Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][N:25]=1>CN(C)C=O.O>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][C:16]2[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[N:25][CH:26]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Sc1ccccc1S
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cnc(Sc2ccccc2Sc2ccc(Br)cn2)nc1
Reaction time: 4 h

Procedure:
To a mixture of 3.0 grams (0.02 mole) dimercaptobenzene and 7.0 grams of potassium carbonate stirring in 50 ml of dimethylformamide, 3.5 grams of 2,5-dichloropyrimidine is added at 0° and the mixture stirred for 4 hours, before adding 5.0 grams of 2,5-dibromopyridine and heating at 80° for 4 additional hours. The mixture is added to excess H2O and extracted with ethyl ether. After washing the ether layer with H2O, saturated NaHCO3, brine, and drying (MgSO4), evaporating the solvent gives the crude product.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[OH2:16]>>[C:14]1(=[O:2])[C:15]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11](=[O:16])[CH:12]=[CH:13]1
Reactant: c1ccc2ccccc2c1
Reactant: O
Reactant: O=S(=O)(O)O
Product: O=C1C=CC(=O)c2ccccc21

Procedure:
The process for the preparation of the quinone according to the present invention is usually conducted in the following manner. Namely, an aqueous sulfuric acid solution containing a predetermined amount of a ceric salt such as ceric sulfate, is reacted with a solution of the starting material such as naphthalene in the above-mentioned inert organic solvent immiscible with water according to the present invention, for a predetermined period of time under stirring at a predetermined temperature. Then, the solvent layer is separated from the aqueous layer. Some of the product still remaining in the aqueous layer is extracted with the above-mentioned organic solvent and combined to the separated solvent layer. The combined solvent layer is then treated depending upon the particularly purpose. For instance, for the purpose of obtaining a quinone such as 1,4-naphthoquinone, the solvent is removed under reduced pressure to obtain the product by precipitation or drying. Whereas, for the purpose of using it for the subsequent reaction step, the solvent layer is subjected to a proper treatment such as washing with water before subjecting it to the reaction step. The above process may be conducted by a multi-stage countercurrent process instead of conducting the above-mentioned reaction steps and the separation steps for the separation of the solvent layer from the aqueous layer by a combination of plurality of reactors and separation tanks.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2.CN(C)[CH:19]=[O:20]>O1CCCC1>[N:15]1[C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[CH:19]=[O:20])[CH:12]=[CH:13][CH:14]=1
Reactant: Brc1cccc2cccnc12
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=Cc1cccc2cccnc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
sec-Butyllithium (1.4 M in cyclohexane, 5.0 ml, 7.0 mmol) is added dropwise to a stirred solution of 8-bromoquinoline (1.29 g, 6.22 mmol) and anhydrous tetrahydrofuran (22 ml) at −78° C. under nitrogen. The reaction is then stirred at −78° C. for 10 min and then dimethylformamide (2.5 ml, 32.3 mmol) is added. The reaction is then stirred for 10 min at −78° C. and then quenched with water. The reaction is poured into saturated sodium bicarbonate (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexanes to yield (0.57 g, 58%) of quinoline-8-carboxaldehyde: mass spectrum (ion spray): m/z=158.0 (+1): 1H NMR (CDCl3): δ=11.46 (1H, s), 9.06-9.04 (1H, m), 8.34-8.32 (1H, m), 8.26-8.23 (1H, m), 8.11-8.08 (1H, m), 7.70-7.66 (1H, m), 7.53-7.50 (1H, m).
Reaction SMILES: [CH3:1][Mg]Br.COC(=O)[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[Cl:14].[Cl-].[NH4+].CC[O:20][CH2:21][CH3:22]>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:21]([OH:20])([CH3:22])[CH3:1])=[C:8]([Cl:14])[CH:9]=1
Reactant: CCOCC
Reactant: C[Mg]Br
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.88 ml of a 3 molar solution of methyl magnesium bromide in ether were added dropwise to a solution of 470 mg (1.88 mmol) of 4-bromo-2-chloro-benzoic acid methyl ester [CAS 185312-82-7] in 20 ml THF at −78° C. The reaction mixture was then warmed to rt and stirred overnight. The mixture was then poured into sat. ammonium chloride solution and extracted with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (0 to 20% ether in pentane). The title compound was obtained as a colorless liquid (415 mg, 82%). 1H NMR (CDCl3, 300 MHz): δ 1.71 (s, 6H), 2.39 (s, 1H), 7.38 (dd, J=8.5 and 2.1 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClC(Cl)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=1
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a stirred solution of 0.200 grams of (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.72 mmol) in 10 mL of dichloroethane was added 0.87 mL (10.82 mmol) of pyridine followed by the addition of 0.56 mL (7.2 mmol) of methanesulfonyl chloride. The reaction was stirred at 80° C. for 2 hours. The volatiles were removed under reduced pressure affording material which was flash chromatographed (25% EtOAc/hexane to 1:1 EtOAc:hexane to 100% EtOAc) to give 0.150 grams of N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-methanesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([F:15])[CH2:12][N:11]([C:16](OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.CCN(C(C)C)C(C)C.ClC1[CH:43]=[CH:42][N:41]=[CH:40][C:39]=1[N+:44]([O-:46])=[O:45]>[Pd].CCOC(C)=O>[F:15][C@@H:13]1[CH2:12][N:11]([C:16]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])[CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](F)CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](F)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of (3S,5S)-benzyl 3-(tert-butoxycarbonylamino)-5-fluoropiperidine-1-carboxylate (1 eq) in 5 methanol and 5 mL of EtOAc was added 10% Pd/C (0.1 eq). The resulting suspension was stirred at H2 atmosphere for 4 hours. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with MeOH, then concentrated in vacuo. The residue was dissolved in 5 mL of isopropanol and DIPEA (1.8 eq) and 4-chloro-3-nitropyridine (1.5 eq) were added. The reaction mixture was stirred at 65° C. for 3 hours, at which point the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with 120 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to give tert-butyl(3S,5S)-5-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate (78%). LC/MS (m/z): 341.1 (MH+), Rt=0.57 min. HPLC: Rt: 2.01 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:12]=[C:13]([NH2:26])[CH:14]=[C:15]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:16]=1.CS(O)(=O)=O>O1CCOCC1.C([O-])(O)=O.[Na+]>[F:9][C:5]1[C:6]([CH3:8])=[N:7][C:2]([NH:26][C:13]2[CH:14]=[C:15]([B:17]3[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:25])([CH3:24])[O:18]3)[CH:16]=[C:11]([CH3:10])[CH:12]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nc(Cl)ncc1F
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(Nc2ncc(F)c(C)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 100 °C
Yield: 62.6 %

Procedure:
To a solution of 2-chloro-5-fluoro-4-methyl-pyrimidine (4.00 g, 27.3 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (8.27 g, 35.5 mmol) in dioxane (40.7 mL) was added methanesulfonic acid (1.77 ml, 27.3 mmol) dropwise during which the reaction exothermed 15.7° C. Subsequently the reaction mixture was heated to 100° C. and allowed to stir over the weekend. The mixture was cooled to room temperature and was diluted with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic extracts were washed with brine and dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography provided (5-fluoro-4-methyl-pyrimidin-2-yl)-[3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]amine (5.87 g, 17.1 mmol) MS ESI: [M+]+ m/z 344.1. 1H NMR (500 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.38 (d, J=1.6, 1H), 7.81-7.62 (m, 2H), 7.07 (s, 1H), 2.36 (d, J=2.3, 3H), 2.26 (s, 3H), 1.27 (s, 12H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][NH:11][C:12](=[O:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:44][CH2:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:65])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]([F:64])([F:63])[F:62])[CH2:50][CH2:49]1)=[O:47].Cl>CN(C=O)C.O>[CH3:10][NH:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([NH:44][CH2:45][C:46](=[O:47])[N:48]2[CH2:49][CH2:50][N:51]([C:54](=[O:65])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:61]([F:64])([F:62])[F:63])[CH2:52][CH2:53]2)=[O:17])[CH:14]=1
Reactant: CNC(=O)c1cccc(C(=O)O)c1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)c1cccc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.18 %

Procedure:
DIPEA (330 mg, 0.44 mL, 2.6 mmol) was added drop wise to N-methyl-isophthalamic acid (145 mg, 0.8 mmol) in DMF (3 mL). EDCI (180 mg, 0.96 mmol) and HOBT (130 mg, 0.96 mmol) were added consecutively and, after 10 minutes, 2-Amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone in its HCl salt form (281 mg, 0.8 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using basic alumina and 10% MeOH in CHCl3 as eluent) to afford 35 mg (9.18% yield) of N-methyl-N′-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-isophthalamide. LCMS Purity: 97.7%. 1H NMR (CDCl3): δ 8.1 (bs, 1H), 7.9 (m, 2H), 7.7 (m, 1H), 7.5 (m, 3H), 7.4 (m, 2H), 6.3 (bs, 1H), 4.2 (m, 2H), 4.0 (m, 2H), 3.6 (m, 5H), 3.4 (m, 1H), 3.2 (m, 2H), 3.0 (d, 3H).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[F:28][C:29]([F:39])([F:38])C1C=C(C=CC=1)C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:29]([F:39])([F:38])[F:28])[CH:19]=2)[O:6][C:7]=1[CH3:8]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2cccc(C(F)(F)F)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-methyl-2-(3-trifluoromethylphenyl)oxazole.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:5][CH2:4][C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[NH2:1]
Reactant: N#Cc1cc(Cl)ccc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
2-Amino-5-chloro-benzonitrile (9.0 g, 59 mmol) in tetrahydrofuran (100 ml) was added dropwise to an ice cooled 1 molar solution of lithium aluminium hydride (100 ml) in tetrahydrofuran and the reaction mixture was stirred at room temperature for 18 hours. Water (10 ml) was added dropwise. The resulting emulsion was dried over magnesium sulphate, filtered and evaporated under reduced pressure to give the title compound as a white solid (4.56 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.CCCCCC>O1CCCC1.CCOCC>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([B:16]([OH:17])[OH:15])[CH:7]=[CH:6][N:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1cc(I)ccn1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccnc(C(F)(F)F)c1
Temperature: -78 °C
Yield: 66.5 %

Procedure:
To a solution of 4-iodo-2-(trifluoromethyl)pyridine [purchased from Matrix Scientific] (2.5 g, 9.16 mmol) and triisopropylborate (2.54 mL, 10.99 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under nitrogen was added dropwise a solution of n-butyl lithium in hexane (2.5 M, 4.03 mL, 10.07 mmol). The reaction was stirred at −78° C. for 2½ hours then allowed to warm slowly to −10° C. over 1 hour. The reaction mixture was then quenched by the addition of water (20 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous phase was diluted with water (40 mL) and washed with ether (2×40 mL). The aqueous phase was then acidified to pH 5 by the addition of acetic acid and the resulting oily suspension extracted with ether (100 mL). The organic phase was separated, washed with saturated brine (2×50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give an off-white foam. Ether (12 mL) and hexanes (24 mL) were added and the resulting suspension stirred vigorously for 30 minutes then filtered to give 2-(trifluoromethyl)pyridine-4-boronic acid (1.163 g, 67% yield) as a cream solid.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH2:8]([O:7][CH2:6][CH:2]([Cl:1])[C:3](=[O:4])[NH:36][CH2:35][C:34]([O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:37])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(Cl)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)C(Cl)COCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
76 g (326.1 mmol) of 2-chloro-3-(benzyloxy)-propionic acid chloride (produced according to Inorg. Chem. Vol. 31; 2422, 1992) is added in drops to 100 g (296.4 mmol) of glycine benzyl ester-p-toluenesulfonic acid salt and 33.0 g (326.1 mmol) of triethylamine in 400 ml of methylene chloride at 0° C., and it is stirred for 2 hours at this temperature. 500 ml of ice water is added, and the water phase is set at pH 2 with 10% aqueous hydorchloric acid. The organic phase is separated, washed once each with 300 ml of 5% aqueous hydrochloric acid, 300 ml of 5% aqueous soda solution and 400 ml of water. The organic phase is dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/acetone=15/5/1).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])=O.[NH3:9]>[H][H]>[NH2:9][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[NH2:9][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: N
Reactant: N#CCCCCC=O
Reactant: [H][H]
Product: N#CCCCCCN
Product: NCCCCCCN
Temperature: 80 °C
Reaction time: 2 h
Yield: 12 %
Yield: 73 %

Procedure:
In an autoclave having a capacity of 300 ml and equipped with a sampling sluice (material HC 4) there were placed 11 g of 5-formylvaleronitrile and 3 g of Ru (3%) on Al2O3 (4 mm extrudates) under protective gas (argon). The autoclave was then sealed and 150 ml of NH3 were forced in. Thorough mixing was effected using a magnetic stirrer. After heating to 80° C. (autogenous pressure: ca. 39 bar) the mixture was kept at 80° C. for a further 2 hours and then the overall pressure was raised, with hydrogen, to 70 bar. The pressure of 70 bar was maintained by constantly forcing in more hydrogen. After 25 hours, the autoclave was depressurized and the hydrogenation effluent analyzed by gas chromatography. The products formed comprised 73% of 6-aminocapronitrile and 12% of hexamethylene diamine. The conversion was 100%.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[N:8][C:9]=2[N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:4]([CH2:28][CH3:29])[N:3]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[NH:82]1[CH2:86][CH2:85][CH2:84][CH2:83]1>C1(C)C=CC=CC=1>[CH2:28]([N:4]1[C:5]2=[N:6][C:7]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[N:8][C:9]([N:11]3[CH2:12][CH:13]4[O:18][CH:16]([CH2:15][CH2:14]4)[CH2:17]3)=[C:10]2[C:2]([N:82]2[CH2:86][CH2:85][CH2:84][CH2:83]2)=[N:3]1)[CH3:29]
Reactant: CCn1nc(Br)c2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Reactant: C1CCNC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCn1nc(N2CCCC2)c2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21

Procedure:
To a solution of 3-bromo-1-ethyl-6-(4-nitrophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (100 mg)(0.21 mmol) in toluene (2.0 mL) was added Pd(dba)3 (20 mg)(10 mol %), Binap (80 mg) (30 mol %), sodium tert butoxide (82 mg) and excess pyrrolidine. The mixture was purged under nitrogen for 5 minutes and then heated to 65 C overnight. Concentrated in vacuo to give an oil that was purified by silica gel chromatography (EtOAc/Hexanes) to afford 35 mg of the desired product as a yellow oil. MS m/z=450 (M+H)
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:20]([C:19]1[CH:18]=[C:17]([CH:30]=[CH:29][CH:28]=1)[O:16][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)(=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(COc3cccc(C(=O)c4ccccc4)c3)cc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 104.6 %

Procedure:
Methyl 1-(4-(bromomethyl)phenyl)cyclopropanecarboxylate (2.478 g, 9.207 mmol) was added to a mixture of 3-hydroxybenzophenone (2.19 g, 11.05 mmol) and potassium carbonate (3.054 g, 22.10 mmol) in dimethyl formamide (46 mL). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with 10% aqueous potassium carbonate (×5), 2M NaOH (×5), brine and dried (magnesium sulfate), filtered, and concentrated under reduced pressure to afford the title compound (3.721 g, quantitative yield). The material was used directly in the next step with no further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.I[CH2:11][C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].P(=O)(O)(O)O>C(OCC)(=O)C.O>[C:12]([CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([OH:14])=[O:13]
Reactant: O=C(O)CI
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OCC(=O)O)cc1
Temperature: 60 °C

Procedure:
To a solution of p-hydroxybenzaldehyde (49 g, 0.40 mol) were added iodoacetic acid (75 g, 0.40 mol) and potassium carbonate (anhydrous, 120 g), and the magnetically stirred mixture was warmed at 60° C. for three days. The resulting solid was dispersed mechanically in a mixture of ethyl acetate (400 ml) and water. The mixture was neutralized cautiously with phosphoric acid. After the dissolution of the solid mass, the neutral aqueous layer was withdrawn. The organic layer was extracted repeatedly with a concentrated solution of dibasic sodium phosphate, to remove additional acidic organic material. The aqueous extracts were combined, filtered through glass wool, and acidified to pH 1 using 6N HCl. This solution was placed in the refrigerator overnight, and a product of tan crystals (21.85 g) was collected. Unreacted p-hydroxybenzaldehyde was recovered upon evaporation of the organic layer. Yield based on recovery of starting material was 60%. Mp 191°-193° C. Analysis (C9H8O4): calc. 60.00% C, 4.48% H; found 59.66% C, 4.37% H.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:14])[CH:3]=1.[ClH:30]>ClCCl.CO>[ClH:30].[ClH:30].[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1C#N
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOc1nc(C(=O)NCC2CCNCC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The compound prepared in Example 225 (0.603 g) was suspended in dichloromethane (30 mL) and methanol (10 mL). Hydrogen chloride solution (4 mol/L in 1,4-dioxane) (10.0 mL) was added and the reaction mixture stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound (0.547 g), which was used without further purification, possessing the following physical data.