Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C.[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([C:35](Cl)=[O:36])=[N:27]1>ClCCl.C(OCC)(=O)C>[F:16][C:3]([F:2])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH:14][C:35]([C:28]2[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:26][N:27]=2)=[O:36])[CH3:13])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1noc2ccccc12
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(NC(=O)c1noc2ccccc12)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (20 mg, 0.078 mmol, Amine-1, single enantiomer) and N,N-diisopropylethylamine (0.054 mL, 0.31 mmol) in dichloromethane (0.5 mL) is added dropwise a solution of benzo[d]isoxazole-3-carbonyl chloride (17 mg, 0.094 mmol) in dichloromethane (0.5 mL) at room temperature. The reaction mixture is stirred at room temperature for 1 hour. The mixture is diluted with ethyl acetate (3 mL) and washed with water (1.5 mL). The organic layer is dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on NH-silica gel eluting with ethyl acetate and then preparative LC-MS to give 9.1 mg (32% yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21]>C1(C)C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]([Cl:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Nc1ccccc1C(F)(F)F)c1ccccc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccccc1N=C(Cl)c1ccccc1
Yield: 101.5 %

Procedure:
Using the procedure of Step B of Example 6, 26.52 g of the product of Step A and 22.9 g of phosphorus pentachloride were reacted in 160 ml of dry toluene to obtain 28.8 g of N-(2-trifluoromethylphenyl)-benzenecarboximidoyl chloride as an oil which was used as is for the next step.
Reaction SMILES: ClC1C=NC(OCC2CCCCC2)=C(C=1)C(O)=O.COC(Cl)=O.[Na].NCC[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.C([O-])(=O)C.[Na+]>O1CCCC1.C(N(CC)CC)C>[C:32]([OH:34])(=[O:33])[C:31]1[CH:35]=[CH:36][CH:28]=[CH:29][CH:30]=1
Reactant: NCCc1ccc(C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: COC(=O)Cl
Agent: O=C(O)c1cc(Cl)cnc1OCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1 g of triethylamine is added to 2.7 g of 5-chloro-2-hexahydrobenzyloxy-nicotinic acid (melting point 150° to 151° C., prepared from 2-chloronicotinic acid by reacting same with hexahydrobenzyl alcohol-sodium with subsequent chlorination with chlorine) in 100 ml of tetrahydrofuran and, after cooling to 0° C., 0.95 g of chloroformic acid methyl ester is added. Stirring of the mixture is continued for 15 minutes at 0° C. and the mixture is added to 10 ml of an about 1 molar solution of 4-(2-aminoethyl)-benzoic acid sodium additionally containing 0.01 mol of sodium acetate, and stirring is continued for 3 hours at room temperature. The major proportion of the solvent is distilled off under reduced pressure and the residue is acidified. The 4-(2-<5-chloro-2-hexahydrobenzyloxy-nicotinamido>-ethyl)-benzoic acid obtained is reprecipitated from ammonia and recrystallized from dilute ethanol. Melting point 177°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C(N1CCOCC1)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Reactant: NCC(=O)O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCC(=O)NCC(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 7.1 %

Procedure:
To a solution of p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and glycine (37 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was added N-ethylmorpholine (128 μl, 1.0 mmol). The mixture was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was chromatographed on a Sephadex, LH20 column (1.5×90 cm, eluent: ethanol). The eluate was evaporated and the residue was crystallized from ethyl ether to give 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinone-6-yl)propionyl-glycine (11 mg), melting at 128°-130° C. Rf=0.34 (Chloroform-methanol-acetic acid (18:2:1), silica gel plate) (briefly Rf1), Rf=0.52 (Ethyl acetate-pyridine-acetic acid-water (60:20:6:10, v/v, silica gel plate) (briefly Rf2)
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)[C@H]1O[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.N[C@@H](CCC(N[C@H](C(NCC(O)=O)=O)CS)=O)C(O)=O.[CH:52]1[CH:57]=[N+:56]([C@@H:58]2[O:62][C@H:61]([CH2:63][O:64][P:65]([O:68][P:69]([O:72][CH2:73][C@H:74]3[O:78][C@@H:77]([N:79]4[C:83]5[N:84]=[CH:85][N:86]=[C:87]([NH2:88])[C:82]=5[N:81]=[CH:80]4)[C@H:76]([O:89][P:90]([OH:93])([OH:92])=[O:91])[C@@H:75]3[OH:94])([OH:71])=[O:70])([OH:67])=[O:66])[C@@H:60]([OH:95])[C@H:59]2[OH:96])[CH:55]=[C:54]([C:97]([NH2:99])=[O:98])[CH:53]=1.[Mg+2].[Cl-].[Cl-].C(OP(O)(O)=O)[C@H]1O[C@H](OP(O)(O)=O)[C@H](O)[C@@H](O)[C@@H]1O.C(OP(O)(O)=O)[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O>>[CH:85]1[N:86]=[C:87]([NH2:88])[C:82]2[N:81]=[CH:80][N:79]([C@@H:77]3[O:78][C@H:74]([CH2:73][O:72][P:69]([O:68][P:65]([O:64][CH2:63][C@H:61]4[O:62][C@@H:58]([N:56]5[CH:55]=[C:54]([C:97]([NH2:99])=[O:98])[CH2:53][CH:52]=[CH:57]5)[C@H:59]([OH:96])[C@@H:60]4[OH:95])([OH:67])=[O:66])([OH:71])=[O:70])[C@@H:75]([OH:94])[C@H:76]3[O:89][P:90]([OH:93])([OH:92])=[O:91])[C:83]=2[N:84]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: O=P(O)(O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=P(O)(O)OC[C@H]1O[C@H](OP(=O)(O)O)[C@H](O)[C@@H](O)[C@@H]1O
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
The activity of the enzyme is determined by the following procedure. That is, a total 100 ml buffer solution of 57 mM potassium phosphate containing 10.8 g of trehalose, 860 mg of glutathione and 17.2 mg of EDTA·2Na, pH 7.0, is prepared. A mixture of 1,400 μl of the buffer solution, 100 μl of 20 mM NADP+ aqueous solution, 100 μl of 26 mM MgCl2 aqueous solution, 100 μl of 1.34 mM glucose 1,6-diphosphate aqueous solution, 100 μl of 31 U/ml phosphoglucomutase aqueous solution, 100 μl of 35 U/ml glucose-6-phosphate dehydrogenase aqueous solution and 100 μl of a test sample enzyme solution is incubated at 30° C. and the amount of NADPH produced is determined by the absorbance at 340 nm with the passage of lime. The quantity of enzyme which produces one μ mole of NADPH in one minute under the above reaction conditions is made one Unit.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH2:11])[CH2:4]2.[I:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](O)=[O:22])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([I:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccc(I)cc1
Agent: Cl
Product: O=C(/C=C/c1ccc(I)cc1)NC1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from racemic 1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-iodophenyl)propenoic acid; MS (ES+) 357 (MH+).
Reaction SMILES: Cl[C:2]1[C:14]2[CH:13]=[C:12]3[N:7]([CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15])[C:6]=2[N:5]=[C:4]([Cl:17])[N:3]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C>>[Cl:17][C:4]1[N:3]=[C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:14]2[CH:13]=[C:12]3[N:7]([C:6]=2[N:5]=1)[CH2:8][CH2:9][O:10][C:11]3([CH3:16])[CH3:15]
Reactant: CC1(C)OCCn2c1cc1c(Cl)nc(Cl)nc12
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: CC1(C)OCCn2c1cc1c(N3CCOCC3)nc(Cl)nc12
Yield: 40 %

Procedure:
Cesium carbonate (1.2 g, 3.7 mmol) and 1,2-dibromoethane (316 μL, 3.7 mmol) were added to a solution of 2-(2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-propan-2-ol (304 mg, 1.23 mmol) in DMF (4 mL) and the reaction mixture was heated at 100° C. for 45 min, then partitioned between water and ethyl acetate. The organic extract was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo affording 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene. A mixture of 1,3-dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene (1.23 mmol), morpholine (236 μL, 2.69 mmol) and triethylamine (342 μL, 2.46 mmol) in IMS (3 mL) was heated at reflux for 3 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0 to 40% ethyl acetate in cyclohexane) affording 3-Chloro-8,8-dimethyl-1-morpholin-4-yl-5,6-dihydro-8H-7-oxa-2,4,4b-triaza-fluorene (159 mg, 40%). LCMS (method A): RT=3.13 min, [M+H]+=323.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[C:27]1([CH:33]([CH3:36])[CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH:33]([CH3:36])[CH2:34][NH:35][S:12]([N:9]2[CH2:10][CH2:11][C:6]3([C:2](=[O:1])[N:3]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[CH2:4][CH2:5]3)[CH2:7][CH2:8]2)(=[O:14])=[O:13])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(CN)c1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: CC(CNS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1)c1ccccc1

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and 2-phenyl-propylamine. MS (ESI): 512.5 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[NH2:13][C:9]1[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[C:10]=1[CH:11]=[CH2:12]
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylic acid methyl ester (200 mg, 0.59 mmol) was dissolved in methanol (15 mL) and 2N sodium hydroxide (1 mL, 2 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h, acidified with a slight excess of 2N HCl, and concentrated. The crystals that formed were filtered off, washed with water, washed with diethyl ether, and dried under vacuum to yield the title compound (136 mg, 71% yield): mp 167-168° C.: 1H NMR (DMSO-d6 and drop of D2O) δ 7.62 (m, 1H), 7.43 (m, 1H), 6.65 (dd, 1H), 5.67 (m, 2H), 3.92 (d, 3H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C([O:12][C:13](=O)[C:14]([F:22])([F:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)C.CO.O>CCOCC.CCCCCC.C(Cl)Cl>[F:22][C:14]([F:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH:13]=[O:12]
Reactant: CCOC(=O)C(F)(F)c1ccccn1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: O=CC(F)(F)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.7 %

Procedure:
DIBAL-H (2 ml) was added to a solution of 2,2-difluoro-2-pyridin-2-ylacetic acid ethyl ester (400 mg, 2 mmol) in dry ether (2.5 ml) at −78° C. After 4 h, methanol (0.5 ml) and water (2 ml) were added. The reaction mixture was warmed to room temperature and the emulsion formed was filtered through celite and washed with ether. The organic layer was separated, washed with brine and dried over MgSO4. The solvent was evaporated to get a thick liquid. To the crude liquid was added DCM (1 ml) and hexane (3 ml) and left overnight in cold. The precipitated solid was filtered and washed with hexane to give 2,2-difluoro-2-pyridin-2-ylacetaldehyde (150 mg) as a white solid. 2,2-Difluoro-2-pyridin-2-ylacetaldehyde was reacted with 3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butylamine as described in Example 1, Step 8 above to give (2,2-difluoro-2-pyridin-2-ylethylidene)-[3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]amine (600 mg) as a thick liquid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]([CH3:13])[CH3:12])[N:3]=1.[F:14][C@@H:15]1[C@@H:19]([CH2:20][OH:21])[O:18][C@@H:17](N2C=CC(=O)NC2=O)[CH2:16]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:17]2[O:18][C@H:19]([CH2:20][OH:21])[C@@H:15]([F:14])[CH2:16]2)=[C:4]([N:11]([CH3:13])[CH3:12])[N:3]=1
Reactant: CN(C)c1nc(N)nc2[nH]cnc12
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(C)c1nc(N)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 456 h
Yield: 26.1 %

Procedure:
2-Amino-6-dimethylamino-9H-purine (0.46 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in potassium phosphate buffer (50 ml, 10 mM), pH 7.0, containing potassium azide 0.04%. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 19 days, MeOH (170 ml) was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (88:12). Solvent was removed and lyophilization yielded 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-(dimethylamino)-9H-purine 0.17 g (26%): mp 96°-100° C.; TLC Rf 0.79 (silica gel, MeCN: 15N NH4OH:H2O/85:5:10);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][NH:30][CH3:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][NH:30][CH3:31])=[CH:4][CH:3]=1
Reactant: CNCCCl
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: CNCCn1cc(C(=O)N2CCC(c3ccccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-methyl-amine gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Cc1cc(N2CCCCC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(N3CCCCC3)n2)ccc1-n1cnc(C)c1
Yield: 78 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.30 mmol) and 2-chloro-4-methyl-6-piperidin-1-yl-pyrimidine (70 mg, 0.33 mmol) in analogous manner as described in example 90. The crude product was purified by stirring with diethyl ether. It was obtained in 78% yield as a light brown solid. MS ISP (m/e): 379.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.21 (s, 1H), 7.97 (s, 1H), 7.63 (s, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 7.01 (s, 1H), 6.19 (s, 1H), 3.77 (s, 3H), 3.62 (m, 4H), 2.20 (s, 3H), 2.14 (s, 3H), 1.63 (m, 2H), 1.53 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[C:4](=[O:13])C(=O)[NH:6]2.[OH:14]O>[OH-].[Na+]>[NH2:6][C:7]1[C:8]([CH3:11])=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[C:4]([OH:13])=[O:14]
Reactant: OO
Reactant: Cc1ccc(F)c2c1NC(=O)C2=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(F)c(C(=O)O)c1N
Temperature: 50 °C

Procedure:
4-Fluoro-7-methylindoline-2,3-dione (6.20 g, 34.6 mmol) in 1M NaOH (114 mL) was treated dropwise with 30% aq. H2O2 (20 mL), heated to 50° C. for 30 min, cooled to rt and filtered. The filtrate was adjusted to pH 4 with conc. HCl, cooled to 4° C. and filtered. The filter cake was dried under vacuum to provide the desired product. 1H NMR (CDCl3, 400 MHz) δ 7.15 (m, 1H), 6.40 (m, 1H), 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11](C(=O)C(OC)=O)=[CH:10][CH:9]=1.ClC1C=CC=CC=1C1C=CC(C(=O)C(OCCC)=O)=CC=1.ClC1C=CC=CC=1C1C=CC(C(=O)C(OC(C)(C)C)=O)=CC=1.ClC1C=CC=CC=1C1C=CC(C(=O)C(OCC2C=CC=CC=2)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)C(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: CC(C)(C)OC(=O)C(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: CCCOC(=O)C(=O)c1ccc(-c2ccccc2Cl)cc1
Agent: O=C(OCc1ccccc1)C(=O)c1ccc(-c2ccccc2Cl)cc1
Product: Clc1ccccc1-c1ccccc1

Procedure:
When ethyl oxalyl chloride in the above example is replaced with methyl oxalyl chloride, propyl oxalyl chloride, i-propyl oxalyl chloride, t-butyl oxalyl chloride, or benzyl oxalyl chloride then the product obtained is methyl 2'-chloro-4-biphenylylglyoxylate, propyl 2'-chloro-4-biphenylylglyoxylate, i-propyl 2'-chloro-4-biphenylylglyoxoylate, t-butyl 2'-chloro-4-biphenylylglyoxylate, or benzyl 2'-chloro-4-biphenylylglyoxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:14]=[N:15][C:16]([F:20])=[C:17]([Cl:19])[CH:18]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Cl:19][C:17]1[CH:18]=[C:13]([C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]=[C:10]([C:21]([N:45]3[CH2:49][C:48](=[O:50])[NH:47][CH2:46]3)=[O:23])[CH:11]=2)[CH:14]=[N:15][C:16]=1[F:20]
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cnc(F)c(Cl)c2)n(-c2cccc(Cl)c2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cnc(F)c(Cl)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
21 mg (0.06 mmol) of the compound of Example 63A is reacted analogously to the synthesis of the compound of Example 1 with 8 mg (0.07 mmol) of 4-imidazolinone-hydrochloride. 15 mg (59% of theory) of the title compound is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](O)(=[O:20])[CH:18]=[CH2:19]>CN(C)C=O>[C:17]([NH:9][C:7]([CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1)=[O:8])(=[O:20])[CH:18]=[CH2:19]
Reactant: NC(=O)C1CCNCC1
Reactant: C=CC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(=O)NC(=O)C1CCNCC1

Procedure:
Into a liquid reaction mixture of 4-piperidinecarboxamide (5.0 mg) and triethylamine (5.3 ml) in dimethylformamide (70 ml), a solution of acrylic acid (3.2 ml) dissolved in dimethylformamide (20 ml) was dropped under ice-cooling over 3 hours. After the completion of the addition, the resultant mixture was stirred at room temperature for 1 hour and then filtered. From the filtrate thus obtained, the solvent was eliminated by using a rotary evaporator. After adding an acetone solution to the residue, the mixture was treated with a silica gel column to give N-acryloyl-4-piperidinecarboxamide (1.4 g).
Reaction SMILES: C(N)CN.[OH-].[Na+].[C-]#N.[Na+].C=O.O.[CH2:13]([N:24]([CH2:29][C:30]([O-:32])=[O:31])[CH2:25][C:26]([O-:28])=[O:27])[CH2:14][N:15]([CH2:20][C:21]([O-:23])=[O:22])[CH2:16][C:17]([O-:19])=[O:18].[Na+].[Na+].[Na+].[Na+].N(CC([O-])=O)(CC([O-])=O)CC([O-])=O.[Na+].[Na+].[Na+]>>[CH2:14]([N:15]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:13][N:24]([CH2:29][C:30]([OH:32])=[O:31])[CH2:25][C:26]([OH:28])=[O:27]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)[O-])CC(=O)[O-]
Agent: C=O
Agent: O=C([O-])CN(CC(=O)[O-])CC(=O)[O-]
Agent: [C-]#N
Solvent: O
Solvent: NCCN
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 70 °C

Procedure:
1-mol of ethylenediamine (60.0-g) is mixed with 0.18-mol sodium hydroxide (14.7-g of 50% NaOH) and raised to 70° C. 4.47-mol of sodium cyanide (729.6-g of 30% aq sln) and 4.55-mol of formaldehyde (273.2-g of 50% aq sln) are added at a constant rate over 4.5-hrs and the reaction is allowed to quickly reach boiling temperature (materials can be obtained at Sigma-Aldrich). Any vapors escaping from the reaction are refluxed back to the reactor for the first half of the addition. After the first half of the addition, vapors are no longer refluxed, but distilled away from the reactor. Upon completion of the addition, the reaction is boiled for 2-hrs to remove any excess ammonia. 222.2-mol of water (151.3-g) are added back to the reaction and the reaction is cooled to room temperature. The resulting product contains 39.90-wt % tetrasodium ethylenediaminetetraacetate (Na4EDTA) and 2.5-wt % trisodium nitrilotriacetate (Na3NTA), as determined by HPLC analysis (see method below).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21]([CH2:29][CH3:30])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1)[CH3:20]>>[CH2:29]([N:21]([CH2:19][CH3:20])[C:22]1[N:23]=[CH:24][C:25]([NH:28][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:26][CH:27]=1)[CH3:30]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CCN(CC)c1ccc(N)cn1
Product: CCN(CC)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-diethylamino-pyridin-3-yl)-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2,N2-diethyl-pyridine-2,5-diamine. LCMS calcd for C20H19F3N4O2 (m/e) 404, obsd 405 (M+H).