Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([CH3:20])[CH2:5][C@@H:6]1[CH2:10][N:9]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:8](=[O:19])[CH2:7]1.[H-].[Na+].[CH3:23]I>CS(C)=O.O>[CH3:23][O:1][CH2:2][CH2:3][CH:4]([CH3:20])[CH2:5][C@@H:6]1[CH2:10][N:9]([C@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[C:8](=[O:19])[CH2:7]1
Reactant: CC(CCO)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCCC(C)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To alcohol 89 (2 g, 7.66 mmol) in DMSO (60 mL) at room temperature was added NaH (368 mg, 60% in oil). After 30 minutes the methyl iodide (1.08 g, 7.66 mmol) was added and the solution stirred at room temperature overnight, upon which the reaction was diluted with water (500 mL). The solution was extracted with ether, and the combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (90% to 50% hexane/acetone) of the residue gave the product 90 as an oil (1.1 g, 52%). MS m/z 290 (M+H, 100%).
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[C:11]([C:12]3[CH:35]=[CH:34][C:15]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=4)[C:21]([N:23]4[CH2:30][CH2:29][CH2:28][C@H:24]4[C:25]([OH:27])=[O:26])=[O:22])=[CH:14][CH:13]=3)=[CH:10][C:9]([F:36])=[C:8]([F:37])[C:6]=2[CH:7]=1)#[N:2].Cl.[NH2:39][OH:40].C(N(CC)CC)C>C(O)C>[NH2:2][C:1](=[N:39][OH:40])[C:3]1[O:4][C:5]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=4)[C:21]([N:23]4[CH2:30][CH2:29][CH2:28][C@H:24]4[C:25]([OH:27])=[O:26])=[O:22])=[CH:34][CH:35]=3)=[CH:10][C:9]([F:36])=[C:8]([F:37])[C:6]=2[CH:7]=1
Reactant: NO
Reactant: N#Cc1cc2c(F)c(F)cc(-c3ccc(OCc4cccc(C(=O)N5CCC[C@H]5C(=O)O)c4)cc3)c2o1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1cc2c(F)c(F)cc(-c3ccc(OCc4cccc(C(=O)N5CCC[C@H]5C(=O)O)c4)cc3)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
The compound (20 mg, 0.04 mmol) of Example 54 was dissolved in ethanol (5 mL), and hydroxylamine hydrochloride (14 mg, 0.21 mmol) and triethylamine (0.058 mL, 0.42 mmol) were added thereto, and stirred at room temperature for 2 hours. After that, the solvent was distilled away, and the resulting residue was purified by reversed-phase HPLC in the same manner as in Step 2 of Example 1 to thus obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: C[C@H](C(=O)O)c1ccc(Cl)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Solvent: CO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)[C@@H](C)c2ccc(Cl)cc2)CC1

Procedure:
Example 166 was prepared from (2S)-2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D=+5.2° (C=1.03, MeOH): 1H NMR (400 MHz, CDCl3) δ 7.55 (d, 1 H, J=2.0 Hz), 7.46 (s, 1 H), 7.34–7.24 (m, 4 H), 7.23–7.17 (m, 1 H), 7.07 (d, 1 H, J=8.0 Hz), 7.04–6.97 (m, 1 H), 3.54 (q, 1 H, J=7.2 Hz), 3.41–3.24 (m, 2 H), 2.95 (ABq, 2 H), 2.72–2.59 (m, 1 H), 2.57–2.45 (m, 1 H), 2.42–2.37 (m, 2 H), 2.27 (s, 3 H), 2.05–1.91 (m, 2 H), 1.82–1.55 (m, 6 H), 1.50 (d, 3 H, J=6.8 Hz), 1.22 (d, 6 H, J=6.8 Hz); ESMS m/e: 484.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]([CH3:11])[C@@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH2:5].C(N(CC)CC)C.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.C(OCC)(=O)C>[CH2:21]([O:28][C:29]([NH:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C@H:3]([C:2]([F:12])([F:13])[F:1])[CH3:11])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
23.5 g of ethyl (3R)-4,4,4-trifluorovalinate (diastereomer mixture, crude product about 70%) and 18.1 ml (130 mmol) of triethylamine were dissolved in 235 ml of THF, and 32.3 g (130 mmol) of N-(benzyloxycarbonyloxy)succinimide were added. The reaction mixture was stirred at RT overnight and then diluted with ethyl acetate. The mixture was washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 6:1). This gave 22.1 g of the target product (about 80% of theory, diastereomer ratio about 2:1).
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1.C1N2CN3CN(C2)CN1C3.[C:25](O)(=[O:27])C.Cl>O>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:3][CH:4]=2)[C:9]=1[CH:25]=[O:27]
Reactant: CC(=O)O
Reactant: COc1ccc2cc(CBr)ccc2c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: COc1ccc2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-bromomethyl-6-methoxynaphthalene (12.68 g), hexamine (14 g), glacial acetic acid (21 ml) and water (21 ml) were heated under reflux with stirring for 30 minutes. Concentrated hydrochloric acid (16.6 ml) was then added and the mixture stirred and refluxed for a further 15 minutes. The reaction was cooled to room temperature and extracted with toluene (2×25 ml). The combined toluene extracts were washed with water (2×10 ml), saturated sodium bicarbonate solution (2×10 ml) and water (1×8 ml) and the toluene solution dried over MgSO4. The drying agent was filtered off and the solvent was removed by distillation under vacuum. This afforded 8.6 g of crude product which was recrystallised twice from isopropanol (2×50 ml) to give 6.07 g of 97.8% purity 2-methoxynaphthaldehyde as a light beige solid. The material had a melting point of 79.2° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[N:3]=1.COC1C=CC=CC=1C1N=[C:37]([NH:39][CH2:40][C:41]2[O:42][C:43]([CH3:46])=[N:44][N:45]=2)C2C(=CC(C)=CC=2)N=1.C(O)(=O)C(O)=O.CC1OC(CN)=NN=1.C(N(CC)CC)C>CN(C=O)C>[CH3:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:39]([CH3:37])[CH2:40][C:41]3[O:42][C:43]([CH3:46])=[N:44][N:45]=3)=[N:3][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccccc1-c1nc(Cl)c2ccc(C)cc2n1
Reactant: COc1ccccc1-c1nc(NCc2nnc(C)o2)c2ccc(C)cc2n1
Agent: Cc1nnc(CN)o1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N(C)Cc3nnc(C)o3)nc(-c3ccccc3O)nc2c1
Reaction time: 6 h
Yield: 56 %

Procedure:
[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine 4-Chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline (400 mg, 1.48 mmol) was dissolved in 10 ml dry DMF followed by the addition of C-(5-Methyl-[1,3,4]oxadiazol-2yl)-methylamine oxalate (234 mg, 1.48 mmol) then triethylamine (413 μl, 2.96 mmol). After 6 hours the reaction was complete, partitioned between EtOAc and water. The organic phase was separated, dried over MgSO4, filtered and concentrated to an oil. Purified by flash chromatography 60% EtOAc/40% hexanes to afford the desired product a white solid. Recovered 290 mg 56% yield. LC/MS (10-99%) M/Z 348.4, retention time 2.17 minutes.
Reaction SMILES: Cl[CH2:2][CH:3]([O:8][CH2:9][CH2:10][CH3:11])[O:4][CH2:5][CH2:6][CH3:7].CC(O)(CC)C.[OH-].[K+]>COC(C)(C)C>[CH2:5]([O:4][C:3]([O:8][CH2:9][CH2:10][CH3:11])=[CH2:2])[CH2:6][CH3:7]
Reactant: CCCOC(CCl)OCCC
Agent: [K+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CCC(C)(C)O
Product: C=C(OCCC)OCCC
Reaction time: 6 h

Procedure:
270.8 g (1.5 mol) of 1-chloro-2,2-dipropoxyethane, 450 ml of tert.-butyl methyl ether, 19.8 g (0.22 mol) of 2-methyl-2-butanol, 12 g of polyethylene glycol-1000 dimethyl ether and 300 g (4.5 mol) of technical grade potassium hydroxide (91%) were heated under reflux while stirring for six hours. The reaction was stopped, the salts filtered off and the product distilled. The conversion was 86.3% of theoretical. The main fraction contained 148.1 g (68.6% of theoretical) of pure 1,1-dipropoxyethene (b.p. 70° C. at 1.2 kPa) .
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:11]1[N:16]=[C:15]2[O:17][C:18]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:19]([C:20]([NH:22][CH3:23])=[O:21])[C:14]2=[CH:13][C:12]=1[CH:31]1[CH2:33][CH2:32]1)[S:7]([CH3:10])(=[O:9])=[O:8].[CH3:34][S:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:37])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:31]1([C:12]2[CH:13]=[C:14]3[C:19]([C:20](=[O:21])[NH:22][CH3:23])=[C:18]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[O:17][C:15]3=[N:16][C:11]=2[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH:38]([S:35]([CH3:34])(=[O:37])=[O:36])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[S:7]([CH3:10])(=[O:9])=[O:8])[CH2:33][CH2:32]1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCBr)S(C)(=O)=O)c(C3CC3)cc12
Reactant: CCOC(=O)CS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCN(c1nc2oc(-c3ccc(C)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O)S(C)(=O)=O
Temperature: 120 °C

Procedure:
To 6-(N-(4-bromobutyl)methylsulfonamido)-5-cyclopropyl-N-methyl-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide (4.5 mg, 8.42 μmol) was added ethyl 2-(methylsulfonyl)acetate (1.399 mg, 8.42 μmol) and CESIUM CARBONATE (5.49 mg, 0.017 mmol) and KI (1.398 mg, 8.42 μmol) and DMF Heated at 120° C. 20 min. Added water and extracted with EtOAc. Conc. on vac to oil. Added 3 mL ACN and 1 mL water. Filtered with 0.45μ filter Purified via HPLC C18 40-100% ACN/H2O (0.1% NH4OH) 40 mL/min over 10 min. to give ethyl 6-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-(p-tolyl)furo[2,3-b]pyridin-6-yl)methylsulfonamido)-2-(methylsulfonyl)hexanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH2:11]Cl)=[CH:4][CH:3]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[CH2:11][C:17]#[N:18])=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: Fc1ccc(Sc2ccccc2CCl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccccc1Sc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 26 h

Procedure:
12.0 g of 2-(4-fluorophenylthio)benzyl chloride are added portionwise over a 30 minute span to a mixture of 2.9 g of sodium cyanide in 120 ml of dimethylsulfoxide. After total addition, the reaction mixture is stirred for 26 hours before being poured onto 150-200 ml of crushed ice. The mixture is extracted four times with 70 ml portions of ether and the combined ether extracts are successively washed four times with 50 ml portions of water, washed once with 25 ml of a saturated sodium chloride solution and dried, providing 2-(4-fluorophenylthio)benzyl cyanide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].C([O:16][C:17]([C:19]1[C:20](Cl)=[N:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=O)C.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:20]2[N:21]=[C:22]([S:25][CH3:26])[N:23]=[CH:24][C:19]=2[C:17]1=[O:16])=[O:13])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCOC(=O)CCNC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CN(C2CCCC2)c2nc(SC)ncc2C1=O
Reaction time: 16 h

Procedure:
3-Cyclopentylamino-propionic acid ethyl ester (1.0 g, 5.4 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.25 g, 5.4 mmol) were combined in DCM (10 mL) and diisopropylethylamine (0.83 g, 6.5 mmol) was added. After 16 h, the solution was partitioned between water and DCM and the organic layer was dried (MgSO4) and concentrated. Chromatography (0-20% EtOAc/hexanes gradient) provided the title compound that was directly carried on to the next step. Sodium (25 wt % dispersion in paraffin wax, 0.25 g, 6.0 mmol) was added to t-butanol (5.0 mL) at rt. After 10 minutes, a solution of 4-[cyclopentyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.0 g, 5.4 mmol) in 10 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4) and concentrated to provide 0.26 g (14%). 1H-NMR (400 MHz, CDCl3:) 5 ppm 12.0 (br s, 1H), 8.20 (s, 1H), 5.10-5.18 (m, 1H), 4.26-4.31 (m, 3H), 3.72 (q, 2H, J=7.0 Hz), 2.50 (s, 3H), 1.63-1.86 (m, 5H), 1.20-1.35 (m, 5H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.C(N(CC)CC)C.[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34](O)=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[F:25][C:26]1[CH:27]=[C:28]([CH2:33][C:34]([NH:1][N:2]2[C:7](=[O:8])[C:6]3[CH:9]=[CH:10][S:11][C:5]=3[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:3]2)=[O:35])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: Nn1nc(-c2ccccc2)c2sccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccccc2)c2sccc2c1=O
Reaction time: 8 h
Yield: 12.3 %

Procedure:
A mixture of the product of Example 9B (31.6 mg, 0.13 mmol), triethylamine (0.028 mL, 0.20 mmol), 2-(3,5-difluorophenyl)acetic acid (25.4 mg, 0.15 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (49.8 mg, 0.16 mmol) in DMF (0.4 mL) was stirred overnight, diluted with EtOAc, washed with 1 N NaOH and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (12% EtOAc/CH2Cl2) to give the title compound as a white solid (6.2 mg, 0.016 mmol). 1H NMR (300 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.24 (d, J=5.2 Hz, 1H), 7.87-7.77 (m, 3H), 7.64-7.55 (m, 3H), 7.22-7.08 (m, 3H), 3.78 (s, 2H); MS (ESI−) M/Z 396.1 (M−H)−.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH2:3]1.[N-:25]=[N+]=[N-].[Na+].O.Cl>CN(C)C=O.C(OCC)(=O)C>[NH2:25][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)CO2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Reaction time: 1 h
Yield: 8.4 %

Procedure:
In 280 ml of N,N-dimethylformamide was dissolved 40.1 g of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. Thereto was added 13.9 g of sodium azide. The mixture was stirred for 1 hour at 70°-75° C. The reaction mixture was introduced into a mixed solvent consisting of 1.5 liters of water and 300 ml of ethyl acetate. The mixture was adjusted to pH 0.1 with conc. hydrochloric acid. The aqueous layer was separated, washed with 200 ml of ethyl acetate, adjusted to pH 4.0 with a 10% aqueous sodium hydroxide solution, and extracted with two 500-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The crystal was recrystallized from ethanol to obtain 2.84 g (yield: 82.1%) of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1 -benzopyran-4-one having a melting point of 162°-163° C.
Reaction SMILES: [OH-].[Na+].[C:3]1([C@H:9]([NH2:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>O>[C:3]1([C@H:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@@H](N)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H](NC(=O)C(C)(C)C)c1ccccc1
Reaction time: 1.5 h

Procedure:
In 1,300 ml of water is dissolved 130 g of sodium hydroxide and in the solution is suspended 188 g of (1R)-1-phenylethylamine, after which 287 ml of pivaloyl chloride is dropwise added to the suspension at 20° C. over 40 minutes. The resulting mixture is stirred at the same temperature for 1.5 hours and the crystals deposited are collected by filtration to obtain 289 g of N-[(1R)-1-phenylethyl]-2,2-dimethylpropanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].O>C(#N)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C(CCc1ccccc1O)NCCOc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccccc1CCC(=O)NCCOc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
N-(4-Chlorophenoxyethyl)-3-(2-hydroxyphenyl)propanamide (11.6 g, 36.3 mmol) was dissolved in acetonitrile (15 mL), and potassium carbonate (15.0 g, 109 mmol) was added thereto. Subsequently, tert-butyl 2-bromoisobutyrate (20.2 g, 90.7 mmol) was added thereto, followed by stirring for 4 days at 70° C. Subsequently, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with brine, and the resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (7.4 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1C(OC)=O.[CH3:13][Mg]Br.C([O:19][CH2:20][CH3:21])(=O)C>CCOCC>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:20]([OH:19])([CH3:21])[CH3:13]
Reactant: C[Mg]Br
Reactant: COC(=O)c1c(N)cccc1Cl
Reactant: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(O)c1c(N)cccc1Cl
Yield: 89 %

Procedure:
This compound was prepared using General Method 1 (EXAMPLE 1) from methyl 2-amino-6-chlorobenzoate (1.7 g, 9.2 mmol) and methyl magnesium bromide (3 M in diethyl ether, 12.2 mL) in 45 mL ether to afford 1.5 g (89%) of 2-(2-amino-6-chlorophenyl)propan-2-ol after flash chromatography (5:3 hexanes:ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.O.Cl.Cl.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>ClC(Cl)Cl>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]([CH:28]([CH3:30])[CH3:29])[C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)c1ccc(F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
4-fluorobenzoic acid chloride (3.7 cc) is added to a solution of 1-benzyl-4-isopropylaminopiperidine dihydrochloride hydrate (3.83 g) and triethylamine (15 cc) in trichloromethane (50 cc). After 6 hours' stirring at 20° C., water (50 cc) is poured in and the mixture is left to stand for 16 hours. Settling is allowed to take place and the aqueous phase is extracted with trichloromethane (50 cc). The organic phases are washed with water (50 cc), then dried over magnesium sulphate and concentrated to dryness under reduced pressure (5.2 kPa). The oil obtained is chromatographed on a column 4 cm in diameter containing silica gel (200 g), eluting first with a dichloromethane/ethanol mixture (95:5 by volume) (1400 cc) and collecting 60-cc fractions. The fractions between 480 and 1980 cc are concentrated to dryness to give an ocher solid which is recrystallized in a diisopropylether/ethanol mixture (95:5 by volume) to obtain N-(1-benzyl-4-piperidyl)-N-isopropyl-4-fluorobenzamide (1.2 g) in the form of a white solid, m.p. 98° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.Br.[Br:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(#N)C>[Br:18][CH2:19][CH2:20][CH2:21][NH:22][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NCCCBr
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1cc(NCCCBr)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.3 %

Procedure:
A solution of 2,4,6-trichloropyrimidine (100 g, 545 mmol) in acetonitrile (2000 mL) was added triethylamine (166 g, 1636 mmol) at 0° C., The reaction mixture was stirred for 5 min at rt, then 3-bromopropan-1-amine hydrobromide (119 g, 545 mmol) was added portionwise. The reaction mixture was stirred for 1 h at rt, and filtered to provide a clear solution. Purification via FC afforded the title compound as a white solid (47 g, 30% yield).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][OH:17])[C:13](=[O:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:26]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][O:17][CH3:26])[C:13](=[O:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 92.8 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-4-(hydroxymethyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (17.37 g, 46.75 mmol) in DCM (480 mL) was added N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (60.1 g, 280.51 mmol). Then it was cooled to 0° C. and trimethyloxonium tetrafluoroborate (20.74 g, 140.25 mmol) was added. It was then stirred at rt for 6 h. Then it was concentrated under reduced pressure. The residue was then taken up in 100 mL Et2O and filtered, washed with 400 mL Et2O. The organic layer was then washed with 10% citric acid, aq. NaHCO3, brine, dried over MgSO4, filtered and concentrated to afford the desired product (16.73 g, 93%) as an oil.