Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:16])(Cl)[C:3]1[CH:12]=[C:11]([Cl:13])[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Sb](Cl)(Cl)(Cl)(Cl)Cl.[Sb](F)(F)(F)(F)[F:24].Cl>ClCCl>[F:24][C:2]([Cl:16])([Cl:1])[C:3]1[CH:12]=[C:11]([Cl:13])[C:10]2[C:5](=[C:6]([CH3:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cccc2c(Cl)cc(C(Cl)(Cl)Cl)nc12
Reactant: F[Sb](F)(F)(F)F
Agent: Cl
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc2c(Cl)cc(C(F)(Cl)Cl)nc12
Reaction time: 4 h

Procedure:
3.0 g of 2-trichloromethyl-8-methyl-4-chloro-quinoline are dissolved in 45 ml of dry dichloromethane and under intense stirring 1.5 ml of antimony-penta-chloride and 1.0 ml of antimony-penta-fluoride are added by dropping at a temperature of -5° to 0° C. The mixture is stirred at this temperature for 4 hours and allowed to stand at room temperature for 48 hours. 6 ml of icy concentrated hydrochloric acid are added, the precipitate is filtered, washed with some dichloromethane, the filtrate is separated, dried, filtered and evaporated. 2.1 g solid product are obtained which is recrystallized from heptane: 1.9 g of a yellowish crystalline substance, 68.2%, m.p.: 90°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])C(O)=O)=[CH:5][CH:4]=1.C([N:16]([CH2:19]C)CC)C.ClC(OCC)=[O:23].[NH4+].[OH-]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:13][C:19]([NH2:16])=[O:23])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(C)C(=O)O)cc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCC(N)=O)cc1
Reaction time: 0.25 h
Yield: 95.9 %

Procedure:
(4-methoxyphenyl)propionic acid (20.0 mg, 0.11 mmol) prepared in Reference Synthetic Example 2 was dissolved in tetrahydrofuran (500 μl) in nitrogen atmosphere, and triethylamine (17 μl, 0.12 mmol) and ethyl chloroformate (11 μl, 0.12 mmol) were dropwise added under cooling with ice, followed by stirring for 15 minutes. A 28% ammonia aqueous solution was dropwise added, followed by stirring for 5 minutes, and the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2 to 1:2) to give the desired compound 3-(4-methoxyphenyl)propionic acid amide (18.9 mg, 95%) as colorless needle crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[C:9]=1[OH:15]>N1C=CC=CC=1.CCOC(C)=O>[Br:7][C:8]1[C:9]2[O:15][C:3]([C:2]([CH3:6])([CH3:5])[CH3:1])=[CH:4][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Oc1c(Br)cccc1Br
Reactant: C#CC(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc2cccc(Br)c2o1
Temperature: 55 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
3,3-Dimethylbut-1-yne (1.6 g, 20 mmol) was added to a solution of 2,6-dibromophenol (5.0 g, 20 mmol) and Cu2O (1.7 g, 12 mmol) in dry pyridine (50 mL) under N2, then the mixture was heated to about 55° C. and stirred overnight. The mixture was filtered and the filtrate was concentrated to give a residue, which was dissolved in EtOAc. This solution was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography to afford 7-bromo-2-tert-butyl-benzofuran (1.3 g, 26%). 1H NMR (CDCl3): 1.40 (S, 9H), 6.41 (s, 1H), 7.04 (t, 1H), 7.38 (d, 1H), 7.42 (d, 1H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][CH2:15][OH:16].N1C=CN=C1>CN(C=O)C>[CH3:10][CH2:11][CH2:5][CH:4]([CH3:7])[CH3:6].[C:4]([Si:1]([CH3:3])([CH3:2])[O:16][CH2:15][CH2:14][C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cccs1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cccs1
Product: CCCC(C)C
Reaction time: 18 h

Procedure:
tert-Butyldimethylsilyl chloride (12.66 g) was added portionwise to 2-(2-thienyl)ethanol (9.0 g) and imidazole (5.7 g) in DMF (35 mL). The resulting solution was stirred for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulphate and the solvents evaporated in vacuo. Purification was by silica gel chromatography, eluting with 99:1 to 96:4 ethyl acetate:isohexane to give the subtitled compound as a clear oil. Yield 16 g.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[C:8](OC(=O)C)(=[O:10])[CH3:9]>N1C=CC=CC=1>[C:8]([O:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)C(=O)O
Solvent: c1ccncc1
Product: CCC(OC(C)=O)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
A mixture of 5.00 g (48.0 mmols) of 2-hydroxybutyric acid, 4.98 ml (52.8 mmols) of acetic anhydride and 60 ml of pyridine was stirred at 0° C. for 10 minutes. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent; chloroform) to give 7.01 g (yield, 100%) of 2-acetoxybutyric acid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5](Cl)=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1.[CH2:14]([OH:19])[C:15]([F:18])([F:17])[F:16]>>[Br:3][C:4]1[C:5]([O:19][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To 1,1,1-trifluoroethanol (180 mL) was added sodium hydride (60% in oil, 10 g, 252.7 mmol) in portions at 0-5° C. and the reaction mixture was stirred at 25° C. for 30 min. To this solution was added 3-bromo-2-chloro-5-nitro-pyridine (CAN 5470-17-7) (6 g, 25.3 mmol) in trifluoroethanol (20 mL) drop wise and the reaction mixture was refluxed for 12 h. The solvent was removed in vacuo, and the residue was taken up in water and extracted with ethyl acetate (3×200 mL). Combined organic layers were washed with water (200 mL), brine, dried with Na2SO4 and concentrated. The crude material was purified by column chromatography (Combi-Flash, 40 g, 5% dichloromethane/hexane) to get the title compound (5.7 g, 74.9%) as white solid; NMR complies.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][C:12]1=[O:20].[OH-].[Na+]>>[O:20]=[C:12]1[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13]1
Reactant: COC(=O)CCCCCCCn1c(=O)sc2ccccc21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCn1c(=O)sc2ccccc21

Procedure:
The product is produced as described in example 22 from 20 g. of 8-(2-oxo-benzthiazolin-3-yl)-caprylic acid methyl ester and 2.6 g. of NaOH.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(O)(=O)C.[C:26]([O:30][C:31](=[O:37])[N:32]([CH3:36])[CH2:33][CH:34]=O)([CH3:29])([CH3:28])[CH3:27].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[C:26]([O:30][C:31](=[O:37])[N:32]([CH2:33][CH2:34][NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)[CH3:36])([CH3:29])([CH3:28])[CH3:27]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(CCNc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A mixture of (R)—N2-indan-1-yl-quinoline-2,6-diamine (453 mg, 1.645 mmol) in Methanol (10 mL) with acetic acid (0.3 mL, 4.935 mmol) and commercially available methyl-(2-oxo-ethyl)carbamic acid tert-butyl ester (300 mg, 1.731 mmol) was stirred at 23° C. for 1 h. Portionwise addition of sodium cyanoborohydride (286 mg, 4.11 mmol) was followed by additional stirring at 23° C. for 3 h. Poured onto saturated NaHCO3-solution and extracted twice with ethyl acetate, dried over Na2SO4 and evaporated totally gave a crude product which was purified by flash chromatography with heptane and ethyl acetate to give the title compound as a yellow foam (550 mg, 73%); MS: m/e=433.4 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:26]>COCCOC>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][Br:26])[CH:7]=1)[CH3:2]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CO)c1
Solvent: COCCOC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To [3-(4-chloro-2-hydroxymethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.9 g 2.6 mmol) in DME was added phosphorus tribromide (0.37 mL, 3.9 mmol), and the reaction was stirred for 3 hours at room temperature. The mixture was worked-up to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH3:19][NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1>>[CH3:19][N:20]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:15](=[O:16])[CH2:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:1])([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Product: CN(C(=O)Cc1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C(=O)O)cc1
Yield: 55.3 %

Procedure:
In a manner similar to Example 4(c), by reaction of 2.46 g (10 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid with 1.65 g (10 mmol) of methyl 4-methylaminobenzoate, 2.1 g (54%) of the expected product are obtained in the form of a colorless oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[C:16]1[CH2:27][CH2:28][CH2:29][CH3:30].C(OCC)C>ClCCl>[NH2:26][C:19]1[C:18]2[N:17]=[C:16]([CH2:27][CH2:28][CH2:29][CH3:30])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:9])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCN
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)Nc1ccccc1
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Phenylisocyanate (0.056 mL, 0.5 mmol) was added to a chilled solution of of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 mL). The ice bath was removed. A white precipitate formed after 5 minutes. The reaction mixture was allowed to stir for 30 minutes and then it was concentrated under reduced pressure to provide an off-white crystalline solid. This material was isolated by filtration using a small amount of diethyl ether to transfer the material to the filter and then dried in an Abderhalden drying apparatus to provide 185 mg of N-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N′-phenylurea, m.p. 195.8-196.8° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1[N:10]2[CH2:11][CH2:12][CH2:13][N:14](C=O)[C:9]2=[CH:8][CH:7]=1.O.[C:18](=O)([O-])[O-:19].[Na+].[Na+]>CN(C)C=O>[N:6]1[N:10]2[CH2:11][CH2:12][CH2:13][NH:14][C:9]2=[C:8]([CH:18]=[O:19])[CH:7]=1
Reactant: O=CN1CCCn2nccc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c1NCCC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To N,N-dimethylformamide (307 ml) was added dropwise phosphorus oxychloride (123 ml) under ice-cooling. To the mixture was added a solution of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-4-carbaldehyde (100 g) in N,N-dimethylformamide (200 ml) under ice-cooling. The reaction mixture was stirred at 80° C. for 2 hours. After cooling, water was added to the reaction mixture, and the mixture was neutralized with sodium carbonate. The mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with hexane and dried in vacuo to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (65 g) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[C:24](/[CH:26]=[C:27]3/[C:28](=[O:33])[NH:29][C:30](=[O:32])[S:31]/3)[CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1)[CH2:10][C:11](O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.CCN(C(C)C)C(C)C.[F:48][C:49]([F:60])([F:59])[O:50][C:51]1[CH:52]=[C:53]([CH2:57][NH2:58])[CH:54]=[CH:55][CH:56]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[O:32]=[C:30]1[NH:29][C:28](=[O:33])/[C:27](=[CH:26]/[C:24]2[CH:23]=[CH:22][N:21]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][C:11](=[O:12])[NH:58][CH2:57][C:53]4[CH:54]=[CH:55][CH:56]=[C:51]([O:50][C:49]([F:48])([F:59])[F:60])[CH:52]=4)[CH2:15][CH2:16]3)[N:25]=2)/[S:31]1
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)C1CCN(c2nccc(/C=C3\SC(=O)NC3=O)n2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(CC(=O)NCc1cccc(OC(F)(F)F)c1)C1CCN(c2nccc(/C=C3\SC(=O)NC3=O)n2)CC1
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
A 2-dram round-bottomed vial was charged with (Z)-3-((tert-butoxycarbonyl)amino)-3-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)propanoic acid, prepared using the general displacement procedure, (25 mg, 0.052 mmol), DMF (1 mL), DIPEA (34.9 μL, 0.209 mmol, 4 equiv.), and (3-(trifluoromethoxy)phenyl)methanamine (7.85 μL, 0.052 mmol, 1 equiv.). The reaction mixture was shaken for 20 minutes then HBTU (29.8 mg, 0.079 mmol, 1.5 equiv.) was added and the reaction mixture was shaken at RT for 3 h. The solvent was removed under reduced pressure (Genevac HT-4) and the resulting solid was washed with water (2×1 mL) and dried under high vacuum to provide 20 mg of (Z)-tert-butyl (1-(1-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)piperidin-4-yl)-3-oxo-3-((3-(trifluoromethoxy)benzyl)amino)propyl)carbamate (20 mg, 34.1 mg theoretical, 58.7%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12](O)=[O:13])[CH:7]=[CH:8][CH:9]=1.C(Cl)(=O)C(Cl)=O.[NH3:23]>C1COCC1.CN(C)C=O>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([NH2:23])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: N
Reactant: O=C(O)C=Cc1cccc(OC(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1cccc(OC(F)(F)F)c1
Reaction time: 3 h
Yield: 45 %

Procedure:
To a suspension of 3-(3-trifluoromethoxy-phenyl)-acrylic acid (2.21 g, 9.53 mmol) in THF (15 ml) and N,N-dimethyl formamide (0.2 ml) a solution oxalyl chloride (2.42 g, 19.06 mmol) was added dropwise at 0° C. within 45 min. Stirring was continued at 0–5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 12 ml of a 25% aqueous ammonia solution. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo yielding 0.99 g (45%) 3-(3-trifluoromethoxy-phenyl)-acrylamide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:34]2[CH2:33][CH2:32][N:31]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=3)[CH2:36][CH2:35]2)=[S:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: COc1cc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc(C)c(C)cc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate(0.2 g, 0.7 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(0.16 g, 0.7 mmol) were dissolved in tetrahydrofuran(10 ml) and thereto DBU(0.11 g, 0.7 mmole) was added, followed by stirring at room temperature for 2 hours. The resulting product was concentrated and purified by chromatography to obtain the titled compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@@H:16]3[CH2:19][CH2:18][NH:17]3)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ncc(OC[C@@H]2CCN2)cc1-c1ccccc1
Reaction time: 0.5 h

Procedure:
To 5-phenyl-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 67a (380 mg) was added TFA in CH2Cl2 at 0° C., and the mixture was stirred for 30 minutes. The volatiles were then removed under vacuum. The residue was neutralized with NaHCO3 to pH 8, then extracted with CH2Cl2, which was dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with CH2Cl2:MeOH:NH4OH 10:1:0.1 to afford to give the free base of the title compound. MS (CI/NH3) m/z 275 (M+H)+, 277 (M+2H)+. 1H NMR (CDCl3, 300 MHz) δ 2.21-2.46 (m, 2H), 3.41-3.50 (m, 1H), 3.73 (dd, J=7.5, 8.0 Hz, 1H), 4.0-4.12 (m, 2H), 4.25-4.35 (m, 1H), 7.26 (d, J=3 Hz, 1H), 7.41-7.48 (m, 5H), 8.09 (d, J=3 Hz, 1H). The base was converted to the salt by treatment with hydrogen chloride saturated EtOH to give the title compound (256 mg). mp 148-150° C. MS (CI/NH3) m/z 275 (M+H)+. 1H NMR (D2O, 300 MHz) δ: 2.66-274 (m, 2H), 4.06-4.21 (m, 3H), 4.46 (d, J=4.1, 2H), 4.92-5.01 (m, 1H), 7.50-7.59 (m, 5H), 7.60 (d, J=3.0, 1H), 8.20 (d, J=3.0, 1H). Anal. Calcd for C15H15N2OCl.2 HCl: C, 51.82; H, 4.93; N, 8.06. Found: C, 52.10; H, 5.29; N, 7.70. [α]25D=+7.5° (c 0.16, MeOH).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)[C:12](Cl)=[O:13].[NH2:17][C:18]1[N:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=2)=[CH:20][CH:19]=1.O>ClCCCl.C1COCC1>[C:32]([NH:31][C:27]1[CH:26]=[C:25]([O:24][C:21]2[CH:20]=[CH:19][C:18]([NH:17][C:12]([NH:10][C:8](=[O:9])[CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:13])=[N:23][CH:22]=2)[CH:30]=[CH:29][N:28]=1)(=[O:34])[CH3:33]
Reactant: NC(=O)CC1CCCCC1
Reactant: CC(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCCl
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)CC3CCCCC3)nc2)ccn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
A solution 2-cyclohexylacetamide (0.104 g, 0.737 mmol) in DCE (4 mL) was treated with oxalyl chloride (0.129 mL, 1.474 mmol) and heated at 70° C. overnight. The mixture was concentrated to dryness, added to a solution of Example A2 (0.09 g, 0.368 mmol) and TEA (0.154 mL, 1.105 mmol) in THF (3 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The resulting residue was suspended in 60% EtOAc/Hex, sonicated and the solid collected via filtration and dried to afford N-((5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)-2-cyclohexylacetamide (77 mg, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 10.83 (s, 1H), 10.56 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.18 (d, J=5.7 Hz, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.68 (dd, J=5.7, 2.4 Hz, 1H), 2.27 (d, J=7.0 Hz, 2H), 2.02 (s, 3H), 1.73-1.56 (br m, 5H), 1.18-1.13 (m, 4H), 0.97-0.94 (m, 2H); MS (ESI) m/z: 412.2 (M+H+).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:15](=[O:21])OC(Cl)(Cl)Cl)Cl.Cl.Cl.N1C=CC([CH:31]2[CH2:37][CH:36]3[NH:38][CH:33]([CH2:34][CH2:35]3)[CH2:32]2)=CC=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.ClCCl>[N:1]1[CH:10]=[CH:5][CH:4]=[C:3]([CH:37]2[CH:36]3[N:38]([C:15]([N:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:4][CH2:3][CH2:2]4)=[O:21])[CH:33]([CH2:34][CH2:35]3)[CH2:32][CH2:31]2)[CH:2]=1
Reactant: c1cc(C2CC3CCC(C2)N3)ccn1
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCCc2ccccc21)N1C2CCC(c3cccnc3)C1CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
0.241 g of 1,2,3,4-tetrahydroquinoline, 20 ml of dichloromethane and 0.24 ml of triethylamine are placed in a 50 ml round-bottomed flask under a nitrogen atmosphere. 0.178 g of triphosgene is added at 0° C. and then the reaction mixture is left to stir at ambient temperature for 3 h. 0.34 g of 3-pyridin-4-yl-8-azabicyclo[3.2.1]octane dihydrochloride and 1.19 ml of triethylamine are subsequently added and the reaction mixture is then refluxed for three hours. 200 ml of a saturated aqueous solution of sodium hydrogen carbonate are added and the aqueous phase is then extracted three times with dichloromethane. The organic phases are combined, dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel with a 9/1 mixture of dichloromethane/methanol. 0.04 g of 1-[(4-pyridin-3-yl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1,2,3,4-tetrahydroquinoline is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH2:11](OC1C=C(COC2C=C([C@@H](C)CC(O)=O)C=CC=2)C=CC=1C1C=C(OC)C=CC=1F)[CH2:12][CH2:13]C>>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[C:12]([CH3:13])[CH3:11])[C:4](=[O:9])[O:3]1
Reactant: CCCCOc1cc(COc2cccc([C@@H](C)CC(=O)O)c2)ccc1-c1cc(OC)ccc1F
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CC(C)=C1C(=O)OC(C)(C)OC1=O

Procedure:
The 2,2-dimethyl-5-(propan-2-ylidene)-1,3-dioxane-4,6-dione (85.B) was prepared from 2,2-dimethyl-1,3-dioxane-4,6-dione 85.A (commercially available from Aldrich) via the same procedure described in Vogt, P. F.; et. al.; Synthetic Communications; 2001, (5); pp. 679-684.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1.[NH:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>>[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([C:33]([N:8]2[CH2:13][CH2:12][C@H:11]([N:22]3[CH2:27][CH2:26][S:25][CH2:24][CH2:23]3)[C@H:10]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[CH2:9]2)=[O:34])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: C1CSCCN1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(C2CN(Cc3ccccc3)CCC2=O)cc1
Product: Cc1ccc([C@@H]2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]2N2CCSCC2)cc1

Procedure:
The title compound, MS: m/e=517.3 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-(4-methyl-phenyl)-piperidin-4-one, thiomorpholine and 3,5-bistrifluoromethyl-benzoyl chloride.