Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH2:27]([O:34]CCCO)[C:28]1C=CC=C[CH:29]=1>[Pd].[H][H]>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:29][CH2:28][CH2:27][OH:34])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Reactant: [H][H]
Reactant: OCCCOCc1ccccc1
Agent: [Pd]
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCO)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 and 3-(benzyloxy)propan-1-ol using an analogous procedure to that outlined in the preparation of Compound 210 followed by debenzylation using Pd/C—H2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (t, J=7.33 Hz, 3H) 2.01 (t, J=6.19 Hz, 2H) 2.27 (s, 3H) 3.41 (q, J=7.33 Hz, 2H) 3.72 (q, J=5.98 Hz, 2H) 4.30 (t, J=6.19 Hz, 2H) 4.57 (t, J=5.18 Hz, 1H) 7.06-7.17 (m, 2H) 7.55 (s, 1H) 7.85 (t, J=7.71 Hz, 1H) 8.00 (br. s., 1H) 7.98 (d, J=5.05 Hz, 2H) 8.08 (s, 1H) 8.28 (s, 1H) 11.99 (s, 1H); ESI-MS: m/z calc'd for C23H24N2O4S 424.15; found 425.3 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.O=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.[C-:20]#[N:21].C([Al+]CC)C>ClCCCl.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:20]([C:9]1([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)#[N:21]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: [C-]#N
Reactant: OC1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Al+]CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)N1CCC(C#N)(N2CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.1 %

Procedure:
To a stirred solution of 4-hydroxypiperidine (1.01 g, 10.0 mmol) and ethyl 4-oxopiperidine-1-carboxylate (1.71 g, 10.0 mmol) in 1,2-dichloroethane (25 mL) was added titanium isopropoxide (2.3 mL, 11.0 mmol), and the mixture was stirred at room temperature for 18 h. Then a 1.0 M solution of diethylaluminum cyanide (24.0 mL, 24.0 mmol) was added at room temperature, stirred for 24 h, and diluted with EtOAc. The reaction was quenched at 0° C. with saturated NaHCO3 (10 mL) and the mixture was further stirred for 2 h. The mixture was then filtered through Celite and the filtrate was concentrated in vacuo and purified by flash chromatography (ethyl acetate/hexane) to afford the title compound (2.45 g, 87%) as an oil. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.19 (t, J=7.08 Hz, 3H), 1.45-1.67 (m, 4H), 1.85 (d, J=10.16 Hz, 2H), 2.00 (d, J=12.89 Hz, 2H), 2.20-2.28 (m, 2H), 2.81-2.92 (m, 2H), 3.04-3.23 (m, 3H), 3.58-3.71 (m, 1H), 3.81-3.98 (m, 2H), 4.06 (q, J=7.08 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[S:24])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][C:16](=[O:18])[C:15]([C:19](=O)[CH2:20][CH3:21])=[C:14]([OH:23])[CH2:13]2)=[CH:8][CH:7]=1)[CH3:2].[CH2:25]([O:27][NH2:28])[CH3:26]>C(Cl)(Cl)Cl>[CH2:25]([O:27][N:28]=[C:19]([C:15]1[C:16](=[O:18])[CH2:17][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:4]([NH:3][CH2:1][CH3:2])=[S:24])=[CH:11][CH:10]=2)[CH2:13][C:14]=1[OH:23])[CH2:20][CH3:21])[CH3:26]
Reactant: CCNC(=S)Nc1ccc(C2CC(=O)C(C(=O)CC)=C(O)C2)cc1
Reactant: CCON
Solvent: ClC(Cl)Cl
Product: CCNC(=S)Nc1ccc(C2CC(=O)C(C(CC)=NOCC)=C(O)C2)cc1
Reaction time: 15 h
Yield: 88.9 %

Procedure:
Into 10 ml of chloroform was dissolved 1.4 g of 5-{4-[3-(ethyl)thioureido]phenyl}-3-hydroxy-2-propionyl-2-cyclohexen-1-one and to the solution was added 1.0 g of ethoxyamine. The mixture was kept for 15 hours at room temperature and the reacting mixture was washed with a dilute hydrochloric acid solution and water. The solution was dried with anhydrous magnesium sulfate and the chloroform was distilled off from it under reduced pressure and 1.4 g of the desired compound was obtained. It was in the form of colorless crystals having a decomposition point of 116°-118° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22](=O)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[CH3:2][C:3]1[C:11]([C:12]2[S:14][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:22]([CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:13]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)C1CCOCC1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1C1CCOCC1
Yield: 79.3 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (400 mg, 1.8 mmol) produced in Example 11-B(v), ethyl 2-chloro-3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (1.0 g, 4.3 mmol) produced above and 2-propanol (40 mL) as starting materials and in the same manner as in Example 11-B(vi), the title compound (530 mg, 81%) was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27](=[O:30])[CH2:28][CH2:29][N:23]4[N:22]=3)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1.[CH2:41](O)[CH2:42][OH:43].O.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)(C(F)(F)F)=O>C1C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:26][C:27]5([CH2:28][CH2:29][N:23]4[N:22]=3)[O:43][CH2:42][CH2:41][O:30]5)=[CH:16][C:15]=2[O:39][CH3:40])[CH:13]=1
Reactant: OCCO
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2nc3n(n2)CCC2(CC3c3ccc(F)cc3)OCCO2)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Yield: 35 %

Procedure:
A solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (84 mg, 0.180 mmol, from example 137) in benzene (1 mL) was treated with ethylene glycol (0.011 mL, 0.198 mmol), and 4-methylbenzenesulfonic acid, hydrate (34.2 mg, 0.180 mmol). The mixture was heated to reflux using a Dean-Stark trap for 6 h, the mixture was cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate and the combined organic layers were combined and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (39.4 mg, 34% yield) as a TFA salt. LC-MS (M+H)+ 511.3. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.75 (1 H, br. s.), 7.30-7.33 (1 H, m), 7.25-7.29 (2 H, m), 7.09-7.17 (3 H, m), 7.06 (1 H, br. s.), 7.02 (1 H, dd, J=8.5, 2.4 Hz), 4.45-4.54 (1 H, m), 4.32-4.42 (2 H, m), 4.02-4.11 (4 H, m), 3.83 (3 H, s), 2.32-2.40 (1 H, m), 2.23 (1 H, d, J=13.7 Hz), 2.08-2.19 (2 H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:32][S:33]([O:22][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: OC(c1ccc(F)cc1)C(c1cccnc1)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)OC(c1ccc(F)cc1)C(c1cccnc1)c1cccnc1
Reaction time: 10 h

Procedure:
To the solution of 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethanol (0.2 g, 0.68 mmol) in THF (4 mL) was added i-Pr2NEt (0.4 mL, 2.3 mmol) at 0° C. followed by methanesulfonyl chloride (0.1 mL, 1.3 mmol). The reaction mixture was stirred for 10 h. Diluted with saturated NaHCO3 and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give 1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl methanesulfonate. LRMS m/z (M+H) Calcd: 373.4. found: 373.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH:22]=O)=[CH:7]2.CC1C=CC=C2C=1N=C(C1C=CC=CC=1C(F)(F)F)C(CO)=C2.O=S(Cl)[Cl:49]>C1COCC1.C(Cl)(Cl)Cl>[Cl:49][CH2:22][C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:20])([F:21])[F:19])=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1]
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3C(F)(F)F)nc12
Reactant: O=S(Cl)Cl
Agent: Cc1cccc2cc(CO)c(-c3ccccc3C(F)(F)F)nc12
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1cccc2cc(CCl)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure B using 8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde (1.6541 g, 5.25 mmol) and solid NaBH (0.2977 g, 7.87 mmol, 1.5 eq) in THF (26 mL) followed by Procedure C using the crude (8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanol and SOCl2 (1.9 mL, 26.23 mmol, 5 eq) in CHCl3 (26 mL). After purification, 3-(chloromethyl)-8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline was obtained as yellow syrup. 1H NMR (DMSO-d6) δ ppm 8.60 (1 H, s), 7.92 (2 H, dd, J=11.5, 8.0 Hz), 7.72-7.85 (2 H, m), 7.67 (2 H, dd, J=14.3, 7.2 Hz), 7.54-7.62 (1 H, m), 4.71 (2 H, dd, J=89.8, 11.9 Hz), 2.62 (3 H, s). Mass Spectrum (ESI) m/e=336.1 (M+1).
Reaction SMILES: [Mg].[CH2:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH:3]=[CH2:4].[B:12]([O:17]C)([O:15]C)[O:13]C.Cl>O1CCCC1>[CH2:2]([C:5]1[CH:10]=[CH:9][C:8]([O:13][B:12]([OH:17])[OH:15])=[CH:7][CH:6]=1)[CH:3]=[CH2:4]
Reactant: COB(OC)OC
Reactant: C=CCc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCc1ccc(OB(O)O)cc1
Yield: 65.8 %

Procedure:
To a mixture comprising sufficiently dried metal magnesium (120 mmol) and 30 ml of tetrahydrofuran (hereinafter referred to as THF), was gradually added a solution of 120 mmol of the 4-allyl-bromobenzene in 200 ml of THF to prepare a Grignard reagent. To this reagent was added dropwise a solution of trimethyl borate (120 mmol) in 100 ml of THF at a temperature not exceeding -65° C., stirred for a whole day and night. Subsequently, the mixture was kept at 0° C., 200 ml of 10% hydrochloric acid was gradually added thereto at the same temperature, and then the reaction mixture was stirred for 30 min. The mixture thus obtained was extracted twice with 500 ml of diethyl ether, the organic layer was washed with a saturated brine solution, and then the solvent was removed under a reduced pressure. The residue was sufficiently washed with 500 ml of heptane and then dried to obtain 4-allylphenyl boric acid (79 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1([CH2:11]C(O)=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N-:16]=[N+]=[N-].[N-]=C=O>>[NH2:16][CH2:11][C:5]1([CH2:4][C:3]([O:2][CH3:1])=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COC(=O)CC1(CC(=O)O)CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [N-]=C=O
Product: COC(=O)CC1(CN)CCCCC1

Procedure:
1,1-Cyclohexanediacetic acid monomethyl ester is converted via the corresponding acid chloride into the azide. The azide is degraded by the Curtius method to the isocyanate. The isocyanate is then hydrolyzed to give methyl 1-aminomethyl-1-cyclohexaneacetate. Heating this substance in alkaline methanol under reflux for three days affords 8-azaspiro[5,4]decan-9-one or gabapentin lactam. GBP-L was characterized by means of Thin Layer Chromatography, Infrared-Spectroscopy, [1H]-NMR and [13C]-NMR (Nuclear Magnetic Resonance Spectroscopy) and FAB-MS (Fast Atom Bombardment Mass Spectroscopy).
Reaction SMILES: [F:1][C:2]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[Mg]Br>>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:4]([C:3]1[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([F:15])([F:16])[F:17])[C:2]=1[F:1])=[O:5]
Reactant: COc1ccc([Mg]Br)c(OC)c1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1F
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)c(OC)c1

Procedure:
Prepared according to Method A step B from 2-fluoro-3-trifluoromethyl-N-methoxy-N-methylbenzamide (4.42 g, 17.6 mmol) and 2,4-dimethoxyphenylmagnesium bromide (32 mL, 0.5 M in THF) to give 1.67 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)[N:12]([C:20]3[CH:29]=[CH:28][C:23]4[O:24][CH2:25][CH2:26][O:27][C:22]=4[CH:21]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ON1C2C=CC=CC=2N=N1.Cl.[CH3:41][N:42](C)[CH2:43]CCN=C=NCC.C(N(C(C)C)C(C)C)C.Cl.CNC>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([CH2:15][CH2:16][C:17]([N:42]([CH3:43])[CH3:41])=[O:19])[N:12]([C:20]3[CH:29]=[CH:28][C:23]4[O:24][CH2:25][CH2:26][O:27][C:22]=4[CH:21]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCc1nc(Nc2ccc(F)c(F)c2)nn1-c1ccc2c(c1)OCCO2
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(C)C(=O)CCc1nc(Nc2ccc(F)c(F)c2)nn1-c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound E1 (prepared according to Ex.1) (0.00062 mol) was dissolved in DMF (5 ml). 1-Hydroxy-1H-benzotriazole (0.00186 mol), (3-Dimethylamino-propyl)-ethyl-carbodiimide.hydrochloride (1:1) (0.00186 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.00248 mol) were added, followed by addition of dimethylamine hydrochloride (1:1) (0.00124 mol). The reaction mixture was stirred for 3 hours at r.t. The reaction mixture was poured into water. The mixture was extracted with CHCl3. The organic layer was separated, washed with a 1M HCl solution, then washed with brine and filtered through a hydrophobic frit. The solvents were evaporated under reduced pressure to give a yellow solid residue that was dried further for one hour (in the GeneVac®). The residue was triturated with diethyl ether, filtered off and dried. Yield: 0.245 g of compound E3 (92%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[NH4+].[Cl-]>C(Cl)Cl>[O:31]1[CH2:32][CH2:33][N:28]([S:2]([C:5]2[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3])[CH2:29][CH2:30]1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1.3 h

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (0.3 g, 991 μmol, Buttpark Ltd.) in CH2Cl2 (1.0 mL) were added DIPEA (192 mg, 260 μL, 1.49 mmol) and morpholine (86.4 mg, 86.4 μL, 991 μmol). The clear light yellow solution was stirred at room temperature for 1.3 hours and then poured on saturated aqueous NH4Cl solution and CH2Cl2. The layers were separated and the aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. Light brown solid (0.357 g; 91%). MS (EI): m/z=353 [M].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[H][H]>[Pd]>[C:4]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([O:3][CH2:1][CH3:2])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Pd]
Product: CCOC(=O)C1CCC(=O)CC1

Procedure:
Into a 1-liter magnetically stirred autoclave is placed 489 grams of ethyl-p-hydroxybenzoate having the structure: ##STR139## and 5% palladium on carbon catalyst (4 grams). The autoclave is sealed and hydrogenated at 125°-140° C. and 50 psig hydrogen pressure until the uptake of hydrogen is approximately 70% of theory. GLC analysis indicates that the reaction product at this point contains 71% ketone having the structure: ##STR140## 7.6% alcohol having the structure: ##STR141## and 20% starting material having the structure: ##STR142##
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([N:26]2[C:30](=[O:31])[CH2:29][NH:28][C:27]2=[O:32])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])C1C=CC=CC=1>C(O)C.[Pd]>[F:19][C:17]([C:20]1[CH:21]=[C:22]([N:26]2[C:30](=[O:31])[CH2:29][NH:28][C:27]2=[O:32])[CH:23]=[CH:24][CH:25]=1)([F:18])[CH2:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: O=C1CNC(=O)N1c1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: O=C1CNC(=O)N1c1cccc(C(F)(F)COCCCCCCO)c1
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a solution of Intermediate 61 (2.52 g, 5.65 mmol) in ethanol (120 mL) was added palladium on charcoal (300 mg). The mixture was bidrogenated at 40 psi for 4 hours. The catalyst was filtered through Celite and the solvent removed under pressure to give the title compound (1.94 g, 96%) as oil.
Reaction SMILES: [N+:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])([O-])=O.[C:12](OC(=O)C)(=[O:14])[CH3:13].[H][H]>[Pd].CO>[OH:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=1[NH:1][C:12](=[O:14])[CH3:13]
Reactant: O=[N+]([O-])c1c(O)cccc1O
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1c(O)cccc1O
Yield: 65.2 %

Procedure:
A mixture of 2-nitro-1,3-benzenediol (1.55 g 10 mmol), acetic anhydride (1.59 g, 1.47 mL, 15 mmol) and 10% palladium on charcoal (0.3 g) in methanol (100 mL) was stirred in the atmosphere of hydrogen at atmospheric pressure for 2 h. The catalyst was filtered through celite, the solvent evaporated in vacuo. The oily residue was treated with dichloromethane to afford colourless crystals, which were collected by filteration and dried to give the subtitle compound (1.09 g, 65%).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>CO>[C:1]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)#[N:2]
Reactant: [C-]#N
Reactant: Oc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CO
Product: N#CCc1ccc(O)cc1
Yield: 45 %

Procedure:
A solution of p-chloromethyl phenol in acetonitrile (Example 12) was reacted with equimolar sodium cyanide in excess methanol (800 parts methanol/mole sodium cyanide) and the reaction mixture was refluxed for one hour. The oil after solvent evaporation (washed as in Experiment 18) was fractionated to yield 45% of α-cyano-p-cresol (b.p. 150°-155°/1 mm. of mercury; M.P. 68°-70°). Infrared spectra confirmed the identity of the product.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](SC)=[N:11][C:10]=2[CH:16]=1)(=[O:5])=[O:4].[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1>CC(N(C)C)=O>[CH2:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:12]2[O:13][C:9]3[CH:8]=[CH:7][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:17])[CH3:1])=[CH:16][C:10]=3[N:11]=2)[CH2:24][CH2:23]1)=[O:26])[CH3:29]
Reactant: CSc1nc2cc(S(=O)(=O)N(C)C)ccc2o1
Reactant: CCOC(=O)N1CCC(N)CC1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCC(Nc2nc3cc(S(=O)(=O)N(C)C)ccc3o2)CC1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
A mixture of 2-methylsulfanyl-benzooxazole-5-sulfonic acid dimethylamide (1.43 g, 5.25 mmol, 1.0 equiv) and ethyl 4-amino-1-piperidine carboxylate (1.36 g, 7.88 mmol, 1.5 equiv) in anhydrous DMAc (7.5 mL) was heated to 100° C. for 48 h. The solution was concentrated by evaporation under reduced pressure and the crude reaction product purified with column chromatography on silica eluting with ethyl acetate/hexane (2:1) to give 1.40 g (67%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.19 (t, J=7.1 Hz, 3H), 1.37-1.49 (m, 2H), 1.94-1.99 (m, 2H), 2.59 (s, 6H), 2.94-3.02 (m, 2H), 3.80-3.83 (m, 1H), 3.91-3.95 (m, 2H), 4.04 (q, J=7.1 Hz, 2H), 7.39 (dd, J=8.2 Hz, J=1.8 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 8.39 (d, J=7.6 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 14.56, 31.07, 37.62, 42.05, 49.70, 60.65, 108.88, 114.22, 120.40, 130.37, 143.98, 150.67, 154.59, 162.76. MS (ISP): 397.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:15]=[C:16]2[NH:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([N:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[N:20][C:17]2=[N:18][CH:19]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:13][C:14]2[CH:15]=[C:16]3[NH:22][C:21]([C:23]4[CH:24]=[CH:25][C:26]([N:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=4)=[N:20][C:17]3=[N:18][CH:19]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(-c2nc3ncc(N)cc3[nH]2)cc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Product: CN(C)c1ccc(C(=O)Nc2cnc3nc(-c4ccc(N(C)C)cc4)[nH]c3c2)cc1

Procedure:
Compound 631 was prepared according to the procedure similar to that described in Scheme III from 4-dimethylaminobenzoic acid and 6-amino-2-(4-dimethylaminophenyl)-1H-imidazo[4,5-b]pyridine. [M+H]+ calcd for C23H24N6O: 401.20; found 401.07.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH2:19][OH:20])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:30][C:31]([O:20][CH2:19][C@H:10]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:33]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC[C@@H](COCc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)OC[C@@H](COCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 200 %

Procedure:
A mixture consisting of 0.50 ml (1.98 mmol) of (S)-(−)-1,2-dibenzylglycerol and 0.69 ml (3.96 mmol) of N,N-diisopropylethylamine was dissolved in 5 ml of dichloromethane. The obtained solution was added dropwise to 5 ml of a dichloromethane solution containing 294 mg (0.99 mmol) of triphosgene under cooling on ice. The obtained mixture was stirred at a room temperature for 30 minutes. Thereafter, the reaction solution was concentrated, and the concentrate was then dissolved in 5 ml of dichloromethane, so as to obtain a dichloromethane solution of (R)-2,3-bis-benzyloxy-propyl chloroformate (1.98 mmol/5 ml).
Reaction SMILES: CS(O[CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[N:21]([CH:6]1[CH2:9][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH2:7]1)=[N+:22]=[N-:23]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(OS(C)(=O)=O)C2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC(N=[N+]=[N-])C2)C1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of 0.46 g (1.51 mmol) of tert-butyl 2-methanesulfonyloxy-6-azaspiro[3.4]octane-6-carboxylate, prepared in step 6.2., and 0.19 g (3.01 mmol) of sodium azide in 5 mL of N,N-dimethylformamide is refluxed for 12 hours under an inert atmosphere. The reaction medium is allowed to cool to room temperature and is then taken up in ethyl acetate and water. The aqueous phase is separated out and extracted twice with ethyl acetate, and the combined organic phases are washed with saturated aqueous ammonium chloride solution and dried over sodium sulfate. After evaporating off the solvent, 0.380 g of product is obtained in the form of an orange-coloured oil, which is used without further purification in the following step.