[CH:35][CH:34]=2)[C:29]([F:44])=[CH:28][N:27]=1
Reactant: O=C1CCCc2ccc(Nc3nc(Cl)ncc3F)cc21
Agent: CC(C)C[Al]CC(C)C
Agent: NC12OCCON1C(Nc1ccc3oc(CO)cc3c1)=NC=C2F
Product: OC1CCCc2ccc(Nc3nc(Cl)ncc3F)cc21

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxy)-5-fluoro-N2-[2-(hydroxymethyl)benzofuran-5-yl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-oxonaphthalen-7-yl)-4-pyrimidineamine was reduced with Dibal-H to yield 2-chloro-5-fluoro-N4-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.05 (d, 1H, J=3.0 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.14 (d, 1H, J=8.1 Hz), 6.93 (bs, 1H), 4.82-4.78 (m, 1H), 2.82-2.71 (m, 2H), 2.08-1.74 (m, 5H); 19F NMR (282 MHz, CDCl3): −44661; LCMS: purity: 94%; MS (m/e): 294 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][NH2:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C.[CH3:48][O:49][C:50]1[C:55]2[O:56][C:57]([CH3:60])([CH3:59])[O:58][C:54]=2[CH:53]=[C:52]([C:61](Cl)=[O:62])[CH:51]=1>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][N:26]([C:61]([C:52]1[CH:51]=[C:50]([O:49][CH3:48])[C:55]2[O:56][C:57]([CH3:60])([CH3:59])[O:58][C:54]=2[CH:53]=1)=[O:62])[CH2:11][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: O=Cc1cnc2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2cnc3ccccc3n2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc2c1OC(C)(C)O2

Procedure:
Experimental conditions analogous Example 1, 0.12 g (0.81 mmol) of quinoxaline-2-carbaldehyde, 0.24 g (1.22 mmol) of (S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, 5 mL dichloromethane, and 0.25 g (1.22 mmol) of sodium triacetoxyborohydride. The reaction was quenched with aqueous sodium bicarbonate. The residue from the organic layer was purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 40 min. Fractions containing pure product were evaporated in vacuum and dissolved in 3 mL dichloromethane. To this solution were added 0.34 mL (2.43 mmol) of triethylamine and 196 mg (0.81 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride. After 4 hours the reaction mixture was purified using flash chromatography (ethyl acetate in hexane), gave 280 mg as a yellow solid. LC-MSD, m/z for C30H36N4O6 [M+H]+: 549.7.
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.N1C=CC=CC=1C(Cl)=O.[CH2:34]([N:36]([C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:46]=1[CH:53]1[CH2:62][CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[C:58]([O:63][CH3:64])[CH:59]=2)[CH2:54]1)[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)=O)[CH3:35]>>[CH2:34]([N:36]([C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:46]=1[CH:53]1[CH2:62][CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[C:58]([O:63][CH3:64])[CH:59]=2)[CH2:54]1)[CH2:37][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH3:35]
Reactant: CCN(C(=O)c1ccccn1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(Cl)c1ccccn1
Product: CCN(Cc1ccccn1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 80.2 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and picolinoyl chloride hydrochloride according to an analogous synthetic method to Preparation Example 87, pyridine-2-carboxylic acid ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amide (129 mg) was used according to an analogous synthetic method to Example 337 described below to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]pyridin-2-ylmethylamine (100 mg). This compound (93 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (108 mg).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.Cl[CH2:25][C:26](=[O:28])[CH3:27]>>[O:28]=[C:26]([CH3:27])[CH2:25][S:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S)cc1
Reactant: CC(=O)CCl
Product: CC(=O)CSc1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1

Procedure:
Reaction of 2-(4-mercaptophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (see EXAMPLE 146, 363 mg, 1.04 mmol) with chloroacetone (90 μL, 1.10 mmol), employing a procedure similar to that described in EXAMPLE 146, furnished 2-[4-(2-oxopropylsulfanyl)phenyl]-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=405.3 [M+H]+. TBA-OX (2.46 g, 2.44 mmol) was added to a stirred solution of the abovementioned thioether (399 mg, 0.99 mmol) in CH2Cl2 (20 mL). After 19 h, the reaction mixture was treated with more TBA-OX (0.97 g, 0.96 mmol). An additional quantity of TBA-OX (1.09 g, 1.07 mmol) was added 20 h later, then the mixture was stirred further for 3d. Solvent evaporation and flash chromatography (IH-EtOAc, 3:2 to 0:1) afforded the title compound: RTA=3.12 min; m/z (ES+)=437.2 [M+H]+.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C1COCC1>CCOCC.[Zn]>[F:16][C:10]([F:17])([CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A stirred suspension of zinc (0.981 g, 15.00 mmol) in a solution of benzaldehyde (0.531 g, 5 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.522 g, 7.50 mmol) in an. THF (10 mL) was sonicated for 4-5 h and then stirred at rt overnight. The reaction was cooled and diluted with ether and washed with 1 N HCl, water, brine and dried (MgSO4). Evaporation of solvents afforded a clear oil which was purified by silica gel FCC (0-10% EtOAc in DCM) to afford ethyl 2,2-difluoro-3-hydroxy-3-phenylpropanoate as a clear oil (619 mg, ˜54%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.49-7.44 (m, 2H), 7.43-7.39 (m, 3H), 5.23-5.12 (m, J=15.3, 8.0, 5.5 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.87-2.76 (m, 1H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(O[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)C.[Cl:15]C=CCCCC.C=CCCCC>>[Cl:15][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC=CCl
Reactant: CCCCC=CCCCCOC(C)=O
Solvent: C=CCCCC
Product: CCCCC=CCCCCCl

Procedure:
FIG. 1B is a reaction diagram showing the second step of the synthesis of 5-decenyl acetate, in which 1-chloro-hexene is reacted with 1-hexene in the presence of Catalyst 823 to yield 1-chloro-5-decene.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1>C(O)C.O>[N:18]1([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[N:4]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: c1c[nH]cn1
Reactant: ClCc1nc2ccccc2n1-c1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc(-n2c(Cn3ccnc3)nc3ccccc32)cc1
Yield: 69 %

Procedure:
A solution of 2-chloromethyl-1-phenyl-1H-benzimidazole (3.4 g) and imidazole (4.8 g) in ethanol (25 ml) was stirred at 60° C for 7 hours. The reaction mixture was concentrated under reduced pressure to give an oil, which was diluted with water and extracted three times with dichloromethane. The combined extract was washed twice with water and once with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (100 g) with a mixture of methanol and dichloromethane (3:97) as an eluent to afford an oil, which was crystallized from a mixture of ethyl acetate and hexane to give 2-(imidazol-1-yl)methyl-1-phenyl-1H-benzimidazole (2.65 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[N:28]=[C:29]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:24]=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:34][CH2:33][CH:32]([C:29]3[S:30][CH:31]=[C:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=4)[N:28]=3)[CH2:37][CH2:36]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: Fc1cccc(-c2csc(C3CCNCC3)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(NC(=O)N2CCC(c3nc(-c4cccc(F)c4)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (274 mg, 0.839 mmol), 4-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperidine (200 mg, 0.762 mmol) and diisopropylethylamine (0.266 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (193 mg, 57.5%) as a solid.