Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]([CH3:13])[CH2:10][CH:11]=[CH2:12].[OH-].[Na+]>CC[Al](Cl)CC.CC[Al](Cl)Cl>[CH3:12][CH:11]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])[CH2:10][CH:9]([CH3:13])[CH3:8]
Reactant: C=CCC(C)C
Reactant: Nc1ccccc1
Agent: CC[Al](Cl)CC
Agent: CC[Al](Cl)Cl
Agent: [Na+]
Product: CC(C)CC(C)c1ccccc1N
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.7 %

Procedure:
Aniline (209.5 g, 2.25 mol) was treated with ethylaluminum sesquichioride (39.0 g, 0.158 mol) in the reactor as described in Example 1. 4-Methyl-1-pentene (190 g, 2.26 mol) was added and the mixture was held at 260-262° C. for 17 hours. Reactor contents were cooled to ambient temperature and treated with 25% aqueous sodium hydroxide solution. Aqueous phase was removed and the organic phase (388 g) was analyzed to contain 21.9 wt % aniline and 41.1 wt % 2-(1,3-dimethylbutyl)aniline. Aniline conversion was found to be 59.4% and 2-(1,3-dimethylbutyl)aniline yield was found to be 40% based on aniline charged or 67.3% based on aniline reacted. Crude product from this and from another similar experiment were combined and the total (767 g) was fractionally distilled at reduced pressure to give 290 g of pure 2-(1,3-dimethylbutyl)aniline (290 g, 36% yield based on aniline charged).
Reaction SMILES: [OH-].[Na+].[CH3:3]/[C:4](=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[C:5]([O:7]CC)=[O:6]>CO.O>[CH3:3]/[C:4](=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)/[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)/C(C)=C/CCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C/C(=C\CCCCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
Sodium hydroxide (1.4 g, 35 mmol) is added to a solution of (E)-ethyl 2-methyl-7-phenyl-hept-2-enoate (8.6 g, 35 mmol) in MeOH (40 mL) and water (2 mL) at 0° C. The reaction is stirred at 23° C. for 2 hours and then heated at 50° C. for 24 hours. After cooling, the reaction is concentrated in vacuo and partitioned between 2N HCl (15 mL) and CH2Cl2 (60 mL). The aqueous layer is back-extracted with CH2Cl2 (2×30 mL) and the organic layers are combined and dried (MgSO4). The solution is concentrated in vacuo and purified by gradient elution chromatography (silica, 20 to 40% ether in petroleum ether) to yield (E)-2-Methyl-7-phenyl-hept-2-enoic acid (4.9 g, 65%): 1H NMR (CDCl3) δ 7.30-7.23 (m, 2H), 7.20-7.14 (m, 3H), 6.90 (dt, J=15.4, 1.3 Hz, 1 H), 2.62 (t, J=7.5 Hz, 2H), 2.22 (q, J=7.0 Hz, 2H), 1.81 (s, 3H), 1.69-1.58 (m, 2H), 1.55-1.43 (m, 2H); MS (FAB) m/e 219 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]1=[O:22].COC(=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>CN(C=O)C>[CH3:3][O:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([CH2:33][C:32]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:14]1=[O:22]
Reactant: COC(=O)CCCCCCCBr
Reactant: COC(=O)CCCCCCCn1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(Cc2ccccc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 0.75 g. of NaH (80% suspension in mineral oil), 5.6 g. of 1-benzylbenzimidazolin-2-one (produced in usual manners by alkylation of benzimidazolin-2-one with benzylchloride according to example 8), 50 cc. of DMF, 5.9 g. of 8-bromocaprylic acid methyl ester and 0.75 g. of NaJ.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[N:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].[CH3:23][O:24][CH2:25]Cl>O1CCCC1>[CH3:23][O:24][CH2:25][O:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[N:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCCl
Reactant: Oc1c(-c2ccccc2)sc2ncccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCOc1c(-c2ccccc2)sc2ncccc12

Procedure:
A suspension of 4.54 g (20 mmol) of 3-hydroxy-2-phenyl-7-azabenzo[b]thiophene and 2.75 g (22 mmol) of potassium t-butoxide in 50 mL of tetrahydrofuran was stirred until the solid dissolved. Then 2.0 g (25 mmol) of chloromethyl methyl ether was added and the solution was stirred at room temperature for 2 hours. The solution was partitioned between ether and water and the aqueous layer was washed with two portions of ether. The ether extracts were washed with brine, dried over MgSO4, and concentrated to 4.33 g (80%) of an oil that crystallized upon standing, m.p. 54° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(OC(=O)[NH:22][NH2:23])(OC(C)(C)C)=O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.[ClH:51]>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I.C(OCC)C>[ClH:51].[NH:22]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1)[NH2:23]
Reactant: CC(C)(C)OC(=O)OC(=O)NN
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: I[Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)Cc1ccc(NN)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A solution of methyl 4-iodophenylacetate (4.25 g, 15.39 mmol) was dissolved in DMF (25 mL). BOC-carbazate (2.44 g, 18.47 mmol), 1,10-phenanthroline (278 mg, 1.54 mmol), copper iodide (147 mg, 0.77 mmol) and cesium carbonate (7.0 g, 21.55 mmol) were added and the mixture heated at 120° C. for 60 min. The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (3×10 mL) and brine (10 mL), dried (MgSO4) and evaporated to leave a brown oil which was purified by flash chromatography on silica gel (elution gradient 0-50% EtOAc in isohexane) to give a colourless oil. The oil was dissolved in 4M HCl Dioxan (20 mL) and stirred at ambient temperature for 3 h giving a thick precipitate. Diethyl ether (100 mL) was added and the precipitate recovered by filtration, washed with ether (2×20 mL) and dried under vacuum to leave methyl 2-(4-hydrazinylphenyl)acetate_hydrochloride as a light brown solid. (1.63 g, 49%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:22]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)Cl>[Br:22][C:6]1[CH:5]=[C:4]2[C:9](=[N:8][CH:7]=1)[NH:1][CH2:2][CH2:3]2
Reactant: c1cnc2c(c1)CCN2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Brc1cnc2c(c1)CCN2
Temperature: 25 °C

Procedure:
The bromination may be carried out by any of the procedures known for such a reaction. The bromination may be carried out, for example, by mixing 7-azaindoline, p-toluene sulphonic acid monohydrate and 1,3-dibromo-5,5-dimethylhydantoin in methylene chloride and stirring the mixture at for example ambient temperature for a period of time, for example 3 hours. Extraction and purification gives 5-bromo-7-azaindoline.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:26])[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].[BH4-].[Na+].C(OCC)(=O)C.Cl>CC(O)C>[OH:26][CH:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:27])[CH3:1])[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)CCCCCCCCCCCC(=O)CC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)CCCCCCCCCCCC(O)CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of benzyl 15-methyl-3-oxohexadecanoate (3.74 g) in 2-propanol (50 ml) was added sodium borohydride (0.38 g) at 0° C. The mixture was stirred at 0° C. for 2 hours and poured into a mixture of ethyl acetate and diluted hydrochloric acid. The organic layer was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed on a silica gel column eluting with a mixture of n-hexane and ethyl acetate (10:1) to give benzyl 3-hydroxy-15-methylhexadecanoate as a colorless oil (2.10 g).
Reaction SMILES: [S-]C#N.[NH4+].Cl[C:6]1[C:11]([C:12]([N:14]=[C:15]=[S:16])=[O:13])=[CH:10][N:9]=[CH:8][CH:7]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([NH:22][CH3:23])=[CH:20][CH:19]=1>CC(C)=O.C1COCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([N:22]([C:15]2[S:16][C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:12](=[O:13])[N:14]=2)[CH3:23])=[CH:20][CH:19]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: O=C(N=C=S)c1cnccc1Cl
Agent: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CN(c1ccc(Cl)cc1)c1nc(=O)c2cnccc2s1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1.416 g (8.99 mmol) of 4-chloronicotinic acid, 15 ml of thionyl chloride and two droplets of DMF was heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure to obtain 4-chloronicotinoyl chloride. The compound thus obtained was then suspended in a mixture of 10 ml of acetone and 10 ml of THF. The suspension thus obtained was then added dropwise to a solution of 753 mg of ammonium thiocyanate in 15 ml of acetone with stirring in 5 minutes. After the termination of dropwise addition, the reaction mixture was heated to a temperature of 40° C. with stirring for 6 minutes to obtain a mixture containing 4-chloronicotinoyl isothiocyanate. To the mixture thus obtained was then added dropwise a solution of 1.55 g of 4-chloro-N-methylaniline in 10 ml of acetone with stirring in 5 minutes. The reaction mixture was stirred at room temperature for 17 hours, concentrated to half the initial volume under reduced pressure, and then poured into about 500 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was purified through silica gel column chromatography (eluant: CHCl3 +1 to 3% methanol), and then recrystallized from ethanol to obtain 717 mg of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3,4-e]-1,3-thiazin-4-one.
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])=[CH:4][C:3]=1[O:15][CH3:16].[CH3:17][O:18][C:19]([O:23][Si](C)(C)C)=[C:20]([CH3:22])[CH3:21]>CN(C=O)C.[F-].[F-].[Zn+2]>[CH3:16][O:15][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:2]=1[C:20]([CH3:22])([CH3:21])[C:19]([O:18][CH3:17])=[O:23])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1Br
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: [F-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1ccc(C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a microwave vial was added ZnF2 (36 mg, 0.35 mmol) and Pd(tBu3P)2 (7.2 mg, 0.014 mmol). The reaction vessel was purged with nitrogen for 10 minutes before tert-butyl 4-bromo-3-methoxy-benzoate (200 mg, 0.70 mmol) dissolved in DMF (2.5 mL) was added followed by (1-methoxy-2-methyl-prop-1-enoxy)-trimethyl-silane (180 mg, 1.1 mmol). The reaction vessel was placed in an 80° C. oil bath under an atmosphere of nitrogen and the mixture was allowed to stir overnight. The mixture was allowed to cool to rt and was filtered through a frit and was washed with brine and EtOAc. The organics were separated and dried over sodium sulfate. The solvent was removed and the residue was taken on to the next step without additional purification. ESI-MS m/z calc. 308.2, found 309.4 (M+1)+; Retention time: 3.12 minutes (4 min run).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33])[CH:27]=O.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([N:21]([CH2:27][C:26]2[CH:29]=[CH:30][C:31]([C:32]([F:33])([F:34])[F:35])=[C:24]([F:23])[CH:25]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (340 mg, 1.06 mmol) in MeOH (6 ml) was added 3-fluoro-4-trifluoromethyl-benzaldehyde (230 mg, 1.20 mmol). Then a solution of NaBH3CN (85 mg, 1.3 mol) in MeOH (1.5 ml) and AcOH (0.01 ml) were added. The reaction mixture was stirred overnight at RT, concentrated under vacuo, diluted with EtOAc, washed with H2O. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, EtOAc/Heptane 1:4) to afford 145 mg (28%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][NH:7][C:8](=[O:31])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:17][C:16]=2[N+:28]([O-])=O)[CH:10]=1>CO.[Pd]>[F:35][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][CH:34]=1)[CH2:6][NH:7][C:8](=[O:31])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH:18]=[CH:17][C:16]=2[NH2:28])[CH:10]=1
Reactant: CCCN(CCC)c1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-(dipropylamino)-2-nitrophenyl)isonicotinamide (400 mg, 0.80 mmol, −1.00 equiv) in methanol (20 mL). The solution was treated with Pd/C (400 mg, 10%), and stirred under an atmosphere of hydrogen for 4 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The product was obtained as 300 mg (80%) of a yellow to green oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C@H:19]12[O:28][C@H:23]([O:24][C@@H:25]1[CH2:26][OH:27])[CH2:22][NH:21][CH2:20]2.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:27][CH2:26][C@@H:25]1[C@@H:19]2[O:28][C@@H:23]([CH2:22][N:21]([C:16]([C:13]3[S:14][CH:15]=[C:11]([C:7]4[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=4[CH3:10])[N:12]=3)=[O:17])[CH2:20]2)[O:24]1
Reactant: OC[C@H]1O[C@@H]2CNC[C@H]1O2
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3C[C@H]4O[C@H](CO)[C@@H](C3)O4)n2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). (1R,5R,7R)-6,8-Dioxa-3-azabicyclo[3.2.1]oct-7-ylmethanol, synthesized according the literature (Guarna et al., 1999, J. Org. Chem., 64, 7347) (96.2 mg; 0.66 mmol; 1 eq.), and triethylamine (0.37 ml; 2.65 mmol; 4 eq.) are added and the mixture is stirred 1 hour at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (51) as a white-off powder (110 mg; 40%). M− (ESI): 408.99; M+ (ESI): 410.89. HPLC (method A), Rt: 2.15 min (purity: 99.8%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)[C:5]=1[O:19][CH2:20][CH3:21])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[Cl:12][C:10]1[C:7]([C:8]#[N:9])=[C:6]([N:13]2[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]2)[C:5]([O:19][CH2:20][CH3:21])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:11]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1N1CC(OC)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1c(C(C)O)cc(Cl)c(C#N)c1N1CC(OC)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
4-Acetyl-6-chloro-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile (30 mg, 0.1 mmol was dissolved in methanol (5 mL) cooled to 0° C. and sodium tetrahydroborate (5.5 mg, 0.14 mmol) was added. Reaction was stirred for 1 h at 0° C. The reaction was partitioned between EtOAc and water. The combined organic layer was washed with water and saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give crude 6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-(3-methoxyazetidin-1-yl)benzonitrile (0.030 g, 100%). LCMS calculated for C15H20ClN2O3(M+H)+: m/z=311.1; found: 311.1.
Reaction SMILES: C(O[CH:4](OCC)[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)=O)C.Cl.[NH2:21][NH:22][C:23]([NH2:25])=[O:24].C(N(CC)C(C)C)(C)C.CO>ClCCCl.C(Cl)Cl>[O:24]=[C:23]1[N:25]=[CH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=2)=[N:21][NH:22]1
Reactant: CCOC(OCC)C(=O)c1ccc(C(=O)OC)cc1
Reactant: NNC(N)=O
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2cnc(=O)[nH]n2)cc1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 4-(diethoxyacetyl)benzoate (15.4 g, 0.0578 mol), semicarbazide hydrochloride (7.1 g, 0.064 mol), N,N-diisopropylethylamine (12 mL, 0.069 mol) in 1,2-dichloroethane (150 mL), and methanol (2 mL) was heated at 95° C. for 4 h. To the mixture was added an additional 0.1 equivalents of semicarbazide hydrochloride. The mixture was stirred at 95° C. for 1 h. After cooling, the mixture was diluted with methylene chloride and washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was refluxed with acetic acid (100 mL) and water (1.0 mL) overnight. The mixture was concentrated to yield quantitative crude material which was directly used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12][CH2:13][C:14]#[N:15].C(N(C(C)C)CC)(C)C.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>ClCCl.CN(C1C=CN=CC=1)C>[C:14]([CH2:13][S:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])#[N:15]
Reactant: N#CCSc1ccc(C(F)(F)F)cc1N
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Nc1cc(C(F)(F)F)ccc1SCC#N
Temperature: 0 °C
Reaction time: 24 h

Procedure:
(2-Amino-4-trifluoromethylphenylsulfanyl)acetonitrile (1.33 g) dissolved in dichloromethane (5 ml) was stirred on an ice bath at 0° C. Diisopropylethylamine (1 ml) and butyric acid chloride (0.9 ml) was added, and the resulting solution was allowed to reach room temperature. After 22 h more butyric acid chloride (0.9 ml) and DMAP (0.70 g) were added at 0° C. and stirring was continued at 40° C. for 24 h. The cold mixture was diluted with dichloromethane (20 ml), extracted with saturated aqueous sodium bicarbonate (10 ml), washed with water (2×50 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/heptane 1:1 as eluent. The title compound was obtained as a sirup. Yield 1.72 g (100%). The compound could be crystallised from ethyl acetate/heptane, mp 88.5-89.5° C.; El SP/MS: 302 (M+). 1H-NMR(CDCl3) δ (ppm): 8.85 (br, 1H), 8.38 (br, 1H), 7.28 (d, 1H), 7.38 (dd, 1H), 3.50 (s, 2H), 2.46 (t, 2H), 1.82 (sextet), 1.03 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10]COC)[C:5]([CH3:8])=[N:6][CH:7]=1.O.[OH-].[Na+].C(=O)([O-])O.[Na+]>O1CCOCC1.Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: COCOCc1cc(F)cnc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ncc(F)cc1CO
Temperature: 35 °C
Reaction time: 1 h
Yield: 109.8 %

Procedure:
To a solution of 0.49 g of 5-fluoro-3-((methoxymethoxy)methyl)-2-methylpyridine in 20 mL of dioxane, 10 mL of 6.0 mol/L hydrochloric acid was added, and the mixture was stirred at 30 to 40° C. for 1 hour. Thereto were added water and ethyl acetate, and the mixture was adjusted to pH 5.5 with a 20% aqueous sodium hydroxide solution and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.41 g of (5-fluoro-2-methylpyridin-3-yl)methanol as a light yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>CCOCC>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CN(C)CCOc1ccc2c(c1)CCCC2=O

Procedure:
Ether linked analogs such as 61, are prepared by the convergent synthesis depicted in scheme 15. The 6-hydroxy-1-tetralone 15 is reacted with an amine, such as N,N-dimethylethanolamine, preferably in the presence of PPh3 and DEAD at a temperature preferably between about 0° C. and about RT to form the 6-(2-dimethylamino-ethoxy)-3,4-dihydro-2H-naphthalen-1-one 59. The 6-(2-dimethylamino-ethoxy)-3,4-dihydro-2H-naphthalen-1-one 59 is reacted with hydroxylamine hydrochloride and base, such as Et3N. The reaction is heated above RT, preferably at reflux to form the oxime 60. Hydrogenation of the oxime 60, such as with Pd/C and H2 provides the amine 61.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26]O)[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:26][CH2:25][CH2:24][CH2:23][N:19]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)N(CCCCO)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)N(CCCCBr)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of 1.50 g of 4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]-1-butanol and 1.18 g of triphenylphosphine in 20 ml of dichloromethane was ice-cooled and 1.49 g of carbon tetrabromide was added. After stirring for one hour, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.18 g of the desired compound as a yellow oily substance.