Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N2[C:11](=[O:12])[C:10]3=[C:13]([F:20])[C:14]([F:19])=[C:15]([F:18])[C:16]([F:17])=C3C2=O)CCCCC1.S(=O)(=O)(O)[OH:23].Cl.[C:28]([OH:31])(=[O:30])[CH3:29]>>[F:17][C:16]1[C:15]([F:18])=[C:14]([F:19])[C:13]([F:20])=[C:10]([C:11]([OH:23])=[O:12])[C:29]=1[C:28]([OH:31])=[O:30]
Reactant: O=C1c2c(F)c(F)c(F)c(F)c2C(=O)N1C1CCCCC1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Yield: 90 %

Procedure:
After mixing 50 g of the above dried N-cyclohexyl-tetrafluorophthalimide with 80 ml of 85% sulfuric acid, 80 ml of acetic acid was added to the mixture and it was reacted for 5 hours at 120° to 130° C. with stirring. After the reaction was completed, acetic acid was distilled off from the reaction mixture under a reduced pressure and the product was continuously extracted with toluene for 24 hours. When the toluene layer obtained was concentrated by distillation under a reduced pressure, crude crystals of yellow tetrafluorophthalic anhydride were precipitated. The concentrate was distilled under a reduced pressure (20 mmHg) at 150° C. and the crystals thus obtained were hydolyzed by adding 100 ml of an aqueous 6N hydrochloric acid solution. The hydrolyzed product was cooled and then extracted with ether to provide white crystals of tetrafluorophthalic acid (yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:19][CH2:20][C@H:21]([CH3:22])[N:8]3[CH:7]=[C:6]([C:23]([O:25][CH:26]3[CH2:31][O:30]C(C4C=CC=CC=4)[O:28][CH2:27]3)=[O:24])[C:5]2=[O:38])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1>ClCCl.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([O:19][CH2:20][C@H:21]([CH3:22])[N:8]3[CH:7]=[C:6]([C:23]([O:25][CH:26]([CH2:31][OH:30])[CH2:27][OH:28])=[O:24])[C:5]2=[O:38])[C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1
Reactant: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)OC4COC(c5ccccc5)OC4)cn1c23
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)OC(CO)CO)cn1c23
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
(S)-2-phenyl-1,3-dioxan-5-yl 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate (0.50 g, 9.55 mmol), was dissolved in a mixture of dichloromethane/methanol (2:1.5, 87.5 ml) under argon. Palladium catalyst (10 wt % Pd/C) (180 mg) was added, the flask was evacuated and allowed to stir 1 atm of hydrogen gas at room temperature for 16 hours. The crude reaction mixture was passed through a glass microfiber on a sintered funnel. The volatiles were removed under reduced pressure yielding 370 mg (88%) of a yellow gum.
Reaction SMILES: [BrH:1].[C:2]([O:5][C@@H:6]1[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:17]([O:18]C(=O)C)[C@H:12]([O:13]C(=O)C)[C@H:7]1[O:8]C(=O)C)(=[O:4])[CH3:3]>>[C:2]([OH:5])(=[O:4])[CH3:3].[C:2]([OH:5])(=[O:4])[CH3:3].[C:2]([OH:5])(=[O:4])[CH3:3].[C:2]([OH:5])(=[O:4])[CH3:3].[Br:1][C@@:6]1([O:23][C@H:22]([CH2:24][OH:25])[C@@H:17]([OH:18])[C@H:12]([OH:13])[C@H:7]1[OH:8])[OH:5]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Product: CC(=O)O
Product: OC[C@H]1O[C@@](O)(Br)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 325.2 %

Procedure:
Hydrobromic acid (30% in acetic acid, 11.85 ml, 55.4 mmol) was added to β-D-glucose pentaacetate (12.01 g, 30.8 mmol) at 0° C. After 10 minutes, the resulting solution was warmed to room temperature and stirred for 4 hours. The reaction mixture was slowly poured, with stirring, into ice water (250 ml) and was stirred until the product solidified. The product was collected by vacuum filtration and washed with cold water. The white solid was dissolved in carbon tetrachloride (60 ml) and washed with H2O (1×20 ml), saturated aqueous NaHCO3 (3×20 ml, until pH=7), H2O (1×20 ml), dried with CaCl2, and poured into cold petroleum ether (250 ml). After 30 min, the crystalline product was collected by vacuum filtration to give the target compound as a white solid (10.0 g, 80%).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH2:16][CH3:17].[Li+].[OH-]>C1COCC1.CO>[CH2:14]([O:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[CH:5]=[CH:4][C:3]([OH:18])=[O:2])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1cc(F)ccc1C=CC(=O)O
Yield: 101.5 %

Procedure:
3-(2-Butoxy-4-fluoro-phenyl)-acrylic acid methyl ester (121 mg) was reacted with 1N LiOH (5 ml) in THF and CH3OH for 2 hrs as described above to yield title compound (116 mg).
Reaction SMILES: [CH3:1][C:2]1([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.C([Li])CCC.[S:20](=[O:22])=[O:21].O.O.O.C([O-])(=O)C.[Na+].[NH2:31]OS(O)(=O)=O>CCCCCC.O.C1COCC1>[CH3:1][C:2]1([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[S:20]([NH2:31])(=[O:22])=[O:21])[O:3][CH2:4][C:5]([CH3:8])([CH3:9])[CH2:6][O:7]1
Reactant: CC1(C)COC(C)(c2ccsc2)OC1
Reactant: O=S=O
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(C)(c2ccsc2S(N)(=O)=O)OC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2,5,5-trimethyl-1,3-dioxan-2-yl)thiophene (106 g, 0.5 mol) in hexane (1200 mL) at -60° C. was added a 2.5M solution of n-butyllithium in hexane (240 mL, 0.6 mmol) over 40 min. The mixture was allowed to warm to room temperature (approximately 1.5 hr) and then once again cooled to -60° C. and anhydrous THF (400 mL) added. Sulfur dioxide was passed over the surface of the reaction mixture for 30 min at which point the reaction mixture was allowed to warm to room temperature under a positive SO2 pressure (approximately 1 hr). The solvent was removed and the residue dissolved in water (1200 mL) to which sodium acetate trihydrate (217.73 g, 1.6 mol) was added. The solution was cooled (ice bath) to 0° C. and hydroxylamine-O-sulfonic acid (107 g, 0.95 mol) was slowly added. The mixture was stirred at room temperature for 18 hr and then extracted with ethyl acetate. The combined extracts were washed with a saturated aqueous sodium bicarbonate solution, brine, dried (Na2SO4) and evaporated to give a viscous brown oil (174.05 g); this product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[NH:7][N:6]=1)=[O:4].[H-].[Na+].[H][H].[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O.O.CN(C=O)C>[C:18]1([C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:7]2[C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C(=O)OC)[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)OC)n(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1.84 g. (10 mmol) of 3,5-pyrazoledicarboxylic acid dimethyl ester* in 15 ml. of DMF, stirred at 0° under argon, was added 480 mg. (10 mmol) of 50% NaH (suspension in mineral oil). After the evolution of hydrogen had ceased, 2.7 g. (10 mmol) of triphenylmethyl chloride in 20 ml. of DMF was added dropwise. The mixture was allowed to warm to room temperature, stirred 1.5 hours, poured into H2O, and the resulting precipitate filtered. After recrystallization from 2-ethoxyethanol-H2O, there was obtained the end product. The analytical sample was obtained as colorless needles by recrystallization from DMF-H2O; mp 212°-213.5°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([CH:9]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:9][N+:6]([O-:8])=[O:7])(=[O:4])=[O:3]
Reactant: O=[N+]([O-])C=C1NCCCS1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g of methanesulfonyl chloride in 150 ml of methylene chloride was added drop-by-drop over a 55 minute period to a stirred mixture of 20 g of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine and 40 ml of triethylamine in 150 ml of methylene chloride, at -30° C., in a nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at -30° C., and then washed with 2% hydrochloric acid. The aqueous phase was washed twice with methylene chloride. The resulting organic phases were combined, dried (Na2SO4), concentrated to about 50 ml, cooled to 0° C., and filtered. The crystalline solid was triturated with cold methylene chloride, to give N-(methylsulfonyl)-2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (1A), as a crystalline solid, m.p.: 144-145° C. (with decomposition).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:24]=[CH:23][C:22]3[O:21][C:20]4[C:15](=[CH:16][C:17]([C:25](=[O:40])[CH2:26][CH2:27][CH2:28][N:29]5C(=O)C6=CC=CC=C6C5=O)=[CH:18][CH:19]=4)[CH2:14][C:13]=3[CH:12]=2)=[O:10])C(=O)C2=CC=CC=C12.C1(=O)N(CCCC([Cl:57])=O)C(=O)C2=CC=CC=C12.C1C2CC3C(=CC=CC=3)OC=2C=CC=1.[ClH:78]>C(O)(=O)C>[ClH:57].[ClH:78].[NH2:29][CH2:28][CH2:27][CH2:26][C:25]([C:17]1[CH:18]=[CH:19][C:20]2[O:21][C:22]3[C:13](=[CH:12][C:11]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][NH2:5])=[CH:24][CH:23]=3)[CH2:14][C:15]=2[CH:16]=1)=[O:40]
Reactant: O=C(Cl)CCCN1C(=O)c2ccccc2C1=O
Reactant: O=C(CCCN1C(=O)c2ccccc2C1=O)c1ccc2c(c1)Cc1cc(C(=O)CCCN3C(=O)c4ccccc4C3=O)ccc1O2
Agent: Cl
Agent: c1ccc2c(c1)Cc1ccccc1O2
Solvent: CC(=O)O
Product: NCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCN)ccc1O2

Procedure:
2,7-Bis(4-phthalimidobutyryl)xanthene, prepared from 4-phthalimidobutyryl chloride and xanthene by the method of S. S. Cheng et al., J. Med. Chem. 9, 945 (1966), is treated with 700 ml. of hot glacial acetic acid after which 200 ml. of concentrated hydrochloric acid is added gradually with stirring. The mixture is heated to reflux for 24 hours with a constant stream of HCl gas passing through the mixture The reaction mixture is stirred and refluxed for an additional 24 hours, cooled, and the product worked up in the usual manner.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([Sn:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>>[SH:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5].[CH2:7]([Sn+2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].[SH:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5]
Reactant: O=C(O)CCS
Reactant: CCCC[Sn](=O)CCCC
Product: CCCC[Sn+2]CCCC
Product: O=C([O-])CCS

Procedure:
A mixture of 2.475 kg (23.3 tool) of 3-mercaptopropionic acid and 5.97 kg (24 mol) of dibutyltin oxide is continuously fed into a screw drier whose heat exchange areas consist of two heating and one cooling zone. Behind each heating zone, a suction device is present for removing the water of reaction formed.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[C:11]([CH3:19])[C:10]=2[CH:20]=1.[BH4-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH:14]([OH:18])[CH:15]([CH3:16])[CH3:17])=[C:11]([CH3:19])[C:10]=2[CH:20]=1
Reactant: COCCOc1ccc2oc(C(=O)C(C)C)c(C)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1ccc2oc(C(O)C(C)C)c(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
1-[5-(2-Methoxyethoxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropan-1-one (0.71 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (5 mL) and methanol (0.5 mL), and sodium borohydride (90%, 0.21 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (1 mL) and 1N hydrochloric acid (5 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (0.70 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)[CH2:11]1)C(=O)OC(C)(C)C.C([Cl:24])(=O)C>C(O)C>[ClH:24].[ClH:24].[CH3:1][NH:2][CH:10]1[CH2:11][N:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)[CH2:13]1
Reactant: Cc1cc(N2CC(N(C)C(=O)OC(C)(C)C)C2)ccn1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CNC1CN(c2ccnc(C)c2)C1
Product: Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
tert-Butyl methyl(1-(2-methylpyridin-4-yl)azetidin-3-yl)carbamate (1.37 mmol, 1 eq) was dissolved in ethanol (5 ml), and acetyl chloride (6.85 mmol, 5.0 eq) was added while cooling with ice. The reaction mixture was then stirred for 2 hours at 40° C. The solvent was removed in vacuo and the residue was dried. Yield: 99%
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]1=[O:26].C(=O)([O-])[O-:28].[Na+].[Na+].O>C1(C)C=CC=CC=1>[ClH:1].[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][C:20]([OH:26])=[O:28])[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCC(=O)N1CCCCBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCCC(=O)NCCCCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
4-Phenyl-1,2,3,6-tetrahydropyridine hydrochloride (10 g) is converted to its free base and combined with 11.0 g of N-(4-bromobutyl)glutarimide and 18 g of sodium carbonate in 200 ml of toluene. The mixture is refluxed for 5 hours, cooled to 25°C and 50 ml of water is added. After stirring for 15 minutes, the layers are separated and the organic layer is filtered through fritted glass to remove insoluble material and then extracted with 10% hydrochloric acid. The acid solution is allowed to stand in an open beaker for 1 week during which time the product precipitates out. It is filtered off and dried at 70° C, 0.1 mm of Hg, for 12 hours to yield 6.3 g of the title compound, melting point 163°-165°C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:15]([F:16])=[CH:14][C:13](/[CH:17]=[C:18](\[CH3:24])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][C:11]=2[F:25])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:28]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH2:42])=[N+:29]=[N-:30].C(N(CC)CC)C.O>C(Cl)Cl>[N:28]([CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][S:2]([C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:15]([F:16])=[CH:14][C:13](/[CH:17]=[C:18](\[CH3:24])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][C:11]=2[F:25])=[CH:7][CH:6]=1)(=[O:4])=[O:3])=[N+:29]=[N-:30]
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)Cl)cc2)c(F)c1
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])cc2)c(F)c1
Reaction time: 0.25 h
Yield: 47.1 %

Procedure:
To a solution of (E)-ethyl 3-(4-(4-(chlorosulfonyl)phenoxy)-3,5-difluorophenyl)-2-methylacrylate (intermediate 41.3) (250 mg, 0.60 mmol) in DCM (3 mL) was added a solution of 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (157 mg, 0.72 mmol) and triethylamine (72 mg, 0.72 mmol) in DCM (2 mL). After 15 minutes, water (10 mL) was added and the reaction mixture was extracted with DCM (2×25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography on silica gel eluting with 50% EtOAc in DCM to give the title compound (169 mg).
Reaction SMILES: [CH:1](=[O:8])[C:2]1C=CC=C[CH:3]=1.[CH2:9]([NH:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][N:19]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:35]([O-:40])(=[O:39])[C:36]([O-:38])=[O:37]>>[C:35]([OH:40])(=[O:39])[C:36]([OH:38])=[O:37].[CH2:28]([N:19]1[CH2:20][CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]1[CH2:17][N:16]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:1](=[O:8])[CH2:2][CH3:3])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C([O-])C(=O)[O-]
Reactant: O=Cc1ccccc1
Reactant: c1ccc(CNCC2c3ccccc3CCN2Cc2ccccc2)cc1
Product: CCC(=O)N(Cc1ccccc1)CC1c2ccccc2CCN1Cc1ccccc1
Product: O=C(O)C(=O)O

Procedure:
Title Compound I, in which R=CH2C6H5 ; R'=H; A=CH; pY=C2H2O4, q=0 and n=1, was prepared by reducing 2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (6.7 g; 0.025 mole) with LiAlH4 by the same procedure as used in Example I to obtain 3.77 g (60% theory) of 1-aminomethyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline as a yellow oil. This compound was reacted with benzaldehyde and reduced as in Example II. The resultant 1-(N-benzyl)aminomethyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline was propionylated as in Example I and the oxalate (having a melting range of 159°-61°) formed.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH2:16])=[O:15])[CH:5]=[C:4](Cl)[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])#[N:19]>O1CCOCC1.C([O-])(O)=O.[Na+].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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH2:16])=[O:15])[CH:5]=[C:4]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([F:29])[CH:22]=2)[N:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: NC(=O)C1COCCN1c1cc(Cl)nc(N)n1
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: C1COCCO1
Product: N#Cc1ccc(-c2cc(N3CCOCC3C(N)=O)nc(N)n2)cc1F
Temperature: 95 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
A mixture of 4-(2-amino-6-chloro-4-pyrimidinyl)-3-morpholinecarboxamide (390 mg, 1.51 mmol), Pd(PPh3)4 (91 mg, 0.08 mmol), and (4-cyano-3-fluorophenyl)boronic acid (285 mg, 1.73 mmol) in 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (2 mL) was stirred at 95° C. under argon in a sealed tube for 18 hours. The mixture was cooled, quenched with saturated aqueous NaHCO3 (25 mL) and extracted with EtOAc (3×25 mL). The extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (34 g, SiO2, CH2Cl2 to 90/10/1 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (360 mg) as a white solid. LC-MS (ES) m/z=343 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:15][CH3:16])[CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.C(OC(C)C)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].CC(C)([O-])C.[Li+]>C1COCC1>[CH2:30]([O:29][C:27](=[O:28])[NH:14][C:12](=[O:13])[CH2:11][C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:4][CH:5]=1)[CH2:15][CH3:16])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC[C@H](CC(N)=O)Nc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CC[C@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Temperature: -12 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A clean, dry and nitrogen gas purged flask was charged with (3R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid amide (20.11 g, 77.27 mmol) and isopropyl ether (100 mL) and the mixture was cooled to −12° C. Benzyl chloroformate (13.25 mL, 92.8 mmol) was then added followed by the slow addition of 1.0 M lithium tert-butoxide in THF solution (185.5 mL). The lithium tert-butoxide solution was added at such a rate that the internal temperature remained below 0° C. Fifteen minutes after the completion of base addition, the reaction was quenched by adding the mixture to isopropyl ether (100 mL) and 1.5 M hydrochloric acid (130 mL). The phases were separated and the organic layer was washed with saturated aqueous sodium chloride solution (130 mL). The phases were separated, the organic layer was dried (MgSO4), filtered, and concentrated under partial vacuum (at 40° C.) to a total volume of 100 mL. Additional isopropylether (200 mL) was added and the solution was again concentrated under partial vacuum (at 40° C.) to a total volume of 100 mL. After cooling, the solution was seeded with (3R)-[3-(4-trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid benzyl ester and allowed to stir at room temperature overnight. The remaining solvent was displaced with cyclohexane using partial vacuum distillation (45° C. bath, 200 mL followed by 100 mL), the resultant slurry was cooled and stirred for 40 minutes, filtered, and dried to provide 25.8714 g (85%) of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CCO[C:20]([CH3:22])=[O:21].O.[CH3:24][N:25]([CH:27]=O)C>>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][O:11][C:24]1[CH:6]=[CH:4][C:5]([C:20](=[O:21])[C:22]2[CH:14]=[CH:13][CH:12]=[CH:9][CH:10]=2)=[CH:27][N:25]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(C)=O
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a solution of N—BOC-L-prolinol (500 mg, 3.25 mmol) in anhydrous DMF (7 ml) was added NaH (124 mg, 60% dispersion in oil, 3.1 mmol) and stirred for 15 min at rt. A solution of product from Example 140, step 2 (364 mg, 1.68 mmol) in anhy.DMF (5 ml) was added dropwise over 5 min. The mixture was stirred at rt for 48 h. The mixture was poured into EtOAc and water, the organic layer dried over MgSO4, and concentrated. Silica gel flash chromatography using EtOAc/hexanes gave the title compound (185 mg, 29%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:16]([O-])=O)=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][C:6]1=[O:19].C(O)C.[H][H]>[Pd].C1COCC1>[NH2:16][C:11]1[CH:10]=[C:9]2[C:14](=[C:13]([F:15])[CH:12]=1)[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])[C:6](=[O:19])[CH2:7][CH2:8]2
Reactant: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])cc(F)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)CCN1C(=O)CCc2cc(N)cc(F)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(2-(Dimethylamino)ethyl)-8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.77 mmol) was weighed into a round bottom flask equipped with a stirbar. Ethanol (10 mL) and THF (2 mL) were added, followed by Pd, 10 wt. % on activated carbon. The flask was fitted with a balloon of hydrogen, evacuated of air and backfilled with hydrogen. The black suspension was stirred for 3 h at room temperature. The solid palladium was then filtered off through a plug of celite and the celite pad washed with methanol. The filtrate was concentrated, then chromatographed on silica gel using 0-10% (2M NH3 in MeOH) in ethyl acetate to give the product. Yield: 325 mg, 72%. EI-MS: 251 (M+, 3), 58 (100).