Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C#CC2CC3(CCN(C(OC(C)(C)C)=O)CC3)ON=2)C=CC=CC=1.[Cl:26][C:27]1[CH:28]=[C:29]([C:33]#[C:34][CH:35]=[N:36][OH:37])[CH:30]=[CH:31][CH:32]=1.[CH2:38]=[C:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[Cl:26][C:27]1[CH:28]=[C:29]([C:33]#[C:34][C:35]2[CH2:38][C:39]3([CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[O:37][N:36]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: C=C1CCOCC1
Reactant: ON=CC#Cc1cccc(Cl)c1
Agent: CC(C)(C)OC(=O)N1CCC2(CC1)CC(C#Cc1ccccc1)=NO2
Product: Clc1cccc(C#CC2=NOC3(CCOCC3)C2)c1

Procedure:
The title compound was prepared following the procedure described for Compound 1b, using Compound 31e instead of Compound 1a and 4-methylenetetrahydropyran (Tetrahedron, 46(7), 2411-2424, 1990) instead of tert-butyl 4-methylenepiperidine-1-carboxylate. After the usual work-up procedure, the residue was purified by means of automated flash chromatography (SP1 ®TM-Biotage; gradient Petroleum Ether-EtOAc from 10:1 to 8:2) to give the title compound as a yellowish solid. Yield: 23.7%.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[CH:10]=[N:11][O:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:20]1[CH:52]=[CH:51][C:23]([CH2:24][CH:25]2[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]2=[O:50])=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[CH:10]=[N:11][O:12][CH2:13][CH2:14][O:15][C:20]2[CH:52]=[CH:51][C:23]([CH2:24][CH:25]3[S:29][C:28](=[O:30])[N:27]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]3=[O:50])=[CH:22][CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCON=Cc1cccc(-c2ccccc2)c1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1SC(Cc2ccc(OCCON=Cc3cccc(-c4ccccc4)c3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 76.2 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 483 mg of 2-(3-phenylbenzylideneaminooxy)ethanol (prepared as described in Preparation 8), 716 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 525 mg of triphenylphosphine and 348 mg of diethyl azodicarboxylate, 807 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:21]2)[CH:12]=[CH:11]1>>[CH3:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]2)[CH:12]=[CH:11]1
Reactant: Cc1cccc(I)c1C
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4cc[nH]c34)CC2)c1
Product: Cc1cccc(-n2ccc3cccc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)c32)c1C

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2,3-dimethylbenzene and N-{3-[1-(1H-indol-7-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 480.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[ClH:19]>>[NH2:12][C:7]1[C:8]([Cl:19])=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[F:1]
Reactant: Cl
Reactant: O=[N+]([O-])c1cnccc1NCc1ccccc1F
Product: Nc1c(NCc2ccccc2F)ccnc1Cl
Reaction time: 0.75 h
Yield: 71 %

Procedure:
A mechanically stirred solution of 4-[(2-fluorobenzyl)amino]-3-nitropyridine (37.62 g, 152.17 mmol) in concentrated hydrochloric acid (400 mL) was heated to 90° under a nitrogen atmosphere. Stannous chloride dihydrate (174.88 g, 775.07 mmol) was added in small portions over a 20 min period. When the reaction became vigorous, the oil bath was removed until the reaction subsided. After 45 min at an increased temperature to 120° for 45 min, the reaction mixture was cooled, diluted with water (350 mL) and spin evaporated in vacuo. The residue was diluted with water (600 mL), cooled in an ice-bath and concentrated ammonium hydroxide (250 mL) was added to adjust the pH to 7-8. The solid were collected and allowed to air dry overnight. The solid cake was broken up and suspended in ethyl acetate (3×1 L). Each suspension was refluxed with the refluxing time varying from 3.5 hrs to 18 hrs. The ethyl acetate was filtered and evaporated in vacuo to yield 3-amino-2-chloro-4-[(2-fluorobenzyl)amino]pyridine (27.13 g, 71%) as an off-white solid, mp.=181°-187°. The analytical sample was prepared by essentially the same preparative method and was purified by column chromatography.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:16])=O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(F)c(C(=O)O)cc1Br
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(F)c(C(=O)Cl)cc1Br
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, 5-bromo-2-fluoro-4-methoxybenzoic acid (10.0 g) was suspended in DMF/toluene solution (50 mL) (DMF concentration: 300 ppm). To the suspension was added dropwise thionyl chloride (5.73 g) at 70° C. After stirring at 70° C. for 2 hr, the completion of the reaction was confirmed by HPLC. Toluene and excess thionyl chloride were evaporated under reduced pressure. To the concentrated residue was added toluene (30 mL), and the mixture was concentrated again under reduced pressure. To the obtained acid chloride (5-bromo-2-fluoro-4-methoxybenzoic acid chloride) was added toluene (30 mL), and the mixture was directly used in the next step.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][OH:11].Cl>C(N(CC)CC)C>[OH:11][NH:10][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:8]
Reactant: NO
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)C1CCCCC1)NO
Yield: 38 %

Procedure:
Following the procedure described in Example 18, step 2, 3, but substituting 2-cyclohexylcarbonyl chloride for benzoyl chloride, and then the resulting carboxylic acid was substituted for 37 in Example 14, step 3, using 1.1 equivalent of NH2OH.HCl and triethylamine each, to afford the title compound 102 obtained in 38% yield. 1H NMR (300 MHz, CDCl3): δ 2.45 (t, J=6.9 Hz, 2H), 2.36 (m, 2H), 2.10 (m, 2H), 1.80-1.25 (m, 17H). 13C NMR (75 MHz, 20% CD3OD in CDCl3): δ 23.13, 25.00, 25.35, 25.53, 28.22, 28.50, 28.51, 32.47, 40.27, 50.61, 177.11, 215.62.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].B(F)(F)F.CCOCC.Cl.[OH-].[Na+]>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]1([NH2:9])[CH2:2][CH2:1]1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccccc1Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Product: NC1(c2ccccc2Br)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 13.7 %

Procedure:
Ethyl magnesium bromide (20.14 ml, 60.4 mmol) was added dropwise to a stirred, cooled −78° C. mixture of 2-bromobenzonitrile (5.0 g, 27.5 mmol) and titanium isopropoxide (8.59 g, 30.2 mmol) in ether (100 ml) and the mixture was stirred at −78° C. for 10 minutes. The yellow solution was warmed to ambient temperature and held for 1 hour. Boron trifluoride etherate (7.8 g, 54.9 mmol) was added dropwise and the mixture was stirred for 1 hour. 1 N HCl (90 ml) was added and the mixture was stirred for 10 minutes. Added 300 ml 1N NaOH and then extracted with ether. The organic portion was washed with brine, dried (MgSO4) and the solvent removed in vacuo. Purification by flash chromatography on 80 g of silica, eluting with a gradient of 0-100% EtOAc in hexanes afforded 0.80 g, 14% of 7-1 as yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[Br:14]Br>C(O)(=O)C>[C:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([Br:14])=[CH:8][CH:7]=2)#[N:2]
Reactant: N#Cc1cc2ccccc2[nH]c1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: N#Cc1cc2cc(Br)ccc2[nH]c1=O
Temperature: 25 °C

Procedure:
A suspension of 3-cyano-2-[1H]-quinolone (13.3 g) in acetic acid (130 cm3) was treated at room temperature with a solution of bromine (4.1 cm3) in acetic acid (10 cm3). After heating under reflux for 4 hours the mixture was cooled to room temperature, filtered, and the solid washed with ethanol to give 3-cyano-6-bromo-2-[1H]-quinolone (14.63 g), a small quantity of which was recrystallised from ethanol, m.p. 308°-311°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([OH:14])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[CH2:25][C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:14][C:26](=[O:27])[CH2:25][C:18]1[C:17]([CH3:16])=[CH:22][C:21]([CH3:23])=[CH:20][C:19]=1[CH3:24])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([O:12][CH3:13])[CH2:10][CH2:11]1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Reactant: COC(=O)C(O)CC1CCN(OC)CC1
Solvent: Cc1ccccc1
Product: COC(=O)C(CC1CCN(OC)CC1)OC(=O)Cc1c(C)cc(C)cc1C

Procedure:
A mixture of 2-hydroxy-3-(1-methoxy-piperidin-4-yl)-propionic acid methyl ester (700 mg, 3.5 mmol) and (2,4,6-trimethyl-phenyl)-acetyl chloride (700 mg, 3.6 mmol) in 10 ml of toluene was refluxed for 6 h. Then, the reaction mixture was concentrated under vacuum to dryness and the residue was purified by column chromatography on silica gel. Yield: 520 mg of 3-(1-methoxy-piperidin-4-yl)-2-[2-(2,4,6-trimethyl-phenyl)-acetoxy]-propionic acid methyl ester (title compound P3.12) as a oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:11]2([O:14][CH3:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:17][CH:18]=1
Reactant: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(c2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
4-(4-Chloro-phenyl)-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester (0.108 g, 0.331 mmol) was dissolved in methylene chloride (6 mL) and cooled in an ice bath. Trifluoroacetic acid (2 mL) was added slowly dropwise. The mixture was stirred for 2 hr as it warmed to room temperature. The reaction mixture was concentrated in vacuo and then redissolved in methylene chloride and washed with saturated sodium bicarbonate (2×10 mL). The pooled aqueous layers were extracted with methylene chloride (2×10 mL). The methylene chloride extracts were pooled, dried over magnesium sulfate, filtered and concentrated in vacuo to give 4-(4-Chloro-phenyl)-4-methoxy-piperidine as a clear oil (72 mg, 97%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.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>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)=[CH:40][CH:41]=2)=[N:8]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
A mixture of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (250 mg) obtained in Step C of Example 35, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (265 mg), tetrakis(triphenylphosphine)palladium(0) (35.3 mg) and 2M aqueous potassium carbonate solution (169 mg) in DMF (2 mL) was stirred under microwave irradiation at 130° C. for 1.5 hr. The reaction mixture was added to water, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (240 mg).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][O:14][CH2:15][CH2:16]O>>[C:1]([O:12][CH2:16][CH2:15][O:14][CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: COCCO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCCOC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and methyl cellosolve as starting materials to give the aimed compound.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:20](O)[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].O>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>[CH:21]12[CH2:20][CH:3]([CH2:4][CH2:5]1)[CH:2]=[C:12]2[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2=CC3CCC2C3)C1
Temperature: 95 °C
Reaction time: 12 h
Yield: 45.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (594 mg, 1.81 mmol), bicyclo[2.2.1]-2-hepten-2-ylboronic acid (250 mg, 1.81 mmol), ethanol (2 ml), 2N aqueous sodium carbonate solution (10 ml), and tetrakis(triphenylphosphine)palladium(0) (253 mg, 0.219 mmol) in toluene (20 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (282 mg, 45.6%) as an oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:25][CH:26]=[CH2:27])[C:11]([O:18]C3CCCCO3)=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:28])#[N:2].Cl>CO>[C:1]([CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH2:25][CH:26]=[CH2:27])[C:11]([OH:18])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:28])#[N:2]
Reactant: C=CCc1cc2c(c(CC=C)c1OC1CCCCO1)CCC(=O)N2CCC#N
Agent: Cl
Solvent: CO
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CCC#N
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1-(2-Cyanoethyl)-5,7-diallyl-3,4-dihydro-6-(2-tetrahydropyranyloxy)-2(1H)-quinolinone (1 g) obtained in Example 95 was dissolved in 50 ml of methanol, then 6N-hydrochloric acid was added thereto and stirred at 60° C. for 30 minutes so as to remove the tetrahydropyranyl group, and concentrated under reduced pressure to dryness. Thus obtained residual product was subjected to purification by means of a silica gel column chromatography, then recrystallized from ethyl acetate-n-hexane, there was obtained 1-(2-cyanoethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:8]=1)[NH2:7].[C:10](=[S:15])(OCC)[S-:11].[K+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]([SH:15])=[N:7][C:6]=2[CH:8]=1
Reactant: Nc1cc(Cl)ccc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Sc1nc2cc(Cl)ccc2s1

Procedure:
A solution of 5-chloro-2-fluoroaniline (2.0 g, 13.7 mmol, 1 eq.) and potassium O-ethyl dithiocarbonate (4.8 g, 30.3 mmol, 2.2 eq) in anhydrous DMF (20 mL) was heated at 100° C. under nitrogen for 4 h. The reaction mixture was cooled to room temp., diluted with water (50 mL), and acidified with 2N HCl with constant stirring at low temperature. Yellowish solid was collected by filtration, and washed with cold water. The wet filter cake was dissolved in ethyl acetate (50 mL), and the solution was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as yellowish solid. 1H-NMR (CDCl3, 300 MHz): δ=7.71 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.27 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][NH:5][C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1.C(N(CC)CC)C.[CH3:20][N:21]([CH3:25])[C:22]([Cl:24])=[O:23].Cl>CCOCC.C(O)C.C1C=CC=CC=1>[ClH:24].[CH3:20][N:21]([CH3:25])[C:22]([N:5]([CH2:4][CH2:3][N:2]([CH3:12])[CH3:1])[C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1)=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(NCCN(C)C)no1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: c1ccccc1
Product: Cc1cc(N(CCN(C)C)C(=O)N(C)C)no1
Temperature: 85 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 8.46 g. (0.05 mole) of N,N-dimethyl-N'-(5-methyl-3-isoxazolyl)-1,2-ethanediamine in 75 ml. of benzene (dry) is added 3.6 g. (0.055 mole) of triethylamine followed by 5.9 g. (0.055 mole) of dimethylcarbamoyl chloride. The solution is slowly heated to 85° C. and stirred at 80°-85° C. for 6 hours. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The reddish liquid residue is taken up in 125 ml. of hexane and filtered through charcoal which is then washed well with ether. Concentration of the combined filtrates in vacuo gives 10.3 g. of a reddish liquid. This is dissolved in 5 ml. of ethanol, cooled in ice and 6.8 ml. of 6 N ethanolic hydrochloric acid is added. Addition of ether precipitates the mono hydrochloride salt (11.5 g.) as an "off white" solid, which is filtered and dried in vacuo. The salt is recrystallized by dissolving it in 15 ml. of hot ethanol, adding ether with stirring to incipient cloudiness (35-40 ml.), and slowly diluting with another 100-110 ml. of ether when crystallization is well underway. Filtration affords 9.9 g. of white solid, m.p. 142.5°-143.5° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[C:20]([O:24][C:25]([CH2:27][C@@H:28]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:29](N1[C@H](C(C)C)COC1=O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1C=CC=C1.O1CCCC1>[CH2:1]([O:8][C:29](=[O:30])[C@H:28]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccccc1
Reactant: OCc1ccccc1
Agent: [Li]CCCC
Solvent: c1ccoc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a stirred solution of dry benzyl alcohol (0.55 ml, 5.33 mmol) in anhydrous tetrahydron furan (18 ml) under a nitrogen atmosphere at 0° C. was added a hexane solution of n-butyllithium (2.58 ml; 4.00 mmol). To this solution was added the product from Example 141 in anhydrous tetrahydrofuran (10 ml). After stirring 1 h at 0° C. the reaction was quenched by adding excess saturated aqueous ammonium chloride. The volatiles were removed by rotary evaporation and the resulting aqueous residue extracted two times with ether. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo provided an oil which was purified by chromatography on SiO2 (15% ether acetate/hexanes) to provide the desired product (0.89 g, 94%) as a colorless oil. Mass spectrum: (M)+ =354.
Reaction SMILES: [C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([N:20]2[CH2:25][CH:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pt](=O)=O>[C:1]([N:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])[C@H:7]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH2:22][CH2:21]2)=[O:19])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1cc(Cl)ccc1C1=CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)Cc1cc(Cl)ccc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 15 h
Yield: 90.2 %

Procedure:
A mixture of methyl [2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-5-chlorophenyl]acetate (1-8) (2.60 mmol) and platinum (IV) oxide (0.300 g) in ethanol/glacial acetic acid (1:1, 20 mL) was hydrogenated at atmospheric pressure for approximately 15 h. The resulting mixture was filtered through a short column of celite®, eluting copiously with ethanol. The filtrate was evaporated and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous phase was re-extracted twice with methylene chloride. The combined organic extracts were washed with water, brine, dried (Na2SO4), and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-15% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) furnished 1-9 (1.25 g) as a colorless foam (m/z (ES) 533 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]3[N:20]=[C:19]([NH:21][NH2:22])[CH2:18][N:17]=[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[C:15]=3[CH:30]=2)=[O:10])=[CH:5][CH:4]=1.[N:31]([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:12]=[CH:13][C:14]3[N:20]4[N:31]=[N:22][N:21]=[C:19]4[CH2:18][N:17]=[C:16]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[C:15]=3[CH:30]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: NNC1=Nc2ccc(C(=O)c3ccc(Cl)cc3)cc2C(c2cccc(Cl)c2)=NC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)=NCc1nnnn1-2
Yield: 65.2 %

Procedure:
HCl 0.5N (30 ml) was cooled. Intermediate (14) (0.00353 mol) was added. The mixture was cooled while stirring vigorously. A solution of sodium nitrite (0.0037 mol) in water (8 ml) was added dropwise. The mixture was stirred at 5° C. for 45 min, basified with K2CO3 10% and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The residue (1.6 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 100%; 35–70 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off, washed with diethyl ether and dried, yielding 1 g (65%) of (4-chlorophenyl)[6-(3-chlorophenyl)-4H-tetrazolo[1,5-a][1,4]benzodiazepin-8-yl]-methanone (intermediate 15), mp. 220° C.