Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH:18]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CCOC(C)=O.CO>[CH3:2][CH2:1][O:3][C:4]1[CH:5]=[C:6]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: CCCN1CC=C(c2ccc([N+](=O)[O-])c(OCC)c2)CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CCC(c2ccc(N)c(OCC)c2)CC1
Reaction time: 8 h
Yield: 101.1 %

Procedure:
4-[3-(ethyloxy)-4-nitrophenyl]-1-propyl-1,2,3,6-tetrahydropyridine (0.536 g, 1.85 mmol) was place in a 40 mL high vial and dissolved in 10 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.196 g, 0.092 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step E (0.491 g, 1.87 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.61 (d, J=1.10 Hz, 1H), 6.47-6.53 (m, 2H), 4.41 (bs, 2H), 3.95 (q, J=6.96 Hz, 2H), 2.91 (d, J=10.07 Hz, 2H), 2.19-2.31 (m, 3H), 1.86-1.97 (m, 2H), 1.61-1.68 (m, 2H), 1.56 (td, J=12.18, 3.11 Hz, 2H), 1.37-1.47 (m, 2H), 1.29 (t, J=6.96 Hz, 3H), 0.83 (t, J=7.33 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:12][O:13][CH2:14][C:15](Cl)=[O:16]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:16]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc2nc(N)sc2c1
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2ccc(C)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-6-methylbenzothiazole (4.9 g) is dissolved in pyridine (100 ml) and thereto is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off and washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (4.1 g) having the following physical properties.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-])=O)[CH:13]=2)[CH2:4][CH2:3]1>[Pd].C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH2:19])[C:15]([NH2:16])=[CH:17][CH:18]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CCCOc2ccc(N)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(CCCOc2ccc(N)c(N)c2)CC1
Reaction time: 2 h
Yield: 95 %

Procedure:
A hydrogenation vessel was charged with 4-(3-(4-methylpiperazin-1-yl)propoxy)-2-nitroaniline (1.4 g, 4.76 mmol), ethanol (100 mL) and 10% palladium on charcoal (1 g). The reaction vessel was shaken on Parr hydrogenation apparatus. After 2 hours, the reaction mixture was filtered through a plug of Celite and washed with methanol. The resulting filtrate was concentrated under reduced pressure to 1.2 g of 4-(3-(4-methylpiperazin-1-yl)propoxy)benzene-1,2-diamine (95% yield), and was used without any further purification. MS (EI: 265 (MH+).
Reaction SMILES: ClC1C=CC(C2C3C=C(C4C=C[N:21]=CC=4)SC=3C(=O)CCC2)=CC=1.COC(OC)N(C)C.O1CCCC1.[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[C:51]3[CH:52]=[C:53]([C:55]4[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=4)[S:54][C:50]=3[C:49](=O)/[C:48](=[CH:62]/[N:63](C)C)/[CH2:47][CH2:46]2)=[CH:41][CH:40]=1.C(O)(=O)C.O.NN>>[Cl:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]2[C:51]3[CH:52]=[C:53]([C:55]4[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=4)[S:54][C:50]=3[C:49]3[NH:21][N:63]=[CH:62][C:48]=3[CH2:47][CH2:46]2)=[CH:41][CH:40]=1
Reactant: O=C1CCCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc21
Reactant: CN(C)/C=C1\CCC(c2ccc(Cl)cc2)c2cc(-c3ccncc3)sc2C1=O
Agent: COC(OC)N(C)C
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(C2CCc3cn[nH]c3-c3sc(-c4ccncc4)cc32)cc1
Temperature: 25 °C
Yield: 9 %

Procedure:
A solution of 4-(4-chlorophenyl)-2-pyridin-4-yl-4,5,6,7-tetrahydro-8H-cyclohepta[b]thiophen-8-one (81.5 mg, 0.230 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.514 mL, 3.87 mmol) in tetrahydrofuran (9.27 mL, 114 mmol) was refluxed under argon for 6 hr. The reaction was cooled to room temperature and concentrated under reduced pressure. The obtained residue (81.0 mg, 0.212 mmol), (7E)-4-(4-chlorophenyl)-7-[(dimethylamino)methylene]-2-pyridin-4-yl-4,5,6,7-tetrahydro-8H-cyclohepta thiophen-8-one, was dissolved in acetic acid (6.55 mL, 115 mmol) then hydrazine hydrate (0.112 mL, 2.30 mmol) was added and the reaction mixture was heated at 50° C. for 16 h. The mixture was allowed to cool to rt and concentrated under reduced pressure. The residue was diluted with ethyl acetate (5 mL) then washed with a saturated aqueous solution of NaHCO3 (5 mL), then brine (5 mL), then dried over anhydrous MgSO4, filtered, and concentrated. The obtained residue was purified by preparative HPLC to yield 7.4 mg product as a white solid (9.0% yield). LCMS: (AA) ES+ , 378. 1H NMR (400 MHz, DMSO-d6) δ: 12.8 (br s, 1H), 8.49-8.52 (dd, J=1.7 Hz, J=4.7 Hz, 2H), 7.53-7.55 (dd, J=1.7 Hz, J=4.7 Hz, 2H), 7.34-7.39 (m, 3H), 7.04-7.08 (m, 2H), 4.65-4.70 (m, 1H), 2.63-2.75 (m, 1H), 2.20-2.32 (m, 2H), 2.0-2.10 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]1[C:7]([CH:13]=[O:14])=[N:8][CH:9]=[C:10](Cl)[N:11]=1)([CH3:4])([CH3:3])[CH3:2].[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1.C(OCC)C>C(#N)C.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]1[C:7]([CH:13]=[O:14])=[N:8][CH:9]=[C:10]([F:15])[N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1nc(Cl)cnc1C=O
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)Oc1nc(F)cnc1C=O
Yield: 3.4 %

Procedure:
After dissolving 5.86 g of the crude 3-tert-butoxy-5-chloropyrazine-2-carboxaldehyde in 55 ml of acetonitrile, 4.77 g of potassium fluoride, 1.13 g of tetraphenylphosphonium bromide and 0.71 g of 18-crown-6 were added and the mixture was heated to reflux for 4 hours. Diethyl ether was added to the reaction mixture, the insoluble portion was filtered out, and the filtrate was distilled off under reduced pressure. Ethyl acetate was added to the residue, the insoluble portion was filtered out, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: toluene/ethyl acetate) to obtain the title compound (183 mg, 3% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:27])[CH:15]([O:24][CH2:25][CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1)[CH3:12].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:11]([O:13][C:14](=[O:27])[CH:15]([O:24][CH2:25][CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[CH:3][CH:4]=2)=[CH:19][CH:18]=1)[CH3:12]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: Nc1ccc(CCO)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Yield: 85.6 %

Procedure:
4-Aminophenethyl alcohol (1.39 g; 10.2 mmole) and 2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester (described in Example 20b) (2.42 g; 10.2 mmole) were dissolved in dichloromethane (35 ml) under argon at room temperature. Azodicarbonyl dipiperidine (3.85 g; 15.2 mmole) and thereafter triphenylphosphine (3.20 g; 12.2 mmole) were added. After stirring at room temperature for 1 minute dichloromethane (30 ml) was added and after 21 hours the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane:ethyl acetate (3:2) as eluant gave 3.12 g (yield 86%) of 3-{4-[2-(4-aminophenyl)ethoxy]phenyl}-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CC(C)([O-])C.[K+].[Cl:19][C:20]1[C:21](F)=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].Cl>CS(C)=O>[Cl:19][C:20]1[C:21]([O:10][CH2:9][C:3]2([C:2]([F:11])([F:12])[F:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]
Reactant: OCC1(C(F)(F)F)CCCCC1
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a solution of (1-(trifluoromethyl)cyclohexyl)methanol (3.20 g, 17.57 mmol) in anhydrous dimethylsulfoxide (50 ml) was added potassium tert-butoxide (4.90 g, 43.66 mmol) and the reaction mixture was stirred at ambient temperature for 30 minutes. 5-chloro-2,4-difluorobenzoic acid (3.38 g, 17.55 mmol) was added to the reaction mixture, and stirring was continued for 2 hours. The reaction mixture was acidified to pH=1 with 5% aqueous hydrochloric acid solution and extracted with ethyl acetate, the combined organic extracts was washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (30% ethyl acetate in hexanes) afforded the title compound (5.20 g, 83%) containing o-substituted regioisomer, which was used for next step without further purification: MS (ES−) m/z 355.2, 353.2 (M−1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15].Cl>C(Cl)Cl>[Cl:5][C:6]1[CH:10]=[CH:9][S:8][C:7]=1[C:14]([C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[Cl:11])=[O:15]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Clc1ccsc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])ccc1Cl)c1sccc1Cl
Yield: 44 %

Procedure:
To a mixture of aluminum chloride (1.33 g, 0.0102 mol) and methylene chloride is added 3-chlorothiophene (1.21 g, 0.0102 mol) dropwise. The resultant mixture is stirred 30 minutes and treated with a solution of 2-chloro-5-nitrobenzoyl chloride (2.20 g, 0.0100 mol) in methylene chloride. The resultant mixture is stirred overnight at room temperature, poured into ice, acidified with concentrated hydrochloric acid and extracted twice with methylene chloride. The combined organic layers are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to a brown oil. Trituration with ether affords the title compound as a brown solid (1.33 g, 44.0%, mp 114-116° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:28])[C:11](=[O:12])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=3)=[CH:15][CH:14]=2)=[CH:9][O:8]1>C(Cl)Cl.C(OCC)C>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[O:8][C:7]([CH3:28])([CH3:6])[C:11](=[O:12])[C:10]=2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][N:22]=3)=[CH:17][CH:18]=2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(COc2ccc(C3=COC(C)(C)C3=O)cc2)nc1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C2=C(c3ccc(OCc4ccc(C)cn4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 162.9 %

Procedure:
Methanesulfonic acid (462 mg, 4.8 mmol) was added to a solution of 544-methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one (2.0 g, 4.8 mmol) in DCM (5 ml) and diethyl ether (50 mL) at RT under an atmosphere of nitrogen. The reaction mixture was stirred at RT for 4 h upon which the solids were collected by filtration, washed with 20% DCM in diethyl ether and dried in vacuo to afford 5-(4-Methoxyphenyl)-2,2-dimethyl-4-(4-((5-methylpyridin-2-yl)methoxy)phenyl)furan-3(2H)-one methanesulfonate (2.0 g, 90.9%) as a white solid. 1H NMR: 200 MHz, DMSO-d6: δ 8.5 (s, 1H), 7.6 (d, 1H), 7.55 (d, 2H), 7.4 (d, 1H), 7.2 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.2 (s, 2H), 3.8 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H), 1.45 (s, 6H), HPLC: (99.3%, Condition-A).
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[F:8][CH:9]([F:20])[C:10]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:12][N:11]=1.[OH-].[Na+].S(OC)(OC)(=O)=O>[Cl-].C[N+](C)(C)C.O>[F:20][CH:9]([F:8])[C:10]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]([CH3:1])[N:11]=1
Reactant: CCOC(=O)c1c[nH]nc1C(F)F
Reactant: Cc1ccccc1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCOC(=O)c1cn(C)nc1C(F)F
Temperature: 20 °C

Procedure:
The toluene solution of crude ethyl 3-difluoromethylpyrazole-4-carboxylate was stirred and cooled to 20° C. Water (260 ml), tetramethylammonium chloride (10% aqueous solution, 15.0 g), and 25% NaOH solution (36-60 g) were added in sequence. Dimethyl sulphate (99.5%, 94.5 g, 0.75 mol) and additional 25% NaOH were fed simultaneously over 2 hours at 20° C. while maintaining the pH between 10.5 and 12.0. After 2 hours post reaction, the bottom aqueous phase was separated off.
Reaction SMILES: C(OCC)(=O)C=O.N[C@@H](C)CO.CC1C=CC(N2N=CC=N2)=C(C=1)C(O)=O.[CH3:28][C@H:29]1[CH2:33][O:32][CH:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:30]1[C:39](=[O:52])[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[N:47]1[N:51]=[CH:50][CH:49]=[N:48]1>C1(C)C=CC=CC=1>[CH3:28][C@H:29]1[CH2:33][O:32][C@@H:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:30]1[C:39](=[O:52])[C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[N:47]1[N:51]=[CH:50][CH:49]=[N:48]1
Reactant: CCOC(=O)C1OC[C@H](C)N1C(=O)c1cc(C)ccc1-n1nccn1
Agent: CCOC(=O)C=O
Agent: C[C@H](N)CO
Agent: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1OC[C@H](C)N1C(=O)c1cc(C)ccc1-n1nccn1

Procedure:
By using ethyl glyoxylate (polymer type, a solution of 47% toluene) (2.0 mL, 9.5 mmol), (2S)-2-aminopropan-1-ol (0.73 mL, 9.5 mmol) and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (1.0 g, 4.9 mmol), the same procedure as in Reference Example 1 was carried out to obtain a diastereomer mixture of ethyl (2RS,4S)-4-methyl-3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,3-oxazolidine-2-carboxylate. The obtained diastereomer mixture was purified by thin layer chromatography (1 mm, hexane/EtOAc=66/34) to obtain ethyl (2S,4S)-4-methyl-3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,3-oxazolidine-2-carboxylate (colorless oil). By using the obtained colorless oil as the raw material, the same procedure as in Reference Example 4 was carried out to obtain the title compound (0.19 g) (colorless solid).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][OH:9])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cc1cccnc1Br
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: Cc1ccccc1
Product: Cc1cccnc1-c1ccc(CO)cc1
Yield: 45.9 %

Procedure:
A mixture of 2-bromo-3-methylpyridine (22.5 g, 0.1312 mol), 4(hydroxymethyl)phenylboronic acid (25 g, 0.164 mol), Pd(PPh3)4 (9.5 g, 0.0082 mol), and sodium carbonate (200 g in 500 ml of water) in toluene (750 ml) were refluxed under nitrogen atmosphere for 15 h. Separated the toluene layer and distilled under reduced pressure to give a residue. The residue was then purified by column chromatography to yield [4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 47%).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O.[OH-].[NH4+]>>[Cl:16][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cccc1-c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ncccc1-c1ccccc1
Temperature: 0 °C
Yield: 31 %

Procedure:
A solution of 3-phenyl-2-(1H)-pyridone (VIII; 20.0 g, 0.12 mole) and phosphorus oxychloride (300 mL) was refluxed for 6 hr and then slowly poured over crushed ice (300 mL). The resulting solution was made basic with ammonium hydroxide which led to formation of a precipitate. The mixture was extracted with ethyl ether (3×500 mL) and the combined organic extracts were dried (Na2SO4). Concentration in vacuo gave a solid which was recrystallized from ethyl acetate to yield 7.0 g (31%) of 2-chloro-3-phenylpyridine (VI), m.p. 52°-56°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1[CH:16]=[C:15]([O:17]C)[C:14]([CH:19]([CH3:21])[CH3:20])=[C:13]([O:22]C)[CH:12]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1[CH:12]=[C:13]([OH:22])[C:14]([CH:19]([CH3:20])[CH3:21])=[C:15]([OH:17])[CH:16]=1
Reactant: COc1cc(C=Cc2ccc(F)cc2F)cc(OC)c1C(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1c(O)cc(C=Cc2ccc(F)cc2F)cc1O
Yield: 44 %

Procedure:
This material was prepared from 1-(2,4-difluorophenyl)-2-(3,5-dimethoxy-4-i-propylphenyl)ethene and pyridine hydrochloride in 44% yield in the same way as described in example 34. 1HNMR (CDCl3, ppm): δ 1.41 (d, J=7.1 Hz, 6H), 3.49 (qint, J=7.1 Hz, 1H), 4.78 (br, 2H), 6.54 (s, 2H), 6.69-7.02 (m, 3H), 7.13 (d, J=16 Hz, 1H), 7.41-7.75 (m, 1H).
Reaction SMILES: COC(=O)[C@@H](N(C(OCC1C=CC=CC=1)=O)CC=O)C.N[C@@H](CCCO)CO.[CH2:29]([O:36][C:37]([N:39]1[CH2:51][CH:43]2[O:44][CH2:45][CH2:46][CH2:47][C@@H:48]([CH2:49][OH:50])[N:42]2[C:41](=[O:52])[C@@H:40]1[CH3:53])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([O:36][C:37]([N:39]1[C@@H:40]([CH3:53])[C:41](=[O:52])[N:42]2[C@@H:48]([CH2:47][CH2:46][CH2:45][OH:44])[CH2:49][O:50][CH:43]2[CH2:51]1)=[O:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OCCC[C@H]2CO
Agent: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Agent: N[C@H](CO)CCCO
Product: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CCCO

Procedure:
Condensation of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 1) with (S)-2-amino-pentane-1,5-diol in analogy with examples 1/2F produced a nearly statistical mixture of the title compound [light yellow gum, MS: 349.3 (M+H)+] and (3S,5S)-5-hydroxymethyl-3-methyl-4-oxo-octahydro-9-oxa-2,4a-diaza-benzocycloheptene-2-carboxylic acid benzyl ester [light yellow gum, MS:349.3 (M+H)|], which were separated by column chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13]O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>[Pd].CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(CO)Cc1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1
Yield: 94 %

Procedure:
A mixture of 153 parts of 3-p-tertiary butylphenyl-2-methyl-propanol, 70 parts of piperidine, 230 parts of methanol and 20 parts of catalyst, comprising 0.5% by weight of Pd and 5% by weight of Nd2O3 on Al2O3, is hydrogenated in a stirred autoclave of 1,000 parts by volume capacity, at 70° C. under a hydrogen pressure of 50 bar, until the pressure remains constant. The autoclave is then allowed to cool, the catalyst is filtered off and the filtrate is purified by distillation. 195 parts of N-(3'-(p-tertiary butylphenyl)-2'-methylpropyl)-piperidine, boiling point 117° C./0.2 mm Hg, are obtained. The yield is 94% of theory.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:6]=1)=[O:4]>C(O)(C)C>[OH:4][CH2:3][C:5]1[N:10]=[C:9]([C:11]([F:13])([F:12])[F:14])[N:8]=[C:7]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C=O)nc(C(F)(F)F)n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(CO)nc(C(F)(F)F)n2)CC1
Reaction time: 1.5 h

Procedure:
Sodium tetrahydroborate (73 mg, 1.9 mmol) was added to a solution of tert-butyl 4-{[6-formyl-2-(trifluoromethyl)pyrimidin-4-yl]amino}piperidine-1-carboxylate (0.90 g, 1.9 mmol, from Step 3) in Isopropyl alcohol (15 mL) at 0° C. After stirring at this temperature for 1.5 hours, the reaction was quenched by the addition of saturated ammonium chloride. The mixture was further diluted with water and extracted with EtOAc. The organic extract was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on a 40 g silica gel cartridge, eluting with a gradient from 0-100% EtOAc in hexanes afforded product as a white solid (0.58 g, 80% over the two steps). 1H NMR (400 MHz, CDCl3) δ 6.50 (s, 1H), 4.66 (d, J=5.1 Hz, 2H), 4.30-3.89 (m, 2H), 2.95 (t, J=12.0 Hz, 2H), 2.73 (t, J=5.2 Hz, 1H), 2.22-1.88 (m, 2H), 1.53-1.33 (m, 11H). 19F NMR (376 MHz, CDCl3) δ −71.74 (s). LCMS (M+H)+: 377.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[O:20][CH3:21])[CH:7]=[CH:6][C:5]=1[NH2:22]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[O:20][CH3:21])[CH:7]=[CH:6][C:5]=1[NH:22][C:3]([O:2][CH3:1])=[O:23]
Reactant: COC(=O)c1cc(CCc2cc(OC)ccc2OC)ccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc(CCc2cc(OC)ccc2OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 115 mg of 5-[2-(2,5-dimethoxyphenyl)ethyl]-2-amino benzoic acid methylester and 50 mg of 4-dimethylaminopyridine in 6 ml of dry dichloromethane is treated with 35 mg of methyl chloroformiate and stirred for 3 hours at room temperature. Then the mixture is poured onto aqueous pH7 buffer solution and extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by silica gel chromatography (cyclohexane/ethyl acetate=8/1) to yield the title compound as colourless crystals. mp: 80-82°.