Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2N=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:33][C:34]([CH3:42])([CH2:37][O:38][CH2:39][C:40]#[CH:41])[CH2:35][OH:36].[C:43]([C:45]1[CH:46]=[N:47][C:48]2[C:53]([CH:54]=1)=[CH:52][C:51]([O:55][CH:56]([S:60][CH3:61])[C:57](O)=[O:58])=[CH:50][CH:49]=2)#[CH:44]>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C.C(N(CC)CC)C>[C:43]([C:45]1[CH:46]=[N:47][C:48]2[C:53]([CH:54]=1)=[CH:52][C:51]([O:55][CH:56]([S:60][CH3:61])[C:57]([NH:33][C:34]([CH3:42])([CH2:37][O:38][CH2:39][C:40]#[CH:41])[CH2:35][OH:36])=[O:58])=[CH:50][CH:49]=2)#[CH:44]
Reactant: C#CCOCC(C)(N)CO
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOCC(C)(CO)NC(=O)C(Oc1ccc2ncc(C#C)cc2c1)SC
Reaction time: 16 h
Yield: 69.7 %

Procedure:
1-hydroxy-7-azabenzotriazole (0.717 g), O-(1H benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.692 g) and 2-amino-2-methyl-3-prop-2-ynyloxy-propan-1-ol hydrochloric salt (0.947 g) were added at room temperature to a solution of triethylamine (2.14 ml) and (3-ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (1.20 g) in 43 ml of dry DMF. The reaction mixture was stirred 16 hrs at R.T and then poured onto a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed with sat. sodium hydrogeno carbonate (1×), with water (1×), with brine(1×) and then dried over sodium sulphate. After filtration and concentration under reduced pressure 2.01 g of a crude mixture were isolated as a dark orange oil. The crude mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate) to give 1.22 g of 2-(3-ethynyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methyl-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanylacetamide in mixture with (3-ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid 2-[2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetylamino]-2-methyl-3-prop-2-ynyloxy-propyl ester resulting from the homo coupling process. This residue was dissolved in 24 ml of THF/H2O (1/1) and treated with 42 mg of LiOH monohydrate at room temperature for 1 h 45. The crude mixture was extracted pH=11) thrice with ethyl acetate. The organic layers were combined, washed with water (1×) and with brine (1×) and then, dried over sodium sulphate. After filtration and concentration under reduced pressure, crude 2-(3-Ethynyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methyl-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl-acetamide (0.944 g) was obtained as a yellow oil and used in the next step without any further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[C:7]([C:11](=[O:32])[C:12](=[C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24]2)[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)=[O:14])[CH:8]=[CH:9][CH:10]=1)[OH:4].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[F:22][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[C:12](=[C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[NH:24]2)[C:11]([C:7]2[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:33](=[O:35])[CH3:34])[CH:10]=[CH:9][CH:8]=2)=[O:32])[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: NCC(O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)NCC(O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
A 137 mg portion of 1-[3-(2-amino-1-hydroxyethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione was dissolved in 10 ml of pyridine, and 35 mg of acetic anhydride was added thereto under ice-cooling. After 2.5 hours of stirring at room temperature, the reaction liquid was mixed with an appropriate amount of sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried with anhydrous sodium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography to obtain 120 mg (80%) of N-(2-{3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}-2-hydroxyethyl)acetamide (Example 15-1) as a yellow foam from a chloroform-methanol (30:1) eluate. FA: 478
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[CH:8][C:9](=[O:12])[NH:10][N:11]=1.Cl[CH2:18][CH2:19][OH:20]>C(O)CCC>[OH:20][CH2:19][CH2:18][N:10]1[C:9](=[O:12])[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[Cl:2])=[N:11]1
Reactant: O=c1ccc(Oc2ccccc2Cl)n[nH]1
Reactant: OCCCl
Agent: [Na]
Solvent: CCCCO
Product: O=c1ccc(Oc2ccccc2Cl)nn1CCO
Temperature: 100 °C

Procedure:
2.4 g sodium are dissolved in 100 ml anhydrous 1-butanol and then 30 g 6-(2-chlorophenoxy)-3-pyridazinone prepared in a manner analogous to Example 1 (M.Pt=182° C.) and the reaction mixture is maintained at 100° C. for 1 hour. 9 g 2-chloroethanol are then introduced without application of heat and then the mixture maintained for 9 hours at reflux temperature. The solvent is removed under reduced pressure, 50 ml aqueous N-sodium hydroxide solution are poured onto the residue and the final product is extracted in diethyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](O)[C:10]#[CH:11]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:10]#[CH:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: Cc1ccc(O)cc1
Product: C#CCOc1ccc(C)cc1

Procedure:
The title compound was synthesized using 4-methylphenol and propargyl alcohol by conducting a reaction similar to that mentioned in Reference example 35.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:23][NH2:24]>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:24][C:23]([C:22]3[CH:25]=[CH:26][C:27]([N+:28]([O-:30])=[O:29])=[C:20]([CH3:19])[CH:21]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC)cc1
Reactant: Cc1cc(CN)ccc1[N+](=O)[O-]
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])c(C)c2)[nH]c1-c1ccc(OC)cc1
Yield: 22.5 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methoxyphenyl)-3-oxopropionate (121.6 g) and 3-methyl-4-nitrobenzylamine (105.4 g) were reacted in the same manner as in Starting Material Synthetic Example 1. After the reaction, the solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography to give ethyl 5-(4-methoxyphenyl)-2-(3-methyl-4-nitrophenyl)imidazole-4-carboxylate (41.5 g), melting point 187-191° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[NH:15][C:16](=[O:59])[C:17]1[CH:22]=[C:21]([NH:23][C:24](=[O:40])[CH:25]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:20]=[C:19]([NH:41][C:42](=[O:58])[CH:43]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:18]=1.[C:60](Cl)(=[O:62])[CH3:61]>C(Cl)Cl>[C:60]([C:11]1[C:10]([O:13][CH3:14])=[CH:9][C:8]([NH:15][C:16](=[O:59])[C:17]2[CH:18]=[C:19]([NH:41][C:42](=[O:58])[CH:43]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH:20]=[C:21]([NH:23][C:24](=[O:40])[CH:25]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:22]=2)=[C:7]([O:6][CH3:5])[CH:12]=1)(=[O:62])[CH3:61]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCC(CCCCCC)C(=O)Nc1cc(NC(=O)C(CCCCCC)CCCCCCCC)cc(C(=O)Nc2cc(OC)ccc2OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCC)C(=O)Nc1cc(NC(=O)C(CCCCCC)CCCCCCCC)cc(C(=O)Nc2cc(OC)c(C(C)=O)cc2OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
In 1.6 l of methylene chloride were dissolved 168 ml of acetyl chloride and 315 g of aluminum chloride. While cooling the resulting solution with ice, 400 g of the compound (7-C) obtained above was added thereto. The mixture was stirred at room temperature for one hour. The reaction mixture was then poured into 10 l of ice water, and the mixture was stirred for one hour. The methylene chloride layer was separated, washed twice with water and concentrated under reduced pressure. To the concentrate, there was added 2 of acetonitrile. The mixture was heated under reflux for one hour and then left to stand to cool it to room temperature. The resulting crystal was recovered by filtration to obtain 383 g of the compound (7-D). Yield: 93%.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[C:10]3[CH:16]=[C:15]4[O:17][CH2:18][O:19][C:14]4=[CH:13][C:11]=3[CH2:12][C:6]2=[N:5][C:4]=1[CH3:29])[CH3:2].C1CCCCC=1>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[C:10]3[CH:16]=[C:15]4[O:17][CH2:18][O:19][C:14]4=[CH:13][C:11]=3[CH2:12][C:6]3=[N:5][C:4]([CH3:29])=[C:3]([CH2:1][CH3:2])[N:7]3[N:8]=2)=[CH:25][CH:24]=1
Reactant: CCc1c(C)nc2n1N=C(c1ccc([N+](=O)[O-])cc1)c1cc3c(cc1C2)OCO3
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCc1c(C)nc2n1N=C(c1ccc(N)cc1)c1cc3c(cc1C2)OCO3
Temperature: 110 °C
Reaction time: 3 h

Procedure:
527 mg of 8-ethyl-9-methyl-5-(4-nitrophenyl)-11H-1,3-dioxolo[4,5-h)imidazo[1,2-c][2,3]benzodiazepine is mixed in 11 ml of ethanol with 5.4 ml of cyclohexene and 106 mg of palladium hydroxide on carbon (Pearlman's catalyst), and it is stirred for 3 hours at a bath temperature of 110° C. After catalyst is filtered out, it is concentrated by evaporation, and the residue is chromatographed on silica gel with ethyl acetate as an eluant. After combining the corresponding fractions and recrystallization from ethanol, 348 mg of 5-(4-aminophenyl)-8-ethyl-9-methyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine with a melting point of 227-228° C. is obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4](CC2C=CC(C3C=CC=CC=3C3N(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=NN=3)=CC=2)[C:5]2[N:6]([N:8]=[C:9]([CH2:13][O:14][CH3:15])[C:10]=2[CH2:11][CH3:12])[N:7]=1)[CH3:2].[CH2:53]([C:55]1[N:56]=[C:57]2[C:62]([CH2:63][CH3:64])=[C:61]([CH2:65][O:66][CH3:67])[N:60]([CH2:68][C:69]3[CH:74]=[CH:73][C:72]([C:75]4[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=4[C:81]4[N:85]([C:86]([C:99]5[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=5)([C:93]5[CH:98]=[CH:97][CH:96]=[CH:95][CH:94]=5)[C:87]5[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=5)[N:84]=[N:83][N:82]=4)=[CH:71][CH:70]=3)[N:58]2[N:59]=1)[CH3:54]>>[CH2:53]([C:55]1[N:56]=[C:57]2[C:62]([CH2:63][CH3:64])=[C:61]([CH2:65][O:66][CH3:67])[N:60]([CH2:68][C:69]3[CH:70]=[CH:71][C:72]([C:75]4[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=4[C:81]4[N:85]([C:86]([C:87]5[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=5)([C:99]5[CH:100]=[CH:101][CH:102]=[CH:103][CH:104]=5)[C:93]5[CH:94]=[CH:95][CH:96]=[CH:97][CH:98]=5)[N:84]=[N:83][N:82]=4)=[CH:73][CH:74]=3)[N:58]2[N:59]=1)[CH3:54].[CH2:1]([C:3]1[NH:4][C:5]2[N:6]([N:8]=[C:9]([CH2:13][O:14][CH3:15])[C:10]=2[CH2:11][CH3:12])[N:7]=1)[CH3:2]
Reactant: CCc1c(COC)nn2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c12
Agent: CCc1nc2c(CC)c(COC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Product: CCc1nn2nc(COC)c(CC)c2[nH]1

Procedure:
In the same manner as described in Example 66, 170 mg of 2,7-diethyl-6-methoxymethyl-1-[[2'-(N-triphenylmethyl tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-pyrazolo[1,5-b][1,2,4]triazole (compound 78a) and 2.5 g of 2,7-diethyl-6-methoxymethyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 78b) were obtained from 1.0 g of 2,7-diethyl-6-methoxymethyl-1H-pyrazolo[1,5-b][1,2,4]triazole.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=1.[O:11]=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>C1C=CC=CC=1>[OH:11][CH:12]([S:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=1)[C:13]([Cl:16])([Cl:15])[Cl:14]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CCCCn1cnnc1S
Solvent: c1ccccc1
Product: CCCCn1cnnc1SC(O)C(Cl)(Cl)Cl

Procedure:
3-Mercapto-4-n-butyl-1,2,4-triazole (2.0 g. or 0.127 mole) and chloral (3.68 g. or 0.0254 mole) were heated in benzene (30 ml.) until a precipitate formed (10 minutes). The mixture was cooled, the precipitate was collected, dried, and recrystallized from ether-hexane to give 3-(1-hydroxy-2,2,2-trichloroethylmercapto)-4-n-butyl-1,2,4-triazole melting at 95°-97° C. The structure was confirmed by its nuclear magnetic resonance spectrum.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[F:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@H:36]([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: F[C@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.56 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 442 [M+H]
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[O-:5])[CH3:2].[C:13](#[N:17])/[CH:14]=[CH:15]/[CH3:16].[H-].[Na+].C(O)(=O)C>C(O)C>[C:13]([CH2:14][CH:15]([P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])(=[O:5])[O:3][CH2:1][CH3:2])[CH3:16])#[N:17]
Reactant: C/C=C/C#N
Reactant: CCOC(OCC)P([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(OCC)C(C)CC#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 23.5 g of ethyl(diethoxymethyl)phosphonite and 6.7 g of crotononitrile in 30 ml of dry ethanol is added to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water, and the organic extract is dried over magnesium sulphate, and the concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 2-cyano-1-methylethyl(diethoxymethyl)phosphinate, b.p. 116° C./0.01 mbar, 31P=+42.2 and +42.0 ppm (CDCl3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH3:30])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Cc1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Product: Cc1ccccc1OC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Br)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-methylphenol: ESMS m/e: 548.8 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[H][H].CO>Cl.[Pt]=O>[NH:10]1[CH2:11][CH2:12][CH:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[CH2:8][CH2:9]1
Reactant: c1cc(-c2ccncc2)ccn1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: c1cc(C2CCNCC2)ccn1
Reaction time: 3 h
Yield: 7.5 %

Procedure:
To a solution of 5.00 g of 4,4′-bipyridine in 1 mol/L hydrochloric acid (32 ml) was added 299 mg of platinum oxide, and the reaction mixture was stirred under the conditions of 3.0 atm hydrogen and at 70° C. external temperature. After 3 hours, the solution was under ordinary temperature and ordinary pressure, then, 201 mg of platinum oxide was further added and the reaction was carried out under the conditions of 3.0 atm hydrogen and at 70° C. external temperature. After 4.5 hours, the solution was left to unattended for 16 hours in a state returned to under ordinary temperature and ordinary pressure. MeOH (30 ml) and 483 mg of platinum oxide were further added, and the mixture was stirred under the conditions of 3.0 atm hydrogen and 70° C. external temperature. The solution was stirred for 4 hours, then, filtered with celite, and the solvent of the filtrate was evaporated under reduced pressure. Then, a saturated aqueous solution of NaHCO3 was added to the solution and the resulting mixture was extracted with a mixed solvent of CHCl3:MeOH (10:1). The organic layer was evaporated under reduced pressure. Again, water was added to the solution, extracted with a mixed solvent of CHCl3:MeOH (10:1), and the organic layer was evaporated under reduced pressure. The precipitated solid was washed with water and dried to obtain 390 mg of the title compound (colorless amorphous).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:14]=[C:15]3[N:21]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]5[O:30][CH2:29][CH2:28][C:27]=5[CH:31]=4)[N:20]=[N:19][C:16]3=[N:17][CH:18]=2)[CH2:9]1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[O:30]1[C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:21]3[C:15]4[C:16](=[N:17][CH:18]=[C:13]([N:10]5[CH2:11][CH2:12][C@@H:8]([NH2:7])[CH2:9]5)[N:14]=4)[N:19]=[N:20]3)=[CH:31][C:27]=2[CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5c(c4)CCO5)c3n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@@H]1CCN(c2cnc3nnn(Cc4ccc5c(c4)CCO5)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.5 %

Procedure:
To a solution of {(R)-1-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (67 mg, 0.15 mmol) in CH2Cl2 (10 mL) was added 4M HCl/Dioxane dropwise (2 mL). The reaction was stirred at room temperature for 2 hours. The organic layer was decanted and the crude solid was purified with a reverse-phased preparative HPLC eluting with acetonitrile-water having 0.1% acetic acid to provide 61 mg of (R)-1-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-pyrrolidin-3-ylamine as the acetate salt (99% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH3:17])[CH:11]=2)[CH:5]=1.[C:19]([C:22]1C=C(B(O)O)C=CC=1)([OH:21])=[O:20].BrC1C=C(C)N=C(C)C=1.COC(=O)C1C=CC=C(C2C=CN=C(C)C=2)C=1.OO>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH2:17][O:21][C:19](=[O:20])[CH3:22])[CH:11]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2cc(C)nc(C)c2)c1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: COC(=O)c1cccc(-c2ccnc(C)c2)c1
Agent: Cc1cc(Br)cc(C)n1
Agent: OO
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-c2cc(C)nc(COC(C)=O)c2)c1
Yield: 82 %

Procedure:
Oxidation of 3-(2,6-dimethyl-pyridin-4-yl)-benzoic acid methyl ester (28.8 g, 0.12 mol; prepared from commercially available 3-carboxyphenylboronic acid [CAS-No. 25487-66-5] and 4-bromo-2,6-dimethylpyridine [Chem. Pharm. Bull. 38 (1990) 2446 and J. Org. Chem. 27 (1962) 1665] as described for 3-(2-methyl-pyridin-4-yl)-benzoic acid methyl ester in example K12) with H2O2 (30%, 36.5 ml, 0.36 mol) in acetic acid (117 ml) at 70° C. for 27 h and subsequent reaction of the N-oxide in acetic acid anhydride (31 ml) at 135° C. for 30 min yielded after aqueous work-up 3-(2-acetoxymethyl-6-methyl-pyridin-4-yl)-benzoic acid methyl ester (29.2 g, 82%) as a brown oil.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:10][C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:14]([C:18]2[CH:19]=[CH:20][C:21](=[O:27])[N:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=2)=[N:15][C:16]=1Br.CCOC(C)=O>CN1C(=O)CCC1.O>[NH2:10][C:11]1[N:12]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:14]([C:18]2[CH:19]=[CH:20][C:21](=[O:27])[N:22]([CH:24]([CH3:26])[CH3:25])[CH:23]=2)=[N:15][C:16]=1[S:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)n1cc(-c2nc(Sc3ccccc3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
To a suspension of 60% NaH (52 mg) in NMP (1.0 ml), was added thiophenol (143 mg) under ice-bath cooling. After 10 minute stirring, 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg) was added to the mixture at the same temperature. The mixture was stirred at the same temperature for 10 minutes and then allowed to warm to 25° C. After 2 hours stirring, the mixture was heated at 100° C. for 1 hour. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from MeOH-IPE to give 5-[5-amino-3-phenyl-6-(phenylthio)-2-pyrazinyl]-1-isopropyl-2(1H)-pyridone (93 mg).
Reaction SMILES: [F:1][C:2]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)([F:7])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>C1COCC1>[F:1][C:2]([F:7])([C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)c1ccc(C(F)(F)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(F)(F)C(=O)O)cc1
Reaction time: 16 h

Procedure:
To a solution of methyl 4-(1,1-difluoro-2-methoxy-2-oxoethyl)benzoate (1.0 g, 4.1 mmol) in THF (20 mL) was added sodium hydroxide (4.1 mmol, 4.1 mL of a 1M solution) dropwise at ambient temperature. The resulting solution was stirred for 16 hours. The reaction was partitioned between 1M HCl and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to give difluoro[4-(methoxycarbonyl)phenyl]acetic acid as a white solid. 1H NMR (CDCl3) δ 8.12 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.21 Hz, 2H), 3.94 (s, 3H), 3.0 (bs, 1H); ESIMS calcd 231.0 (M++H), found 231.0 (M++H).
Reaction SMILES: C(OC([N:8]([C:17]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23])[NH:9]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:29]>C(OCC)(=O)C>[ClH:29].[NH:8]([C:17]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23])[NH2:9]
Reactant: CCOC(=O)C1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC(=O)NC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(NN)CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To a solution of the compound of Example 4 (5.77 g) in ethyl acetate (20 ml) was added a solution of 4M hydrogen chloride in ethyl acetate (25 ml) and the mixture was stirred at room temperature for 24 hours. The resulting precipitates were collected by filtering and washed with ethyl acetate to give the desired product (3.02 g, 76%) as powder. The desired product was identified to be a monohydrochloride salt thereof by the results of elementary analysis and X-ray crystallographic analysis.