Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[C:3]([C:6]1C2C([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=1[OH:20])=CC=CC=2)(=[O:5])C.CC(C)([O-])C.[Na+].Br>C1C=CC=CC=1.C(O)(=O)C>[O:5]1[C:17]2[C:18](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:19](=[O:20])[CH2:6][CH2:3]1
Reactant: CC(=O)c1c(O)c2ccccc2c2ccccc12
Agent: Br
Agent: CC(C)(C)[O-]
Agent: O=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: O=C1CCOc2ccccc21

Procedure:
Oxygen derivatives analogous to those of Examples IX and X may be prepared as follows: 9-acetyl-10-hydroxyphenanthrene and the appropriate aldehyde or ketone according to Example IX in benzene are added to a solution of sodium t-butoxide in benzene and the resulting mixture refluxed for 20 hours with stirring. The reaction mixture is poured into a stirred solution of hydrobromic acid (3 parts) and acetic acid (2 parts). The benzene layer is steam distilled and the residue boiled with methanol saturated with dry hydrogen chloride 0.5-1 hour to drive the cyclization to completion. After the solvent has been removed, the chroman-4-one is isolated by chromatography and crystallization from petroleum ether solvent.
Reaction SMILES: O=[C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][C:5]#[N:6].[F:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16](=[S:19])[NH:17][NH2:18]>C(O)C>[F:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:15]=1[C:16]1[S:19][C:2]([CH2:3][CH2:4][C:5]#[N:6])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:18][N:17]=1
Reactant: NNC(=S)c1cc(F)ccc1F
Reactant: N#CCCC(=O)c1ccccc1
Solvent: CCO
Product: N#CCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 90 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 4-oxo-4-phenylbutanenitrile (0.076 g, 0.48 mmol) in ethanol (5 mL) was added 2,5-difluorobenzothiohydrazide (0.09 g, 0.48 mmol). After stirring at 90° C. for 16 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (20% ethyl acetate in hexanes) to provide the product (0.087 g, 55% yield).
Reaction SMILES: [Na].[CH3:2][C:3]([SH:6])([CH3:5])[CH3:4].[H-].[Na+]>C1COCC1.O>[C:3]([S:6][C:3]([CH3:5])([CH3:4])[CH3:2])([CH3:5])([CH3:4])[CH3:2]
Reactant: CC(C)(C)S
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)SC(C)(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a 50 mL round bottom flask containing 0.9 grams (8.82 mmole) of the sodium salt of 2-methyl-2-propanethiol was added 0.25 grams of sodium hydride (11.3 mmole) and the resulting mixture placed under vacuum and then under a nitrogen atmosphere. To the mixture was then added 15 mL of anhydrous tetrahydrofuran and the mixture cooled to 0° C. To the cooled mixture was added 1.5 grams (5.84 mmole) of 9 dissolved in 15 mL of anhydrous THF over a period of 10 minutes. After addition, the reaction mixture was allowed to stir, at room temperature and under a nitrogen atmosphere for 18 hours. After 18 hours the volatile components of the reaction mixture were removed under reduced pressure to give a brown solid. The brown solid was dissolved in 80 mL of H2O and aqueous washed with 100 mL of diethyl ether. The aqueous layer was then acidified with 1 mL of concentrated HCl (pH=1) and then extracted (2×100 mL) with diethyl ether and organic layers combined, dried over MgSO4, filtered and volatile components removed under reduced pressure to give 1.75 grams of the t-butyl thioether product which was used without any further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1)([CH3:3])[CH3:2]>CO.[Ni]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc([N+](=O)[O-])cn1
Agent: [Ni]
Solvent: CO
Product: CC(C)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
2-Isopropyl-5-nitro-pyridine (1.30 g, 7.82 mmol) was dissolved in methyl alcohol (20 mL), and Raney Ni (0.25 g) was added. The mixture was stirred under H2 (1 atm) at room temperature for 2 h. The catalyst was filtered off, and the filtrate was concentrated under vacuum to give 2-isopropyl-5-amino-pyridine (E-9) (0.55 g, 52%). 1H NMR (CDCl3) δ 8.05 (s, 1H), 6.93-6.99 (m, 2H), 3.47 (br s, 2H), 2.92-3.02 (m, 1H), 1.24-1.26 (m, 6H). ESI-MS 137.2 m/z (MH+).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[O:19]C(C)(C)[N:17](C(OC(C)(C)C)=O)[C@@H:16]3[CH2:29][F:30])=[CH:11][CH:10]=2)[O:6][N:5]=1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:17][C@H:16]([CH2:29][F:30])[C@@H:15]([C:12]1[CH:11]=[CH:10][C:9]([C:7]2[O:6][N:5]=[C:4]([CH2:3][C:1]#[N:2])[CH:8]=2)=[CH:14][CH:13]=1)[OH:19]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CC#N)no3)cc2)OC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: N#CCc1cc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of step 1 of Example 12 (50 mg, 0.12 mmol) in CH2Cl2 (2 mL) at 5° C. is treated with trifluoroacetic acid (0.5 mL), stirred 30 minutes at room temperature, diluted with toluene, and concentrated to give the title compound, which is carried on to the next step without purification m/z (Cl) 276 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[N:33]=[C:32]([CH3:34])[C:31]([OH:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:35][C:31]4[C:32]([CH3:34])=[N:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(S(C)(=O)=O)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(S(C)(=O)=O)ccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 160 °C
Yield: 40.9 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 6-methanesulfonyl-2-methyl-pyridin-3-ol (Intermediate 6; 36 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.2 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted three times with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted with dichloromethane and the solvent was evaporated to give 4-[4-(6-methanesulfonyl-2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (30 mg, 42%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.50 (s, 9H), 1.96-2.06 (m, 2H), 2.20-2.34 (m, 2H), 2.92-3.05 (m, 2H), 4.26-4.39 (m, 2H), 4.92-5.04 (m, 1H), 7.76 (d, 1H, J=8.4 Hz), 8.06 (d, 1H, J=8.4 Hz), 8.21 (s, 1H), 8.46 (s, 1H). Mass spectrum (ES) MH+=489. HRMS Calcd. for C22H29N6O5S (MH+): 489.1915. Found: 489.1915.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:15])[CH:3]=1.[CH3:16][C:17]1(C)[C:21](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:4]1[CH:3]=[C:2]([C:17]([CH3:21])=[CH2:16])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a solution of tert-butyl 4-bromo-2-chlorobenzoate (1.0 g, 3.43 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (588 mg, 3.50 mmol) in 1,4-dioxane (40 mL) and water (10 mL) were added sodium carbonate (742 mg, 7.0 mmol) and tetrakis(triphenylphosphine)palladium (40 mg, 0.035 mmol). The resultant reaction mixture was stirred at 90° C. overnight under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was concentrated. The residue was purified by pre-HPLC to get tert-butyl 2-chloro-4-(prop-1-en-2-yl)benzoate (800 mg, 92.3%) as a yellow oil. LRMS (M+H+) m/z: calcd 253.09. found 253.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][NH:35][CH2:36][CH:37]3[CH2:39][CH2:38]3)[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>>[Cl:6][C:7]1[CH:8]=[C:9]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[O:32][CH2:33][CH2:34][N:35]([CH2:36][CH:37]3[CH2:39][CH2:38]3)[C:1](=[O:5])[CH2:2][OH:3])[N:25]=[CH:24][N:23]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Clc1cc(Nc2ncnc3cccc(OCCNCC4CC4)c23)ccc1OCc1ccccn1
Reactant: O=C(O)CO
Product: O=C(CO)N(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)CC1CC1
Yield: 23 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{2-[(cyclopropylmethyl)amino]ethoxy}quinazolin-4-amine (obtained as described in Example 15, preparation of starting materials) to give the title compound in 23% yield; NMR spectrum (DMSO-d6)-0.04-0.04 (m, 2H), 0.13-0.29 (m, 2H), 0.74-0.83 (m, 1H), 2.98 (d, 1H), 3.66-3.80 (m, 2H), 3.85-3.93 (m, 2H), 4.12-4.32 (m, 4H), 5.08 (s, 2H), 6.95 (d, 1H), 7.02 (d, 1H), 7.09-7.17 (m, 2H), 7.30-7.40 (m, 2H), 7.47-7.54 (m, 1H), 7.63-7.68 (m, 1H), 7.73-7.82 (m, 1H), 8.21-8.29 (m, 1H), 8.37 (d, 1H), 9.62 (s, 1H); Mass spectrum MH+ 534.
Reaction SMILES: [CH3:1][C:2]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[N:3]O.[ClH:15]>[Pt].C(O)C>[CH3:1][CH:2]([NH2:3])[C:5]12[CH2:6][CH:7]3[CH2:13][CH:11]([CH2:10][CH:9]([CH2:8]3)[CH2:14]1)[CH2:12]2.[ClH:15]
Reactant: CC(=NO)C12CC3CC(CC(C3)C1)C2
Agent: [Pt]
Agent: Cl
Solvent: CCO
Product: CC(N)C12CC3CC(CC(C3)C1)C2
Reaction time: 8 h
Yield: 75 %

Procedure:
Into a Parr hydrogenation flask were placed 0.35 g of 5% Pt/C, 1.9 g of 1-adamantyl methyl ketoxime, 230 ml of ethanol and 2.0 ml of conc. hydrochloric acid. The flask was purged with hydrogen and then the hydrogenation reaction was initiated. Pressure was set at 34 psia (234 KPa) at ambient temperature and the reaction conducted overnight. The catalyst was removed by filtration and washed with 50 ml ethanol. The combined ethanol solution was distilled to dryness under vacuum. The remaining white solid was dissolved in 70 ml of water, and extracted twice with 50 ml ether. The ether layer was discarded. The aqueous layer was basified to pH 10-13 with sodium hydroxide and extracted twice with 100 ml of ether. The ether layer was dried over potassium hydroxide and magnesium sulfate which was removed by filtration. The dried ether layer was treated with hydrogen chloride gas and rimantadine hydrochloride precipitated. The solid was collected by filtration and dried to give 1.6 g of rimantadine hydrochloride (75% yield).
Reaction SMILES: Br[C:2]1[N:3]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:5][C:6]=1[CH:7]=[O:8].[Cu][C:26]#[N:27]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:4]1[N:3]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[C:2]([C:26]#[N:27])=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: N#C[Cu]
Reactant: O=Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccnc2)c1Br
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1c(C=O)cc(-c2ccccc2F)n1S(=O)(=O)c1cccnc1
Yield: 57.2 %

Procedure:
2-Bromo-5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (340 mg), copper (I) cyanide (400 mg), tris(dibenzylideneacetone)dipalladium (0) (40 mg), 1,1′-bis(diphenylphosphino)ferrocene (70 mg) were mixed in 1,4-dioxane (30 mL), and the mixture was heated under reflux for 24 hr. The reaction mixture was allowed to cool, diluted with ethyl acetate, and filtered. The obtained filtrate was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 169 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([C:17](OCC)=[O:18])=[C:12]2[O:22][CH2:23][CH3:24])=[O:5].[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][OH:18])=[C:12]2[O:22][CH2:23][CH3:24])=[O:5]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1OCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1c(CO)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 50 °C
Reaction time: 4 h
Yield: 34.6 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-4-ethoxy-3-ethoxycarbonylquinoline (179 mg) in tetrahydrofuran was added lithium borohydride (22.5 mg), and the mixture was stirred for 4 hours at 50° C. To the mixture was dropwise added saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 8-(2,6-dichlorobenzoylamino)-4-ethoxy-3-hydroxymethylquinoline (55.9 mg).
Reaction SMILES: C([Li])CCC.[CH:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]>>[F:13][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[CH:18][C:19]=1[CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC=O
Reactant: Fc1ccccc1F
Agent: [Li]CCCC
Product: CCCCCC(O)c1cccc(F)c1F

Procedure:
Quantities: n-butyllithium (31 cm3, 10.0M in hexanes, 0.31 mol), hexanal (31.5 g, 0.31 mol) and 1,2-difluorobenzene (35.5 g, 0.31 mol). The experimental procedure was as described in Example 16.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.CCN(CC)CC.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([N:7]1[CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]1[CH3:8])(=[O:26])[CH3:25]
Reactant: CC1CN(c2ccc(C=O)cc2)CC(C)N1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A solution of 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 4.6 mmol.) in CH2Cl2 (15 mL) was cooled to 0° C. and treated with Et3N (0.64 mL, 4.6 mmol) followed by acetyl chloride (0.33 mL, 4.6 mmol). The reaction stirred for 30 minutes, then concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 0% to 50% EtOAc/CH2Cl2, afforded 4-(4-acetyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 83%).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CC1(C)[N:18](C(OC(C)(C)C)=O)[C@@:17]([CH3:50])([C:26]2[S:27][C:28]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[C:33]([C:46]([F:49])([F:48])[F:47])[CH:32]=3)=[N:29][N:30]=2)[CH2:16][O:15]1>CO>[NH2:18][C@@:17]([C:26]1[S:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[C:33]([C:46]([F:47])([F:49])[F:48])[CH:32]=2)=[N:29][N:30]=1)([CH3:50])[CH2:16][OH:15]
Reactant: CCCCCCCCOc1ccc(-c2nnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCCCCCCCOc1ccc(-c2nnc([C@@](C)(N)CO)s2)cc1C(F)(F)F
Temperature: 20.5 °C
Reaction time: 1.5 h

Procedure:
A 5 L round bottom flask was inerted and charged with p-toluene sulfonic acid monohydrate (208 g, 1.09 mol, 5 equiv) and a solution of (R)-tert-Butyl 2,2,4-trimethyl-4-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)oxazolidine-3-carboxylate (125 g, 0.22 mol) in methanol (2.5 L), and heated to reflux. After 1.5 h HPLC indicated reaction complete. The heat was turned off and the mixture was allowed to cool to room temperature (18 to 23° C.) and stirred for 12 hours. The mixture was concentrated under vacuum to a residue to provide the title product.
Reaction SMILES: [O:1]([C:8]1[CH:27]=[CH:26][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:38][CH2:37][C:36]1=[O:40]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[CH:21][C:22]([NH:23][C:36](=[O:40])[CH2:37][CH3:38])=[CH:24][CH:25]=2)=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Reactant: CN1CCCC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 77 %

Procedure:
N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide was prepared from 4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and pyridine instead of N,N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (77% yield). HPLC: 98%, RT=4.157 min. MS: m/z=411 [M+H]+, RT=3.39 min.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[N:19]([CH3:20])[C:10]2=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]2[N:8]=1.[Na].[CH2:22]([SH:24])[CH3:23].CN1CCCC1=O.[NH4+]>[Cu](I)I.O>[CH2:22]([S:24][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[N:19]([CH3:20])[C:10]2=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]2[N:8]=1)[CH3:23]
Reactant: Cn1c(-c2ccsc2Br)nc2cc(C(F)(F)F)cnc21
Reactant: CCS
Agent: I[Cu]I
Agent: [NH4+]
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCSc1sccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
A mixture of 0.72 g of 2-(2-bromothiophen-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine, 0.25 g of ethyl mercaptan sodium salt (80%), 0.08 g of copper iodide and 4 ml of N-methylpyrrolidinone was stirred at 70° C. for 4 hours. Water and aqueous ammonium (28%) were poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.30 g of 2-(2-ethylthiothiophen-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (13)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O.O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:13]1[CH2:12][CH2:11][CH:10]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:9])[CH2:15][CH2:14]1)[CH3:37]
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CCOC(=O)CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 6 h
Yield: 59.8 %

Procedure:
A solution of 4.4 g (0.018 mole) of 10-bromodecanoic acid, 3 ml of methane sulfonic acid, and 250 ml of absolute ethanol was heated at reflux for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to yield 5.0 g (100%) of ethyl 10-bromodecanoate as a yellow oil. A mixture of 4.6 g (0.015 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 4.2 g (0.015 mole) of ethyl 10-bromodecanoate, 6.4 g (0.015 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 50 ml of N,N-dimethylformamide was heated on a steam bath fo 6 h. The mixture was poured into 1 L of water and extracted three times with 250 ml portions of ethyl acetate. The ethyl acetate extracts were combined, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a dark oil. The oil was purified by high pressure liquid chromatography (Water Associates Prep LC/System 500A; PrepPAK® 500/silica; ethyl acetate-hexane 2:1; flow rate 150 ml/min). The fractions containing the desired product were combined and concentrated under reduced pressure to yield 4.5 g (60%) of the title compound as a golden, viscous oil.
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:19]>>[ClH:19].[CH:13]1([CH2:12][C@@H:9]2[CH2:10][S:7][C:6]([NH2:5])=[N:8]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)CC1CCCCC1
Agent: Cl
Product: NC1=N[C@H](CC2CCCCC2)CS1
Temperature: 100 °C

Procedure:
The process is performed as in Example 1, starting with 2.9 g of N-(tert-butyl)-N′-[(1R)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea in 28 cm3 of aqueous 6N hydrochloric acid by heating at a temperature in the region of 100° C. for 2 h 15 min. By means of an identical work-up, a solid is obtained which is purified by dissolution in 15 cm3 of water and extraction with 10 cm3 of dichloromethane. The aqueous phase is made alkaline by addition of 10 cm3 of 1N sodium hydroxide and is extracted with twice 15 cm3 of ethyl acetate. The combined organic extracts are concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The resulting paste is taken up in twice 20 cm3 of diethyl ether. The solid is filtered off and dried in an oven under reduced pressure (10 Pa) at a temperature in the region of 60° C. 0.4 g of (+)-(4R)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of a white solid melting at 169° C. (αD20=+31.8±0.9 at a concentration of 0.5% in methanol).