Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:22]=1)(=O)=O.S(=O)(=O)(O)O>CN(C)C=O>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH:22]=2)=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CS(=O)(=O)OCc1cn(-c2cccnc2)c2ccccc12
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2cn(-c3cccnc3)c3ccccc23)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4.55 g of ethyl p-hydroxybenzoate in 50 ml of dry dimethylformamide is treated with 1.31 g of 50% sodium hydride dispersion in mineral oil under nitrogen at 0°, stirred for 30 minutes at 0°, and then at room temperature for 15 minutes. A solution of 7.55 g of 3-(methanesulfonyloxymethyl)-N-(3-pyridyl)indole in 10 ml of dry dimethylformamide is added over 5 minutes and the reaction mixture is warmed at 50° for 18 hours. The reaction mixture is poured onto ice, made acidic with concentrated sulfuric acid and extracted with diethyl ether (4×40 ml). The aqueous phase is adjusted to pH=8 and is extracted with diethyl ether (3×100 ml). The organic extracts are washed with water (4×50 ml) and brine (1×50 ml) and dried over anhydrous sodium sulfate. Evaporation and chromatography on 100 g of silica with diethyl ether as the eluent yields 3-[(p-ethoxycarbonylphenoxy)methyl]-N-(3 -pyridyl)indole.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])=O)(C)(C)C.O[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N+:24]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:14]=1[O:11][CH2:10][C@@H:9]([NH2:8])[CH3:12])[C:18]([O:20][CH3:21])=[O:19])([O-:26])=[O:25]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@H](C)N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
To a stirred solution of (S)-2-(N-tert-butoxycarbonylamino)-1-propanol (0.90 g, 5.13 mmol), methyl 4-hydroxy-3-nitrobenzoate (1.01 g, 5.12 mmol), and Ph3P (1.75 g, 6.67 mmol) in THF (15 mL) was added diisopropyl azodicarboxylate (DIAD) (1.31 mL, 6.65 mmol) at room temp, and the resulting mixture was heated under reflux overnight. The solution was evaporated and the residue was dissolved in CH2Cl2 (20 mL) and TFA (10 mL). The mixture was stirred at room temp for 3 hr. The mixture was concentrated in vacuo. The residue was dissolved in CHCl3, washed with sat. NaHCO3, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 313 mg (24%) methyl(S)-3-nitro-4-(2-amino-1-propoxy)benzoate as a pale yellow oil: 1H-NMR (CDCl3) δ1.22 (d, 3 H, J=6.8 Hz), 3.43-3.48 (m, 1 H), 3.69-3.87 (m, 2 H), 3.89 (x 3 H), 6.93-6.95 (m, 1H), 7.99-8.02 (m, 1 H), 8.18-8.21 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH3:19])([CH3:18])[C:13](=[O:20])[C:12]([C:21]([NH:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:22])=[C:11]2[OH:32]>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH3:19])([CH3:18])[C:13](=[O:20])[C:12]([C:21]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22])=[C:11]2[OH:32]
Reactant: Cc1ccccc1-c1ccc2c(c1)C(O)=C(C(=O)NCC(=O)OC(C)(C)C)C(=O)C2(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1ccc2c(c1)C(O)=C(C(=O)NCC(=O)O)C(=O)C2(C)C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
1,1-Dimethylethyl N-((6-(2-methylphenyl)-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (160 mg, 367 μmol) was dissolved in TFA (2 mL) at ambient temperature. The reaction was stirred for 30 minutes and then concentrated, precipitated with hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (57 mg) as a light yellow solid. MS (m/z)=380 (M+H)+. Calculated for C22H21NO5 379.14.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([N:10]2[CH2:15][CH2:14][C@@H:13]([NH:16][C:17](=[O:20])[CH2:18]Cl)[C@H:12]([OH:21])[CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[H-].[Na+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[NH2:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][C@@H:13]3[C@H:12]([O:21][CH2:18][C:17](=[O:20])[NH:16]3)[CH2:11]2)[C:3]=1[Cl:22])[C:8]#[N:9]
Reactant: N#Cc1cc(N)c(Cl)c(N2CC[C@@H](NC(=O)CCl)[C@H](O)C2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: N#Cc1cc(N)c(Cl)c(N2CC[C@H]3NC(=O)CO[C@@H]3C2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.1 %

Procedure:
(+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-hydroxypiperidin-4-yl)-2-chloroacetamide (549 mg, 1.600 mmol) was dissolved in anhydrous THF. The solution was cooled to 0° C. sodium hydride (96 mg, 2.399 mmol) and tetrabutylammonium bromide (77 mg, 0.240 mmol) were added (briefly opening the reaction flask to air). The reaction mixture was stirred at 0° C. for 5 minutes, then the ice bath was removed and the mixture stirred at room temperature for 1.5 hours. The reaction was quenched with aq. NH4Cl solution. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine (+small amount of NaHCO3 solution), then dried over MgSO4. The organic layer was filtered and evaporated to dryness to give 0.85 g crude colorless solid, which was purified via silica gel chromatography: gradient from 100% DCM to 100% EtOAc, then isocratic at 100% EtOAc to afford (+/−)-3-amino-4-chloro-5-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)benzonitrile (197 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:3].C([O-])(=O)C1C(=CC=CC=1)O.O.[OH-].[K+].C(Cl)[Cl:34]>>[CH3:3][N:2]([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:1].[ClH:34]
Reactant: ClCCl
Agent: COc1cccc(C2(O)CCCCC2CN(C)C)c1
Agent: O=C([O-])c1ccccc1O
Agent: [K+]
Solvent: O
Product: Cl
Temperature: 15 °C

Procedure:
In a reaction flask 29 g tramadol salicylate salt was stirred with 87 ml water and pH was adjusted to 11-12 by 10% aqueous KOH solution. The tramadol free base was extracted with methylene chloride, organic extract washed with water, and methylene chloride was evaporated under reduced pressure. The oil obtained was dissolved in 88.0 ml methylene chloride. Stirred and cooled to 15° C. Adjusted pH to 2-2.5 by conc. HCI. Stirred for 1.0 hour at same temperature. Raised the temperature to 25-30° C. and stirred it for 30 minutes. Distilled out solvent completely under vacuum. Charged 42 ml acetone and stirred at 25-30° C. for 30 minutes. Filtered the product and washed solid with acetone. Yield=18.4 gm (85%) (cis=99.98% & trans=0.02% by HPLC area%).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([CH:34]=[CH:35][CH:36]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:14]([CH3:33])[CH:13]=1)=[O:10].[H][H]>CCO.[Pd]>[CH3:37][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:34]=[CH:35][CH:36]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH3:32])[N:26]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[C:14]([CH3:33])[CH:13]=1)=[O:10]
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(C#CCN(C)C)c3)cc2C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(CCCN(C)C)c3)cc2C)n1
Reaction time: 5 h

Procedure:
To a mixture of 3-(3-(dimethylamino)prop-1-ynyl)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide (0.060 g, 0.12 mmol) in EtOH (4 mL) was added a suspension of 10% Pd/C (0.012 g, 0.012 mmol) in ethanol. The reaction was exposed to approximately 30 psi hydrogen and was shaken in a Parr apparatus for 5 h. The reaction was filtered through celite, and the filtrate was concentrated in vacuo. The resulting yellow oil was purified by reverse-phase HPLC using acetonitrile/water/TFA to give 3-(3-(dimethylamino)propyl)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide as an off-white solid. MS m/z=497 [M+1]+. Calc'd for C29H32N6O2: 496.61.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH2:43]([Mg]Br)[CH3:44].Cl>O1CCCC1>[O:42]=[C:17]1[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=[CH:26][N:27]=[C:19]2[N:18]1[C@H:28]1[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](=[O:37])[CH2:43][CH3:44])[CH2:30][CH2:29]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Reactant: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)CC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (1.0 g) was dissolved in tetrahydrofuran (10 mL), ethylmagnesium bromide (1.7 mL, 3.0 M diethyl ether solution) was added dropwise, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.64 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:17])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][N:12]2[CH3:16])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:20][O:17][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:16]
Reactant: COc1cccc(C(O)CC2CCCN2C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C(CC2CCCN2C)OC)c1
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
1.0 g of 1-(3-methoxyphenyl)-2-(1-methyl-2-pyrrolidinyl)-ethanol dissolved in 15 ml of dimethyl formamide is added dropwise within 5 minutes, with stirring and exclusion of moisture, to a suspenion of 0.25 g of 80 p.c. sodium hydride. Stirring is effected for 30 minutes and a solution of 0.85 g methyl iodide in 10 ml of dimethyl formamide is added drop by drop. The mixture is kept at 60° for 2 hours, treated with water and extracted with diethyl ether. The etheral phase is concentrated. There are obtained 0.7 g of the title compound as oily mixture of diastereoisomers.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23][CH2:24][CH:25]([OH:28])[CH2:26]O.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O.C(O)CCC>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:28][CH:25]([CH2:24][O:23][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=2)[CH2:26][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: OCC(O)COc1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCCCO
Solvent: O
Product: Clc1ccc(C2(CBr)OCC(COc3ccc4ccccc4c3)O2)c(Cl)c1

Procedure:
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 13.1 parts of 3-(2-naphtalenyloxy)-1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 180 parts of benzene and 80 parts of butanol is stirred and refluxed for 12 hours with water-separator. The reaction mixture is evaporated and the residue is triturated in methanol. The product is filtered off and crystallized from 2-propanol, yielding A 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-[(2-naphthalenyloxy)methyl]-1,3-dioxo-lane; mp. 117.6° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]=[C:22]=[O:23])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]=[C:2]3[CH3:1])=[O:23])=[CH:18][CH:19]=1
Reactant: O=C=NCc1ccc(Br)cc1
Reactant: Cc1nccc2c(N)cccc12
Solvent: Cc1ccccc1
Product: Cc1nccc2c(NC(=O)NCc3ccc(Br)cc3)cccc12
Temperature: 90 °C

Procedure:
The product from Example 65A (480 mg, 3.04 mmol) in toluene (9 mL) was treated with 1-bromo-4-(isocyanatomethyl)benzene (0.43, 3.07 mmol) with stirring. After heating the mixture at 90° C. for 1 hour, the mixture was allowed to cool to room temperature, filtered, and the filter cake washed with toluene to provide the title compound. The corresponding di-hydrochloride salt was prepared using methanolic HCl (680 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.38 (d, J=6.1 Hz, 1H), 8.25 (d, J=7.8 Hz, 1H), 7.78-7.85 (m, 2H), 7.53-7.61 (m, 3H), 7.32 (d, J=8.5 Hz, 2H), 7.11 (t, J=6.1 Hz, 1H), 4.34 (d, J=6.1 Hz, 2H), 2.88 (s, 3H); MS (ESI+) m/z 370/372 (M+H+, 79Br/81Br).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]([NH:35]S(C(C)(C)C)=O)([C:13]3[C:21]([S:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH3:12])[N:8](COCC[Si](C)(C)C)[C:7]=2[CH:50]=1)#[N:2].C(C1C=CC2N(COCC[Si](C)(C)C)C(C(NS(C(C)(C)C)=O)(C3C(SC)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)C)=NC=2C=1)#N.Cl.CO>>[NH2:35][C:11]([C:9]1[NH:10][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:50][C:7]=2[N:8]=1)([C:13]1[C:21]([S:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]2[C:14]=1[CH:15]=[CH:16][N:17]2[S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=1)(=[O:27])=[O:26])[CH3:12]
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(NS(=O)C(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CO
Product: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(N)c1nc2cc(C#N)ccc2[nH]1
Temperature: 60 °C

Procedure:
To a mixture of (±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (0.63 g, 0.840 mmol), was added 1.25 M HCl in MeOH (14.00 mL, 16.80 mmol) and the reaction mixture was then heated to 60° C. for 2 h. The reaction mixture was then evaporated directly, basified with ammonium hydroxide and directly loaded onto silica gel and purified by FCC and eluted with heptane/EtOAc 1:1 to give the title compound. MS (ESI−) m/z 514.2 (M−1).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)C(C)C)(C)C.[F:15][C:16]([F:23])([F:22])[C:17](=[CH2:21])[C:18](O)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:18](=[O:19])[C:17]([C:16]([F:23])([F:22])[F:15])=[CH2:21]
Reactant: CNOC
Reactant: C=C(C(=O)O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C(=O)N(C)OC)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
16.6 g (167 mmol) of N,O-dimethylhydroxylamine hydrochloride were suspended in 900 ml of CH2Cl2 and 29.1 ml (167 mmol) of N,N-diisopropylethylamine added dropwise at 0° C. The resulting solution was added dropwise to a solution of 20.0 g (143 mmol) of 2-(trifluoromethyl)propenoic acid in 500 ml of CH2Cl2 at −40° C. Afterwards, 34.5 g (167 mmol) of N,N′-dicyclohexylcarbodiimide were added and the mixture stirred at 0° C. for 16 h. The resulting suspension was then filtrated and the filtrate carefully evaporated (the desired product is volatile!). Afterwards, 100 ml of n-pentane were added and the suspension stirred for 30 minutes at ambient temperature. The precipitate was removed by filtration, the filtrate was carefully evaporated. Chromatography on silica gel using ethyl acetate/n-pentane 1:4 yielded 22.8 g of the desired product. Rt=0.56 min (Method P).
Reaction SMILES: IC1C=CN=C(OC)C=1C=O.[CH3:12][O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[N:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1>C(O)(=O)C>[CH3:12][O:13][C:14]1[N:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[CH2:22][NH:21][CH2:20][CH2:19]2
Reactant: COc1nccc2ccncc12
Agent: COc1nccc(I)c1C=O
Solvent: CC(=O)O
Product: COc1nccc2c1CNCC2

Procedure:
4-Iodo-2-methoxypyridine-3-carbaldehyde was converted to 1-methoxy-2,7-naphthyridine using the methods described by A. Numata et al., Synthesis 1999, 306-311. Subsequent hydrogenation in acetic acid, under platinum(IV) oxide catalysis, afforded the requisite 8-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine.
Reaction SMILES: S(Cl)(Cl)=O.C(C1C=CC(C(O)=O)=CC=1)CCCCCCC.C(C1C=CC(C(Cl)=O)=CC=1)CCCCCCC.[Cl:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][C:46]=1[O:47][C:48]1[C:57]2[C:52](=[CH:53][C:54]([O:60][CH3:61])=[C:55]([O:58][CH3:59])[CH:56]=2)[N:51]=[CH:50][CH:49]=1)[NH2:43].[CH2:62]([C:70]1[CH:75]=[CH:74][C:73]([C:76]([N:78]=[C:79]=[S:80])=[O:77])=[CH:72][CH:71]=1)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]>C1(C)C=CC=CC=1.C(O)C>[Cl:39][C:40]1[CH:41]=[C:42]([NH:43][C:79]([NH:78][C:76](=[O:77])[C:73]2[CH:74]=[CH:75][C:70]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])=[CH:71][CH:72]=2)=[S:80])[CH:44]=[CH:45][C:46]=1[O:47][C:48]1[C:57]2[C:52](=[CH:53][C:54]([O:60][CH3:61])=[C:55]([O:58][CH3:59])[CH:56]=2)[N:51]=[CH:50][CH:49]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Reactant: CCCCCCCCc1ccc(C(=O)N=C=S)cc1
Agent: CCCCCCCCc1ccc(C(=O)Cl)cc1
Agent: CCCCCCCCc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCCCCCCCc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-octylbenzoic acid (40 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-octyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-octyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-octyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (53 mg, yield 58%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].C([O:23][C:24](=O)[CH2:25][CH:26]([OH:30])[CH2:27][C:28]#[N:29])C>O1CCCC1>[C:28]([CH2:27][CH:26]([OH:30])[CH2:25][C:24](=[O:23])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:29]
Reactant: CCOC(=O)CC(O)CC#N
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Temperature: -55 °C

Procedure:
To a vessel containing 265 kg of 16.8% n-butyllithium is added a mixture of 80 kg of diisopropylamine in 80 L of tetrahydrofuran maintaining the temperature at less than 20° C. The solution is cooled to −55° C., and 85 kg of tert-butyl acetate is added maintaining the temperature at −50°±5° C. A solution of 25 kg of R 4-cyano-3-hydroxybutanoic acid ethyl ester in 55 L of tetrahydrofuran is then added, and the temperature is allowed to warm to −20° C. for at least 20 minutes. The solution is then quenched by transferring to aqueous hydrochloric acid. The organic layer is separated and the aqueous layer re-extracted with ethyl acetate. The combined organic layers are concentrated by vacuum distillation to afford crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=O>C(O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3ccc(Cl)cc3)cs2)c1
Yield: 81.1 %

Procedure:
To a solution of the compound (500 mg) obtained in Example 1b in ethanol (5 mL) was added 2-bromo-1-[4-chlorophenyl]ethanone (546 mg), and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ether to give the title compound (660 mg) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-ol, sodium hydride and DMF was stirred for 5 minutes at room temperature, then 2-chloro-N,N-dimethylethylamine was added to the resultant and further stirred for 30 minutes at room temperature to give 2-[(1-tert-butoxycarbonylpiperidine-4-yl)oxy]-N,N-dimethylethylamine. A mixture of the obtained 2-[(1-tert-butoxycarbonylpiperidine-4-yl)oxy]-N,N-dimethylethylamine and 4M HCl-dioxane solution was stirred for 7 hours at room temperature to give N,N-dimethyl-2-(piperidine-4-yloxy)ethylamine dihydrochloride.