Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[C:7]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:8]=[CH:9][CH:10]=1.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19].[NH4+].[Cl-]>C1COCC1>[CH3:17][Si:18]([CH3:20])([CH3:19])[C:5]1[CH:6]=[C:7]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC1(c2cccc(Br)c2)OCCO1
Reactant: C[Si](C)(C)Cl
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(c2cccc([Si](C)(C)C)c2)OCCO1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A three-neck flask was charged with magnesium pieces (2.0 g) and tetrahydrofuiran (12 mL) under a nitrogen atmosphere. A small quantity of iodine was added and the mixture turned yellow. To this yellow mixture was added dropwise a solution of the title compound of Step A (20.0 g) in 30 mL of THF. The reaction mixture was warmed to 65° C. during the addition and then was heated at reflux for 1.5 h after the addition was complete. After cooling the reaction to 60° C., a solution of trimethylsilyl chloride (10.4 mL) in THF (12 mL) was added and the mixture was heated at reflux for two hours and then was allowed to stir overnight at room temperature. The reaction mixture was poured into saturated aqueous NH4Cl and the aqueous layer was extracted twice with diethyl ether and then once with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and the was solvent removed to give an oil (20.0 g) which crystallized upon standing. This solid was then recrystallized from pentane to afford 11.2 g of the title compound of Step B as a white solid melting at 54-55° C. 1H NMR (CDCl3): δ 7.63 (s,1H), 7.44 (m,2H), 7.33 (t,1H), 4.0 (m,2H), 3.78 (m,2H), 1.67 (s,3H), 0.27 (s,8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.[CH2:9]([O:11][C:12](=[O:15])[CH2:13]Br)[CH3:10].[H-].[Na+].Cl>CN(C)C=O>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][N:6]1[CH2:7][C:3]([O:2][CH3:1])=[CH:4][C:5]1=[O:8])[CH3:10]
Reactant: CCOC(=O)CBr
Reactant: COC1=CC(=O)NC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC(OC)=CC1=O

Procedure:
4.27 g of 4-methoxy-3-pyrrolin-2-one and 8.30 g of bromoacetic acid ethyl ester were dissolved in 50 ml of dimethylformamide and mixed with 1.41 g of sodium hydride at 0° C., within 20 minutes, in 3 portions, with vigorous stirring and under argon. After 90minutes of reaction time at 0° C., it was neutralized with dilute hydrochloric acid, and the solvent was evaporated off in a vacuum. The residue was taken up in 50 ml of ice water and twice extracted with 50 ml each of methylene chloride. The organic phase was dried over Na2SO4, and evaporated on the rotary evaporator under vacuum. The residue slowly thoroughly recrystallized at room temperature. 8.0 g of product having a melting point of 54° to 56° C. and a content according to GC of 90.8 percent was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:16]([O-:18])=[O:17])=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1
Reactant: O=[N+]([O-])O
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Agent: O=S(=O)(O)O
Product: O=C1CC(=O)CC(c2cc([N+](=O)[O-])ccc2F)C1
Temperature: 0 °C
Yield: 83 %

Procedure:
60 g of 5-(2-fluorophenyl)-cyclohexane-1,3-dione were dissolved in 500 ml of concentrated sulfuric acid at -20° C. and nitrated with 18.3 g of 98% strength nitric acid at -20° C. in the course of 60 minutes. The reaction mixture was stirred into 5 l of ice water, and the precipitated crystals were filtered off under suction and dried. 60.5 g (83% yield) of 5-(2-fluoro-5-nitrophenyl)-cyclohexane-1,3-dione of melting point 171°-173° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:18]=[C:19](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)\[C:20](=[O:22])[CH3:21])[CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].CCOC(C)=O>[NH2:15][C:14]1[CH:13]=[CH:12][C:11](/[CH:18]=[C:19](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)\[C:20](=[O:22])[CH3:21])=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)/C(=C\c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)c1ccccc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(=O)/C(=C\c1ccc(N)c(OCc2ccccc2)c1)c1ccccc1
Reaction time: 18 h

Procedure:
A mixture of (Z) -4-(3-benzyloxy-4-nitrophenyl)-3-phenyl-but-3-en-2-one (760 mg, 2.03 mmol), 5% platinum on carbon (114 mg) in EtOAc (10 mL) is hydrogenated at 1 atm for 18 h. The mixture is filtered through Celite, washed with EtOAc and the filtrate is concentrated. The residue is purified by flash chromatography using methylene chloride/MeOH (100:1) as eluent to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:44]([C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=1)([O-:46])=[O:45]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:18][CH2:17][CH2:16][N:15]([CH2:51][C:50]2[CH:53]=[CH:54][C:47]([N+:44]([O-:46])=[O:45])=[CH:48][CH:49]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN1CCCNCCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CN1CCCN(Cc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.8 %

Procedure:
To a solution of compound (4) (1.17 g, 2.36 mmol) in dry CHCl3 (50 ml) were added triethylamine (0.99 ml, 0.72 g, 7.08 mmol) and 4-nitrobenzyl bromide (0.51 g, 2.36 mmol). After stirring at an ambient temperature for 10 hours, the solvent was removed under reduced pressure, and the residue was purified through column chromatography on alumina (basic). Extraction with a mixture of acetate and methanol (10:2) gave a purified clear oil, which was then solidified to obtain compound (15) (1.13 g, 76% yield). 1H NMR (500 MHz, CDCl3): δ 8.12-8.10 (dd, 2H), 7.51-7.49 (dd, 2H), 7.34-7.27 (m, 10H), 5.11 (s, 2H), 5.05 (s, 2H), 3.55 (s, 2H), 3.39 (s, 2H), 3.34 (s, 2H), 2.81 (brs, 2H), 2.74-2.72 (m, 4H), 2.67-2.64 (m, 6H), 2.59-2.57 (m, 2H), 2.46-2.44 (m, 2H), 1.71 (brs, 2H), 1.61-1.59 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 171.3, 170.8, 148.1, 146.9, 135.7, 129.3, 128.5, 128.2, 128.1, 123.3, 66.0, 65.8, 58.1, 55.5, 53.6, 53.1, 52.5, 52.0, 51.2, 49.6, 47.9, 47.2, 25.7; HRMS (FAB) calculated for C35H46N5O6: 632.3448 [(M+H)+], measured value: 632.3447 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:34][CH2:35][CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:34][CH2:35][CH2:36][C:37](=[O:38])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:16][CH2:17]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=3)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCNCC3)C2=O)c1
Reactant: O=C(CCCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Temperature: 81 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
A mixture of tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (250 mg, 0.57 mmol, 1 equiv), 4-chloro-1-phenylbutan-1-one (91.3 μl, 0.57 mmol, 1 equiv), sodium iodide (34 mg, 0.23 mmol, 0.4 equiv) and potassium carbonate (158 mg, 1.14 mmol, 2 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling, the reaction mixture was filtered, concentrated in vacuo and was purified using the Biotage flash chromatography system (SNAP 10 g cartridge, Rf=0.45, gradient—1%-10% methanol in dichloromethane) to afford the title compound (100 mg, 46%); 1H NMR (400 MHz, DMSO-d6): δ 1.53 (s, 9H); 1.59-1.63 (m, 2H); 1.82 (t, 2H, J=7.2 and 6.4 Hz); 2.19-2.23 (m, 2H); 2.37-2.39 (m, 2H); 2.70 (d, 4H, J=7.2 Hz); 3.02 (t, 2H, J=6.8 and 6.4 Hz); 4.54 (s, 2H); 4.59 (s, 2H); 6.84 (bs, 2H); 7.02 (t, 2H, J=9.6 and 8.8 Hz); 7.48-7.54 (m, 2H); 7.63 (t, 1H, J=8 Hz); 7.79-7.84 (m, 2H); 7.95-7.98 (m, 2H); MS for C35H40FN3O4 m/z 586.5 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH2:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C(Cl)Cl>[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][S:36]([CH2:34][CH3:35])(=[O:38])=[O:37])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(OC2CCN(CCCCN)CC2)c2ncccc2c1
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1cc(OC2CCN(CCCCNS(=O)(=O)CC)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for example, as prepared for Intermediate 37) (248 mg, 0.7 mmol) was dissolved in DCM (5 ml), and treated with triethylamine (156 μl, 1.12 mmol), and ethanesulfonyl chloride (commercially available, for example, from Aldrich) (80 μl, 0.84 mmol). The mixture was stirred at room temperature for 2 h, then left to stand at room temperature overnight. The mixture was washed with saturated aqueous sodium hydrogen carbonate, passed through a hydrophobic frit and the organic solution was concentrated in vacuo. The residue was applied to a silica cartridge (20 g), eluting with DCM-ethanol-aqueous 0.88 s.g. ammonia (100:8:1). The relevant fractions were concentrated in vacuo to give the title compound (as the free base) as a yellow gum (167 mg). LCMS RT=2.66 min, ES+ve m/z 448 (M+H)+; 1H NMR δ (CD3OD) 8.72 (1H, dd, J=4, 1.5 Hz), 8.21 (1H, dd, J=8, 1.5 Hz), 7.48 (1H, dd, J=8, 4 Hz), 7.26 (1H, s), 7.10 (1H, s), 4.74-4.64 (1H, m), 3.10-2.92 (6H, m), 2.78 (2H, t, J=7.5 Hz), 2.50-2.38 (4H, m), 2.20-2.10 (2H, m), 2.08-1.95 (2H, m), 1.76-1.53 (6H, m), 1.47-1.36 (2H, m), 1.30 (3H, t, J=7 Hz), 0.97 (3H, t, J=7 Hz).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:27][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:24]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCc1cccc(OCc2ccccc2)c1
Solvent: CO
Product: N#CNC(=NCc1cccc(OCc2ccccc2)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
Isopropyl N cyano-3-pyridinecarboximidate (0.30 g, 1.6 mmol) was dissolved in methanol (10 ml), and 3-benzyloxybenzylamine (0.41 g, 1.9 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The concentrated residue was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g). Elution with chloroform-methanol (100:1) was conducted, the eluted fractions were concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from methanol-diethyl ether to give the title compound (0.48 g, 1.4 mmol, yield: 88%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>O1CCCC1.[Rh]>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Rh]
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)O
Yield: 80.8 %

Procedure:
8.0 g of 5-chloro-2-nitrobenzoic acid [4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] are dissolved in 90 ml of tetrahydrofuran and the solution is hydrogenated for 6 hours at room temperature under a hydrogen atmosphere in the presence of 4 g of 5% rhodium/carbon. The reaction mixture is then filtered and the solvent is removed by distillation. The resulting crude product is stirred with diethyl ether. 5.5 g of 2-amino-5-chlorobenzoic acid [4-(3-chloro-5-trifluoromethylpyridyl-2-oxy)-anilide] are obtained in the form of white crystals (m.p. 180°-184° C.).
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:30][Mg]Br.C(OCC)C>O1CCCC1>[OH:3][C:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])=[O:9])=[CH:6][CH:5]=1)([CH3:30])[CH3:2]
Reactant: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)=O)cc2)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)(C)O)cc2)cc1
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of 2-(4-acetylbenzoylamino)-N-(4-methoxyphenyl)benzamide (161 mg, 0.410 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was added 3 M methyl magnesium bromide in diethyl ether (0.2 mL, 0.6 mmol). After 1 h, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (2 mL), diluted with ether, and washed with water. The organic layer. was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 15% ethyl acetate/85% hexanes to 35% ethyl acetate/65% hexanes) to give 24 mg (14%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:23][C:25](=[O:27])[CH3:26])([C:19]([F:22])([F:20])[F:21])[C:15]([F:16])([F:17])[F:18])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCn1c(=O)[nH]c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2c1=O
Product: CCn1c(=O)[nH]c2ccc(C(OC(C)=O)(C(F)(F)F)C(F)(F)F)cc2c1=O

Procedure:
Reaction of the compounds of formula I wherein Z is hydroxy with the appropriate acid chloride affords the corresponding alkanoyloxy derivative. For instance, reaction of 3-ethyl-6-(hexafluoro-2-hydroxy-2-propyl)quinazoline-2,4-dione with acetyl chloride yields 3-ethyl-6-(2-acetoxyhexafluoro-2-propyl)quinazoline-2,4-dione.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[CH:22][CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Product: O=CC=Cc1ccc(-n2ccnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-imidazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 199 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13](=[O:26])[CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]1[C:22]([O:24][CH3:25])=[O:23].[CH:27]1[CH:32]=[C:31]([S:33][CH2:34][CH2:35]Cl)[CH:30]=[C:29]([F:37])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:37][C:29]1[CH:30]=[C:31]([S:33][CH2:34][CH2:35][N:19]2[CH2:20][CH2:21][C@@H:16]([CH2:15][CH2:14][C:13]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[O:26])[C@@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18]2)[CH:32]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reactant: Fc1cccc(SCCCl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSc2cccc(F)c2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Temperature: 65 °C
Yield: 22.9 %

Procedure:
A mixture of 6.44 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxopropyl]piperidine-3-carboxylate in 100 cm3 of acetonitrile, 3.43 g of 2-(3-fluorophenylthio)ethyl-1-chloride, 8.85 g of potassium carbonate, and 1.24 g of potassium iodide was heated at a temperature in the region of 65° C. for 48 hours. After cooling, the insoluble material was filtered off. The filtrate was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The oily residue was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 6 cm; 250 g), elution was carried out with a dichloromethane/ethyl acetate/methanol (50/50/3 by volume) mixture, and 50-cm3 fractions were collected. The fractions from 19 to 25 were collected. These fractions were combined and then concentrated under reduced pressure (5 kPa) at approximately 40° C. 2.1 g of methyl (3R,4R)-1-[2-(3-fluorophenylthio)ethyl]-4-[3-(6-methoxyquinolin-4-yl)-3-oxopropyl]piperidine-3-carboxylate were obtained in the form of a mobile brown oil. Methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxopropyl]-piperidine-3-carboxylate was prepared as described in Example 5.
Reaction SMILES: FC1C=CC(N)=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1.[CH3:18][O:19][CH:20]([O:23][CH3:24])[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][CH2:21][CH:20]([O:23][CH3:24])[O:19][CH3:18])=[CH:12][CH:11]=1
Reactant: COC(C=O)OC
Reactant: NCc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Nc1ccc(F)cc1
Agent: [Na+]
Product: COC(CNCc1ccc(F)cc1)OC
Yield: 71 %

Procedure:
Following the procedure as described in step A of Preparation 2, making variations as required to replace 4-fluoroaniline with 4-fluorobenzylamine to react with dimethoxyacetaldehyde followed by the imine reduction with sodium triacetoxyborohydride, N-(4-fluorobenzyl)-2,2-dimethoxyethanamine was obtained in 71% yield: 1H NMR (300 MHz, CDCl3) δ 7.24-7.19 (m, 2H), 6.97-6.89 (m, 2H), 4.43-4.39 (m, 1H), 3.70 (s, 2H), 3.30 (s, 6H), 2.67 (dd, J=5.4, 1.5 Hz, 2H); MS (ES+) m/z 214.3 (M+1).
Reaction SMILES: C(C1C=C(C#CC=C2CCN(C(OC(C)(C)C)=O)CC2)C=NC=1)#N.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=C1CCN(C(OC(C)(C)C)=O)CC1)C#C.Br[C:50]([F:64])=[C:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]1>>[F:64][C:50](=[C:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH2:52]1)[C:32]#[C:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(F)Br)CC1
Agent: C#CC=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cncc(C#N)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(=C(F)C#Cc2ccccc2)CC1

Procedure:
The title product was prepared following the procedure reported for the Compound of Example 45 but using phenylacetylene instead of instead of Compound 2b and Compound 66a instead of 5-bromonicotinonitrile. The residue coming from the usual work-up procedure was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 5:95 to 10:90).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:20]([Cl:21])=[C:19]([O:22][CH2:23][C:24]([OH:26])=[O:25])[CH:18]=[C:17]2[C:9]=1[C:10]1[C:15]([CH2:27][CH3:28])([CH2:16]2)[CH2:14][CH2:13][C:12](=[O:29])[CH:11]=1.Cl[CH2:31][C:32](=[O:34])[CH3:33].O>CN(C)C=O.CCOCC>[Cl:7][C:8]1[C:20]([Cl:21])=[C:19]([O:22][CH2:23][C:24]([O:26][CH2:31][C:32](=[O:34])[CH3:33])=[O:25])[CH:18]=[C:17]2[C:9]=1[C:10]1[C:15]([CH2:27][CH3:28])([CH2:16]2)[CH2:14][CH2:13][C:12](=[O:29])[CH:11]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC(C)=O)c(Cl)c1Cl)C2

Procedure:
Potassium carbonate (0.2 g) is suspended in a solution of [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetic acid (Example 20, Step D) (0.4 g, 0.0011 mole) in dimethylformamide (3 ml). After warming the suspension on a steam bath for 15 minutes, chloroacetone (0.5 g, 0.005 mole) is added and the mixture heated for an additional 15 minutes. The reaction mixture is cooled, poured into water (50 ml) and the product extracted into ether (three 15 ml portions. The extract is dried over Na2SO4. After filtration, the extract is concentrated to give a yellow oil. Trituration with cold ether causes crystallization to occur. The crystalline product weighs 0.1 g and melts at 153°-155° C.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:13](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[CH3:13][O:10][C:9]([CH:8]([OH:12])[CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
L-3-Phenyllactic acid (5 g, 30 mmol) was dissolved in 25 mL of dimethylformamide and cesium carbonate (9.94 g, 30.5 mmol) was added. After the evolution of gas ceased, methyl iodide (8.52 g, 60 mmol) was added and the mixture was stirred for 18 hours at room temperature. Water was then added and the mixture extracted with ethyl acetate. The organic phase was separated, washed with water, dried over magnesium sulfate, and the solvent removed in vacuo to give the title compound as a colorless oil (5.4 g, 100% yield).
Reaction SMILES: [P:1]([O:8]CC)([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:16]([O:15][C:13](=[O:14])[CH2:12][P:1]([O:2][CH2:3][CH3:4])([O:5][CH2:6][CH3:7])=[O:8])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)OC(=O)CBr
Product: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Temperature: 90 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Triethyl phosphite (485 g) is warmed up to 90° C. under N2 atmosphere in a three-necked round-bottomed flask, and t-butyl bromoacetate (541 g) is added dropwise into the system within 2 h. Then the mixture is kept stirring at 90° C. for around 4 h, and then cooled to room temperature. The obtained mixture is distilled under vacuo to remove compounds with low boiling point, and the residue is collected as a colorless liquid compound 5 in 97% yield (680 g) and >98% GC purity.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:15](O)=[O:16].C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)CCl.C(Cl)Cl.C1COCC1>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:15]([C:11]2[NH:10][CH:14]=[CH:13][N:12]=2)=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Br
Reactant: O=C(O)c1ncc[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1c(Br)cccc1NC(=O)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step 1 A solution of 3-bromo-2-methylaniline (0.63 g, 3.39 mmol), 1H-imidazole-2-carboxylic acid (0.455 g, 4.06 mmol), HOAT (0.830 g, 6.10 mmol), and EDC (1.298 g, 6.77 mmol) in 2:1 DCM-THF (100 mL) was treated with DIEA (1.774 mL, 10.16 mmol) and stirred at rt overnight. Additional 1H-imidazole-2-carboxylic acid (0.6 eq, 0.228 g), EDC (0.64 g), HOAT (0.41 g), and DIEA (0.8 mL) were added and the mixture was stirred at rt for 6 days. The mixture was partitioned between NaHCO3 (aq) and DCM, and the organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 94:6 DCM-methanol) to provide N-(3-bromo-2-methylphenyl)-1H-imidazole-2-carboxamide as a solid (80% purity, 0.76 g, 64%). Mass spectrum m/z 280, 282 (M+H)+.