Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.Cl>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: NCCN1CCCC1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Br)cnc1NCCN1CCCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.86 mL (5.05 mmol) ethyldiiopropylamine are added to a solution of 600 mg (2.53 mmol) 5-bromo-2-chloro-3-nitropyridine and 0.32 mL (2.53 mmol) 1-(2-aminoethyl)-pyrrolidine in 3 mL n-butanol. The reaction is heated to 50° C. and stirred for one hour at this temperature. The solvent is eliminated i.vac. and the residue is combined with 40 mL water and acidified with 1 M HCl. The aqueous phase is extracted with 20 mL EtOAc and the aqueous phase is then made alkaline with saturated K2CO3 solution. The aqueous phase is extracted with 40 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac.
Reaction SMILES: [OH:1][C:2]([P:8]([OH:11])(=[O:10])[OH:9])([P:4]([OH:7])(=[O:6])[OH:5])[CH3:3].[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14].Cl>C(N(CC)CC)C>[C:12]([O:1][C:2]([P:4]([OH:7])(=[O:5])[OH:6])([P:8]([OH:11])(=[O:9])[OH:10])[CH3:3])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: CC(O)(P(=O)(O)O)P(=O)(O)O
Reactant: C=C(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(C)(P(=O)(O)O)P(=O)(O)O
Temperature: 25 °C
Yield: 65 %

Procedure:
To 5 g (0.024 mol) of 1-hydroxyethane-1,1-diphosphonic acid in 30 ml of triethylamine was gradually added 15.7 g (0.15 mol) of methacryloyl chloride with ice cooling. After the temperature was raised to room temperature, the mixture was stirred for ten hours. The reaction solution was acidified with aqueous hydrochloric acid and then extracted with diethyl ether. The resulting aqueous phase was alkalized with sodium hydroxide and then extracted again with diethyl ether. The resulting aqueous phase was chromatographed over Amberlite 120B (trade mark, Rohm & Haas Co.) and the solvent of the eluate was evaporated to give 4.3 g of a colorless oily substance which was identified to be 1-methacryloxyethane-1,1-diphosphonic acid (yield 65%).
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].[C:5]([SiH2:9][O:10][C:11]([CH3:23])([CH3:22])[C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH2:21])[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[C:5]([SiH2:9][O:10][C:11]([CH3:23])([CH3:22])[C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH:21][C:1](=[O:2])[CH3:3])[CH:15]=[CH:16][C:17]=1[Cl:18])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CCN)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
AcCl (0.063 mL, 0.88 mmol) was added to a sol. of 2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethylamine (252 mg, 0.840 mmol) and DIPEA (0.575 mL, 3.36 mmol) in CH2Cl2 (8.4 mL). The mixture was stirred at rt for 30 min, and aq. sat. NH4Cl was added. The layers were separated, and the org. layer was washed with aq. 1M NaOH, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2/MeOH 19:1) yielded the title compound (190 mg, 66%). LC-MS: tR=1.09 min; ES+: 342.19.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]=2[CH:6]=[N:7]1)([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COC(=O)c1cc(Br)cc2c1cnn2C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cn[nH]c2)cc2c1cnn2C(C)C

Procedure:
To a stirred solution of methyl 6-bromo-1-isopropyl-1H-indazole-4-carboxylate, 1 (0.8 g, 2.7 mmol) in 1,4-dioxane (20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.576 g, 2.97 mmol) and NaHCO3 (0.567 g, 6.75 mmol) dissolved in water (8 mL). The reaction mixture was degassed with argon gas for 30 min. To the resulting mixture was added PdCl2(dppf)-CH2Cl2 adduct (0.110 g, 0.135 mmol) and the mixture heated at reflux for 3 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 800 mg of crude product. The crude compound was purified by silica gel chromatography (eluent: 5% MeOH/DCM) to the title compound as a pale liquid (375 mg, 47%). LCMS (ES−) m/z=283.11.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[C:3]([CH3:9])([CH3:8])[CH2:2][OH:1]
Reactant: COC(=O)C(C)(C)CO
Reactant: NCc1ccccc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(CO)C(=O)NCc1ccccc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (1.0 g, 7.57 mmol) and 2-chlorobenzylamine (1.09 mL, 9.08 mmol, 1.2 equiv.) in toluene (10 mL) was added trimethylaluminum (2M in hexanes, 5.6 mL, 11.4 mmol, 1.5 equiv.). The reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated. The resulting residue was dissolved in EtOAc (100 mL). The organic layer was washed with saturated NaHCO3, dried over Na2SO4, and concentrated. The resulting residue was purified on silica gel column using a mixture of hexanes and ethyl acetate to give N-(2-chlorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (1.55 g, 84%). LRMS (M+H+) m/z 242.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]([NH2:16])([CH3:15])[CH3:14]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][C:13]([CH3:15])([CH3:14])[CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: C1COCCO1
Product: CC(C)(C)NS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-bromobenzene-1-sulfonyl chloride (2 g, 7.83 mmol, 1.0 eq) and 2-methylpropan-2-amine (1.72 g, 23.5 mmol, 3.0 eq) in dioxane (50 mL) was stirred at room temperature for 1 hours and filtered. The filtrate was concentrated in vacuo to afford 3-bromo-N-tert-butylbenzenesulfonamide (all for the next step). LCMS: 291.9, 293.9 [M+H]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C:16]([O-:18])=[O:17])C(O)=CC=C(C)C=1.[K+].C(=O)=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1
Reactant: Cc1ccc(O)c(C(=O)[O-])c1
Reactant: Oc1ccccc1
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 79.6 %

Procedure:
A pressure vessel was charged with 4.73 g of phenol, 23.52 g of potassium para cresolate being in a dry powder form and 54 ml of a high boiling point light oil fraction (160° to 230° C./10mmHg) . Reaction was carried out at a carbon dioxide pressure of 4 kg/cm2 (G) and at 250° C. for one hour. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 79.6% on the basis of phenol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[SH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][S:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(S)cc1
Reactant: OCCCC1CCN(c2ccc(Cl)nn2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(SCCCC2CCN(c3ccc(Cl)nn3)CC2)cc1
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a stirred solution of 5.6 parts of 1-(6-chloro-3-pyridazinyl)-4-piperidinepropanol, 4.2 parts of ethyl 4-mercaptobenzoate and 6 parts of triphenylposphine in 135 parts of tetrahydrofuran was added dropwise a solution of 4 parts of diethyl diazenedicarboxylate in 45 parts of tetrahydrofuran at 20° C. Upon complete addition, stirring was continued overnight at this temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was ectracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.3 parts (13.5%) of ethyl 4-[[3-[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]propyl]thio]benzoate; mp. 96.3° C. (comp. 164).
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH:5]1[CH2:26][C:8]2=[CH:9][C:10]3[C:11](=[O:25])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C:13](=O)[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3].Cl>CC(O)=O.[Zn]>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:26][C:8]2=[CH:9][C:10]3[C:11](=[O:25])[N:12]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[CH2:13][C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:28][CH3:29]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(F)cc1)C3=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccc(F)cc1)C3

Procedure:
Using procedure 47, 6-(dipropylamino)-2-[(4-fluorophenyl)methyl]-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione (101, 0.56 g, 1.43 mmol) was reduced with Zinc dust (0.94 g, 14.3 mmol) in glacial HOAc (20 mL). Purification using silica gel, eluting with 9:1 CH2Cl2 /MeOH, afforded an oil that was converted to an HCl salt and recrystallized from EtOAc/MeOH to give 132 as a white solid (m.p. 227-228° C.).
Reaction SMILES: [CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([O:10][C:11]3[CH:16]=[CH:15][N+:14]([O-])=[C:13]([CH3:18])[C:12]=3[CH3:19])[CH2:6][O:5]2)[CH2:3][CH2:2]1.C(OC(=O)C)(=[O:22])C.C(N(CC)CC)C.[OH-].[Na+].[Cl-].[NH4+]>CO>[CH2:1]1[C:4]2([O:9][CH2:8][CH:7]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:18][OH:22])[C:12]=3[CH3:19])[CH2:6][O:5]2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(OC2COC3(CCC3)OC2)cc[n+]([O-])c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1c(OC2COC3(CCC3)OC2)ccnc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
The 4-(5,9-dioxaspiro[3.5]non-7-yloxy)-2,3-dimethylpyridine 1-oxide (1.25 g, 4.71 mmol) obtained in the step (9f) was mixed with acetic anhydride (4.45 ml, 47.1 mmol). After the mixture was stirred at room temperature for one hour, it was cooled to 0° C. After triethylamine (656 μl, 4.71 mmol) was added, the mixture was stirred for one hour and stirred at room temperature for another one hour. After stirred at 50° C. for 2 hours, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/heptane=1/3). To the obtained product, methanol (30 ml) and a 5N aqueous sodium hydroxide solution (2.24 ml, 11.2 mol) were added, and the reaction mixture was stirred at room temperature for one hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to adjust the pH of the solution to about 9 and thereafter concentrated. The resultant residue was extracted with ethyl acetate three times. Organic layers were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (630 mg, yield: 49.6%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[C:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:23]=3[CH3:24])[O:16][N:15]=2)[CH:5]=[C:6]([CH3:13])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.C1COCC1.[NH3:34]>CO.[OH-].[Na+]>[NH2:34][CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:14]2[N:18]=[C:17]([C:19]3[S:20][CH:21]=[C:22]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:23]=3[CH3:24])[O:16][N:15]=2)=[CH:5][C:6]=1[CH3:13]
Reactant: N
Reactant: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2noc(-c3scc(CC(C)C)c3C)n2)cc(C)c1OCC(O)CN

Procedure:
A suspension of rac-3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazole (382 mg, 0.959 mmol) in 7 N NH3 in MeOH (10 mL) and THF (5 mL) is stirred at 60° C. for 15 h. The mixture is diluted with 1M aq. NaOH (30 mL) and extracted with DCM (4×75 mL). The combined organic extracts are dried (Na2SO4), filtered and evaporated to give rac-1-amino-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (419 mg) as a pale yellow solid; LC-MS: tR=0.90 min, [M+1]=416.42.
Reaction SMILES: [CH3:1][C:2]([C:11]([OH:13])=[O:12])([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3].[CH2:14]=O.[ClH:16]>>[ClH:16].[CH3:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:14][NH:3]1
Reactant: CC(N)(Cc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cl
Product: CC1(C(=O)O)Cc2ccccc2CN1
Temperature: 60 °C
Reaction time: 48 h
Yield: 40 %

Procedure:
To a suspension of alpha-methyl-DL-phenylalanine (2.00 g, 11.2 mmol) in conc. HCl (30 mL) was added formaldehyde (37%, 4.0 mL, 4.36 g, 4.81 mmol) and the resulting suspension was stirred at 60° C. for 48 h. The precipitated solid was collected and dried in vacuo to give 1.02 g (40%) of 3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride. 1H NMR (400 MHz, CD3OD): δ 7.33-7.24 (m, 4H), 4.53 (d, J=16.8 Hz, 1H), 4.42 (d, J=16.0 Hz, 1H), 3.43 (d, J=17.6 Hz, 1H), 3.18 (d, J=17.2 Hz, 1H), 1.67 (s, 3H); LC-MS (EI) m/z: 192.0 (M+H+). Using the same method as for VP-2851, 3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride (1.01 g, 4.436 mmol) was converted to yield methyl 7-amino-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (600 mg, 38% yield, 2 steps) as a grey solid. 1H NMR (400 MHz, CD3OD): δ 7.48 (d, J=7.6 Hz, 1H), 7.38 (s, 1H), 7.37 (dd, J=8.0, 2.4 Hz, 1H), 4.83 (d, J=15.2 Hz, 1H), 4.78 (d, J=15.2 Hz, 1H), 3.63 (s, 3H), 3.27 (d, J=14.8 Hz, 1H), 3.15 (d, J=14.4 Hz, 1H), 1.51 (s, 3H); LC-MS (EI) m/z: 317.0 (M+H+). Using general method M, methyl 7-amino-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (0.600 g, 1.70 mmol) and pivaloylacetonitrile (0.21 g, 1.7 mmol) were combined to afford methyl 7-(5-amino-3-t-butyl-1H-pyrazol-1-yl)-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (240 mg, 30% yield) as a yellow foam. LC-MS (EI) m/z: 439.0 (M+H+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>[OH-].[Na+].CCOCC>[OH:1][CH:2]1[CH2:6][N:5]([S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2C(=O)O)cc1
Temperature: 5 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
A stirred solution of 52.45 g (0.40 mole) of trans-4-hydroxy-L-proline in 500 ml of sodium hydroxide is treated with 85.79 g (0.45 mole) of p-toluenesulfonyl chloride in 500 ml of ether at room temperature. Stirring is continued for 6 hours, the layers are separated and the aqueous phase is cooled to 5° C. in an ice-bath. The mixture is then acidified while cooling with 30 ml of concentrated hydrochloric acid to pH 2 and the precipitated white solid is collected, washed with 150 ml of cold water, and dried in vacuo yielding 106.2 g of material, melting point 139°-143° C. Crystallization from 300 ml of ethyl acetate yields 98.6 g of the title compound, melting point 142°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:20][C:21]1[C:26]([F:27])=[CH:25][N:24]=[C:23]([N:28]=C(C3C=CC=CC=3)C3C=CC=CC=3)[N:22]=1)=[CH:7]2.CC([O-])=O.[Na+].Cl.NO>CO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:20][C:21]1[C:26]([F:27])=[CH:25][N:24]=[C:23]([NH2:28])[N:22]=1)=[CH:7]2
Reactant: Fc1cnc(N=C(c2ccccc2)c2ccccc2)nc1NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: Nc1ncc(F)c(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of N4-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-N2-(diphenylmethylene)-5-fluoropyrimidine-2,4-diamine (0.1370 g, 0.237 mmol) in 6 ml of MeOH at room temperature was added sodium acetate anhydrous (0.0661 g, 0.805 mmol) followed by hydroxylamine hydrochloride (0.0461 g, 0.663 mmol), and the mixture was stirred at room temperature for 15 hr. Then mixture was heated under reflux. After 6 hr at 70° C., the mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography on a 40 g of Redi-Sep™ column using 0-100% gradient of EtOAc in Hexane over 14 min and then 100% isocratic of EtOAc for 10 min as eluent to give N4-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-5-fluoropyrimidine-2,4-diamine as a yellow syrup and the yellow syrup was purified by semi-prep-HPLC on a Gemini™ 10μ C18 column (250×21.2 mm, 10 μm) using 10-90% gradient of CH3CN (0.1% of TFA) in water (0.1% of TFA) over 28 min as eluent to give the desired product as a TFA salt. The purified product as a TFA salt was treated with saturated NaHCO3 (20 ml) and extracted with CH2Cl2 (30 ml×2). The combined organic layers were washed with H2O (30 ml×2), dried over Na2SO4, filtered, concentrated under reduced pressure to give N4-((8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)-5-fluoropyrimidine-2,4-diamine as a light yellow film: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (1H, s), 8.07 (1H, dd, J=8.4, 1. Hz), 7.95 (1H, dd, J=7.5, 1. Hz), 7.48-7.67 (7H, m), 5.76 (2H, br. s.), 4.42 (2H, d, J=19.4 Hz); LC-MS (ESI) m/z 414.0 and 416.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][N:13](C)C(=O)C>O>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Solvent: O
Product: N#Cc1ncc(Br)cc1[N+](=O)[O-]

Procedure:
Heat a solution of 2,5-dibromo-3-nitropyridine (1.77 g, 6.3 mmol; Malinowski (1988) Bull. Soc. Chim. Belg. 97:51; see also U.S. Pat. No. 5,801,183) and cuprous cyanide (0.60 g, 6.69 mmol) in N,N-dimethylacetamide (25 mL) at 100° C. for 72 hours. After cooling, dilute the mixture with water (25 mL) and extract twice with EtOAc (25 mL each), then wash twice with water (25 mL each). The combined EtOAc extracts are dried (Na2SO4), evaporated, and purified by flash chromatography (50% EtOAc-hexane) to obtain 5-bromo-3-nitropyridine-2-carbonitrile as a pale solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][N+:14]([O-])=O)[CH2:9][C:8]2=[O:17])=[CH:4][CH:3]=1>C(O)C.[Ni].O>[NH2:14][CH2:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=2)[C:8](=[O:17])[CH2:9]1
Reactant: O=C1CC(C[N+](=O)[O-])CCN1Cc1ccc(F)cc1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: NCC1CCN(Cc2ccc(F)cc2)C(=O)C1
Reaction time: 16 h

Procedure:
To a degassed solution of 1-(4-fluorobenzyl)-4-(nitromethyl)piperidin-2-one (1.4 g, 5.3 mmol) in absolute ethanol (80 mL) was added wet Raney nickel catalyst (1.4 g of a 50% weight slurry in water) which was washed to neutral pH with deionized water and absolute ethanol. The reaction mixture was shaken under an atmosphere of 55 psi of hydrogen for 16 hours. The product mixture was filtered through celite and the filtrate was concentrated under vacuum to afford the title compound as colorless viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 2H), 7.01 (t, J=8.7 Hz, 2H), 4.64 (d, J=14.6 Hz, 1H), 4.44 (d, 1H), 3.23 (m, 2H), 2.65 (m, 2H), 2.16-1.28 (m).
Reaction SMILES: [Cl-].FC1C=CC(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([Li])CCC.[CH2:34]([N:41]1[CH2:46][CH:45]2[CH2:47][CH2:48][CH:42]1[C:43](=O)[CH2:44]2)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[Na+]>O1CCCC1>[C:35]1([CH2:34][N:41]2[CH2:46][CH:45]3[CH2:47][CH2:48][CH:42]2[CH2:43][CH2:44]3)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1CC2CCC1N(Cc1ccccc1)C2
Agent: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(CN2CC3CCC2CC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 150.8 %

Procedure:
To a vigorously stirring suspension of p-fluorobenzyltriphenylphosphonium chloride (5.7 g, 14 mmol, Aldrich) in dry tetrahydrofuran (30 mL) at −78° C. was added 2.5 M n-butyllithium (4.7 mL, 12 mmol) in hexanes via syringe. After 30 min, the orange-yellow mixture was warmed to 0° C., and the suspension became deep red. After 5 min, 2-benzyl-2-azabicyclo[2.2.2]octan-6-one (1.2 g, 5.6 mmol) was added as a solution in dry tetrahydrofuran (25 mL) via cannula. Upon stirring vigorously for 2.5 hrs, the reaction was poured into saturated aqueous sodium chloride (70 mL), and the aqueous layer was extracted with ethyl acetate (3×70 mL). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, and concentrated in vacuo. The resulting yellow solid was purified by flash chromatography (20%-70% ethyl acetate in hexanes) to yield 6-[4-fluorophenyl)methylene]-2-(phenylmethyl)-2-azabicyclo[2.2.2]octane (1.7 g, 99%) as a pale yellow oil. MS (ESI) 308 (M+H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:14][C:15]([CH:17]([CH2:27][CH2:28][CH3:29])[CH2:18][C:19]1([C:24](O)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[Cl:4][C:24]([C:19]1([CH2:18][CH:17]([CH2:27][CH2:28][CH3:29])[C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:16])[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:25]
Reactant: CCCC(CC1(C(=O)O)CCCC1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCC(CC1(C(=O)Cl)CCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.15 ml, 13.2 mmol) was added to an ice-cooled solution of 1-{2-[(benzyloxy)carbonyl]pentyl}cyclopentanecarboxylic acid (EP 274234) (2.0 g, 6.3 mmol) in dry dichloromethane (20 ml), and the solution stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue azetroed with dichloromethane (3×), to give the title compound as a golden oil, 2.1 g; 1H NMR (CDCl3, 300 MHz) δ: 0.88 (t, 3H), 1.28 (m, 2H), 1.43 (m, 2H), 1.63 (m, 6H), 2.00 (m, 1H), 2.08-2.35 (m, 3H), 2.44 (m, 1H), 5.15 (s, 2H), 7.28 (m, 5H).