Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][N:11]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:12][C:13]([CH3:36])=[CH:14][CH2:15][C:16]1[C:17]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[C:18]2[C:22](=[C:23]([CH3:27])[C:24]=1[O:25][CH3:26])[CH2:21][O:20][C:19]2=[O:28])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(CCNCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOP(=O)(CCN(CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)Cc1ccccc1)OCC
Yield: 43.2 %

Procedure:
A solution of (2-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enylamino}-ethyl)-phosphonic acid diethyl ester (30 mg, 0.055 mmol), benzaldehyde (5.6 μL, 0.055 mmol), and sodium triacetoxyborohydride (23 mg, 0.11 mmol) was stirred with acetic acid (15.7 μL, 0.28 mmol) in DMF (0.5 mL) at room temperature over night. The reaction was quenched with a 10% aqueous Na2CO3 solution and the product was extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure. The product was purified purified by RP HPLC using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA to provide 15 mg of the product (43%) as a clear gel. 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 1.18-1.25 (m, 2H), 1.24 (t, 6H, J=7 Hz), 1.86 (s, 3H), 1.88-2.02 (m, 2H), 2.16 (s, 3H), 2.65-2.74 (m, 2H), 3.93 (s, 2H), 3.46 (br d, 4H, J=7 Hz), 3.76 (s, 3H), 4.00 (pent, 4H, J=7 Hz), 4.25-4.34 (m, 2H), 5.11 (s, 2H), 5.34-5.43 (m, 1H), 7.18-7.33 (m, 5H) ppm; 31P (121.4 MHz, CDCl3) δ 30.9 ppm; MS (m/z) 632.4 [M+H]+, 654.3 [M+Na]+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[N:5][N:6]=1.CN(C)[CH:22]=[CH:23][C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=O>C(O)(=O)C>[CH2:13]([N:10]1[CH2:11][CH2:12][N:7]([C:4]2[N:3]=[C:2]3[N:1]=[CH:22][CH:23]=[C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[N:6]3[N:5]=2)[CH2:8][CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Nc1nnc(N2CCN(Cc3ccccc3)CC2)[nH]1
Solvent: CC(=O)O
Product: c1ccc(CN2CCN(c3nc4nccc(-c5cccnc5)n4n3)CC2)cc1

Procedure:
A mixture of 2.58 g of (1-(5-amino-4H-1,2,4-triazol-3-yl)-4-benzylpiperazine and 1.76 g of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (U.S. Pat. No. 4,281,000, Example 1) in 35 ml of glacial acetic acid was refluxed for 12 hours. The solution was taken to dryness in vacuo. The residue was partitioned between saturated sodium bicarbonate and dichloromethane (1:2). The dichloromethane layer was separated, dried over anhydrous sodium sulfate and filtered through a short column of magnesium silicate. The effluent was refluxed on a steam bath with the gradual addition of hexane until turbidity was noted. After cooling the precipitate was collected by filtration. The solid was recrystallized from dichloromethane/hexane and gave 2.20 g of the desired product as pale yellow crystals, mp 149°-150° C.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([C:11]([NH2:13])=[O:12])[C:5]2[N:6]([N:8]=[N:9][N:10]=2)[N:7]=1.C(=O)(O)[O-].[Na+].CC(O[CH2:23][C:24]1[CH2:33][S:32][C@@H:27]2[C@H:28]([NH2:31])[C:29](=[O:30])[N:26]2[C:25]=1[C:34]([OH:36])=[O:35])=O>P([O-])([O-])([O-])=O>[NH2:31][CH:28]1[C:29](=[O:30])[N:26]2[C:25]([C:34]([OH:36])=[O:35])=[C:24]([CH2:23][S:1][C:2]3[CH:3]=[C:4]([C:11]([NH2:13])=[O:12])[C:5]4[N:6]([N:8]=[N:9][N:10]=4)[N:7]=3)[CH2:33][S:32][C@H:27]12
Reactant: NC(=O)c1cc(S)nn2nnnc12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: NC(=O)c1cc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)nn2nnnc12
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a hot solution (50°-55° C.) of 6-mercapto-8-aminocarbonyl-tetrazolo[1,5-b]pyridazine (2 g; 0.010 mole) and 2.8 g of sodium bicarbonate in 90 ml of buffer phosphate (pH 6.4), 7-ACA (4.6 g; 0.017 mole) was added portionwise and the mixture was heated at 60° C. for 4 hours. After cooling at 10° C. the precipitated 7-amino-3-[(8-aminocarbonyl-6-tetrazolo[1,5-b]pyridazinyl-thiomethyl]-3-cephem-4-carboxylic acid was collected by filtration. The solid was suspended in 150 ml of Me2CO:H2O (1:2), stirred for 30 minutes and filtered again. The collected precipitate was washed with Me2CO and dried under vacuum at 60° C. to give the title compound (80%), m.p. 228°-230° C. (dec.).
Reaction SMILES: [O:1]1[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:2]1.[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH:28]([CH2:31][OH:32])[O:29][CH3:30]>>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:27][CH:28]([O:29][CH3:30])[CH2:31][O:32][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(CO)COC1CCCCO1
Reactant: CCCCCCCCCCCCCCCCC1=CO1
Product: CCCCCCCCCCCCCCCCC(O)COCC(COC1CCCCO1)OC
Yield: 54.2 %

Procedure:
The above 1,2-epoxyoctadecane (23) (5.5 g, 20.5 mmoles) was reacted with 7.8 g (41 mmoles) of 2-methylglycerol monotetrahydropyranyl ether in the same manner as Example 1-2 to give 5.1 g (55%) of the desired compound (24) as a colorless wax.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4](OS(C(F)(F)F)(=O)=O)[CH3:5].Cl.Cl.[NH2:17][C@@H:18]([C@H:21]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C@@H:22]([N:32]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)CO.C(N(CC)CC)C>ClCCl>[CH2:48]([O:47][C@@H:21]([C@@H:18]1[NH:17][C@@H:4]([CH3:5])[C:3](=[O:14])[O:2][CH2:1]1)[C@@H:22]([N:32]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Reactant: N[C@H](CO)[C@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1N[C@@H]([C@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1=O
Temperature: 25 °C
Yield: 64.7 %

Procedure:
Add 2(R)-trifluoromethanesulfonyloxypropionic acid methyl ester (6 g, 25.42 mmol) to a solution of (2R,3S,4S)-2-amino-3-benzyloxy-4-dibenzylamino-5-(3,5-difluorophenyl)-pentan-1-ol bishydrochloride (4.7 g, 7.94 mmol) and triethylamine (5 mL, 35.87 mmol) in dichloromethane (150 mL). Stir the reaction mixture at room temperature for 68-hours. Dilute with dichloromethane and wash with 5% aqueous citric acid, saturated aqueous sodium chloride, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes) to give the desired compound (2.93 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[N:12]=[C:11]([CH2:13][C:14]#[N:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([NH2:15])=[O:18])[O:10][N:9]=2)=[O:7])=[CH:16][CH:17]=1
Reactant: N#CCc1nc(C(=O)c2ccc(F)cc2)no1
Reactant: O=S(=O)(O)O
Product: NC(=O)Cc1nc(C(=O)c2ccc(F)cc2)no1
Temperature: 0 °C
Yield: 96 %

Procedure:
A solution of [3-(4-fluorobenzoyl)-1,2,4-oxadiazol-5-yl]acetonitrile (5.0 g) in 98% H2SO4 (50 ml) was stirred at room temperature for 3 hours. The resulting solution was added slowly to a liter of ice water with mechanical stirring. The precipitated solid was collected by filtration and washed with water (5×300 ml) and cold isopropanol (3×150 ml). The amide was dried in vacuum to yield 5.2 g (96%) of a powder, m.p. 197°-199°.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=O.[Br:13][C:14]1[C:18]2[CH:19]=[C:20]([CH2:23][N:24]3[C:28]([C:29]([OH:31])=O)=[C:27]([CH3:32])[N:26]=[C:25]3[CH3:33])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40][S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42]>C1COCC1>[Br:13][C:14]1[C:18]2[CH:19]=[C:20]([CH2:23][N:24]3[C:28]([C:29]([NH:3][CH3:1])=[O:31])=[C:27]([CH3:32])[N:26]=[C:25]3[CH3:33])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40][S:41]([C:44]([F:46])([F:45])[F:47])(=[O:42])=[O:43]
Reactant: Cc1nc(C)n(Cc2ccc3oc(-c4ccccc4NS(=O)(=O)C(F)(F)F)c(Br)c3c2)c1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CNC(=O)c1c(C)nc(C)n1Cc1ccc2oc(-c3ccccc3NS(=O)(=O)C(F)(F)F)c(Br)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.8 %

Procedure:
Carbonyldiimidazole (0.17 g) was added to a solution of the product of Example 101 (0.2 g) in dry THF (15 ml) under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 4 h, concentrated in vacuo to ~5 ml and then poured into an autoclave with 20 ml of liquid methylamine. The autoclave was heated to 60° C. for 1.5 h and then cooled to -40° C. before opening. The solution was diluted with cold methanol (-35° C.; 50 ml). The resulting solution was concentrated in vacuo and the residue was purified by flash chromatography eluting with chloroform-methanol (10:3) followed by another column eluted with 10-20% methanol in ethyl acetate to give the title compound as a white solid (104 mg), m.p. 208°-210° C.
Reaction SMILES: O[CH:2]1[O:6][C:5](=O)[CH:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.O.[NH2:17][NH2:18]>C(O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:2]=[N:18][NH:17][C:5](=[O:6])[CH:4]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: COc1ccc(C2=CC(=O)OC2O)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2cn[nH]c(=O)c2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
A suspension of 5-hydroxy-4-(4-methoxyphenyl)-5H-furan-2-one (2.00 g, 9.7 mmol) in 15 mL of ethanol was stirred as hydrazine hydrate (0.97 g, 2.0 eq) was added in dropwise. The reaction was stirred at 85° C. overnight, and then the solvent was reduced. The solid was collected and washed with cold EtOH to give 1.7 g (87%) of 5-(4-methoxy-phenyl)-2H-pyridazin-3-one: MS m/z 203 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[C:17]([OH:19])=[O:18])=[CH:14][C:13]([O:20][CH3:21])=[CH:12][CH:11]=2.[CH3:22]O>>[CH3:22][O:18][C:17]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH3:21])[CH:14]=2)[N:9]=[CH:8][C:7]=1[OH:6])=[O:19]
Reactant: CO
Reactant: COc1ccc2ncc(O)c(C(=O)O)c2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(O)cnc2ccc(OC)cc12
Temperature: 65 °C
Yield: 97 %

Procedure:
Concentrated sulfuric acid (36N, 50 mL) is added dropwise at room temperature to a stirred suspension of 3-hydroxy-6-methoxyquinoline-4-carboxylic acid (14.5 g, 66.15 mmol, 1.0 eq) in methanol (250 mL) and the resulting mixture is heated at 65° C. for 36 hours. Solvent is then evaporated and the residue is quenched with the dropwise addition at 0° C. of saturated sodium hydrogen carbonate aqueous solution. The resulting precipitate is collected by filtration and dried under vacuum to afford 3-hydroxy-6-methoxyquinoline-4-carboxylic acid methyl ester as an off-white powder (15.0 g, 97% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=[C:14]2[C:13]1=[O:23])[CH3:2].[H][H]>C(OCC)(=O)C.[Ni]>[CH2:1]([C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[C:16](=[O:17])[C:15]2=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=[C:14]2[C:13]1=[O:23])[CH3:2]
Reactant: [H][H]
Reactant: CCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CCc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Yield: 53.3 %

Procedure:
The solution of 1.65 g of N-(2-ethyl-4-nitrophenyl)-4-chlorophthalimide in 80 ml of ethyl acetate is hydrogenated over 5 g of Raney Nickel at 2.5 atm. of hydrogen pressure for 5 hours. After filtration the residue of 1.5 g is crystallized from ethyl acetate-hexane to give 800 mg of the N-(2-ethyl-4-aminophenyl)-4-chlorophthalimide melting at 118°-120°.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)(=[O:17])=[O:16])[CH:13]=2)[NH:8][N:7]=1)=[O:4].Cl[C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl>[F:26][C:2]([F:1])([F:25])[C:3]([NH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)(=[O:16])=[O:17])[CH:13]=2)[N:8]([C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:7]=1)=[O:4]
Reactant: O=C(Nc1n[nH]c2ccc(S(=O)(=O)c3cccc(F)c3)cc12)C(F)(F)F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cccc(F)c3)cc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2,2,2-Trifluoro-N-[5-(3-fluoro-benzenesulfonyl)-1H-indazol-3-yl]-acetamide, (17.93 g, 46.33 mmol) in dry dichloromethane (300 mL) was treated with chlorotriphenylmethane (14.22 g, 50.96 mmol) and triethylamine (14.2 mL, 102 mmol). After stirring at room temperature for two days, the reaction was washed with a solution of NH4Cl, dried and evaporated. The crude was used as such in the next step without any further purification.
Reaction SMILES: FC(F)(F)C1C=[C:5]([N:9]2CCC(CCNC(=O)OCC(N)=O)CC2)C=CC=1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[N:37]1[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44][N:45]2[C:49](=[O:50])[CH2:48][O:47][C:46]2=[O:51])[CH2:39][CH2:38]1.CN>O1CCCC1>[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[N:37]1[CH2:42][CH2:41][CH:40]([CH2:43][CH2:44][NH:45][C:46](=[O:51])[O:47][CH2:48][C:49]([NH:9][CH3:5])=[O:50])[CH2:39][CH2:38]1
Reactant: NC(=O)COC(=O)NCCC1CCN(c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C1COC(=O)N1CCC1CCN(c2ccc3ccccc3n2)CC1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)NCCC1CCN(c2ccc3ccccc3n2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.5). Starting with 1.5 g (4.42 mmol) of 3{2-[1-(2-quinolyl)-4-piperidyl]ethyl-1,3-oxazolidine-2,4-dione, obtained in step 8.2, and 11 ml (22.10 mmol) of a solution (2M) of methylamine in tetrahydrofuran, and after chromatography on silica gel, eluting with a 98/2/0.2 and then 95/5/0.5 mixture of dichloromethane, methanol and 28% aqueous ammonia, followed by crystallization from ethyl acetate, 0.405 g of pure product is obtained in the form of a white solid.
Reaction SMILES: O[CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2.O=S(Cl)[Cl:24]>>[Cl:24][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3O)nc1
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3Cl)nc1
Reaction time: 3.5 h

Procedure:
Charge flask with 6-(5-Hydroxy-5,6,7,8-tetrahydro-naphthalen-2-yloxy) nicotinamide (288 mg, 1.01 mmol) and SOCl2 (5 ml) and beat at 50° C. under nitrogen atmosphere with stirring. After 3.5 hours, concentrate on rotary evaporator to give the title compound as a yellow oil. Due to instability, use this material without purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]([C:14]([NH2:16])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)(Cl)[Cl:26]>P(Cl)(Cl)(Cl)=O>[Cl:26][C:4]1[C:5]([C:14]#[N:16])=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1[nH]c(=O)c(C(N)=O)nc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(Cl)c(C#N)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 75a-c, 1-phenyl-1,2-propanedione and 2-aminomalonamide were heated in an aqueous solution to give 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide. Then, the 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide was treated with triethylamine and phosphorus pentachloride in phosphorus oxychloride at reflux to give 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile. The 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was finally treated with 1-(4-fluorophenyl)piperazine and N-ethyldiiso-propyl-amine in N,N-dimethylformamide at room temperature to yield the 4-(4-fluoro-phenyl)-6′-methyl-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrile as yellow solid; m.p. 117-120° C.; MS: 374 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:17](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH:16]([CH3:35])[O:15][C:14]([CH3:37])([CH3:36])[C:13]=3[CH:38]=2)=[CH:5][CH:4]=1)#[N:2].N1CCCCC1>CN(C=O)C>[CH3:8][N:7]1[C:6]([C:9]2[CH:10]=[CH:11][C:12]3[NH:17][CH:16]([CH3:35])[O:15][C:14]([CH3:37])([CH3:36])[C:13]=3[CH:38]=2)=[CH:5][CH:4]=[C:3]1[C:1]#[N:2]
Reactant: CC1OC(C)(C)c2cc(-c3ccc(C#N)n3C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC1Nc2ccc(-c3ccc(C#N)n3C)cc2C(C)(C)O1

Procedure:
Prepared according to the procedure for Example 20 from 9H-fluoren-9-ylmethyl 6-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,4,4-trimethyl-2H-3,1-benzoxazine-1(4H)-carboxylate (0.3 g, 0.6 mmol) and 20% piperidine in DMF. A white solid (0.07 g, 42%): mp 195-196° C.; 1H-NMR (DMSO-d6) δ 7.16 (d, 1H, J=2.8 Hz), 7.08 (dd, 1H, J=8.1, 1.9 Hz), 6.98 (d, 1H, J=4.1 Hz), 6.63 (d, 1H, J=8.5 Hz), 6.61 (s, 1H), 6.20 (d, 1H, J=4.1 Hz), 4.79-4.81 (m, 1H), 3.67 (s, 3H), 1.49 (s, 3H), 1.27 (d, 3H, J=5.5 Hz); MS (ESI) m/z 282 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][CH:8]1[NH2:19].[CH2:24]([O:26][C:27](Cl)=[O:28])[CH3:25]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][CH:8]1[NH:19][C:27](=[O:28])[O:26][CH2:24][CH3:25]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NC1CCc2ccc(OC)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To 1-(3,4-dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (1.95 g, 5.80 mmol) in pyridine 10 ml) the ethylchloroformate (1.00 g, 9.28 mmol) was added slowly under nitrogen. The mixture was stirred over night at RT. The solvent was reduced under vacuo and extracted with CH2Cl2 after addition of HCl (1N). The organic layer was washed with HCl (1N), NaHCO3 solution, and NaCl solution, then dried on MgSO4 and the solvent was removed. The product was obtained as an orange oil that precipitates after a few hours (2.10 g, 5.14 mmol, 89%).
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][N:3]=1.[Cl:11][C:12]1[C:17]([F:18])=[CH:16][C:15](B2OC(CC)(CC)C(CC)(CC)O2)=[CH:14][N:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OC)(C)(C)C>[Cl:11][C:12]1[N:13]=[CH:14][C:15]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH3:10])=[CH:4][N:3]=2)=[CH:16][C:17]=1[F:18]
Reactant: CCC1(CC)OB(c2cnc(Cl)c(F)c2)OC1(CC)CC
Reactant: CCCc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CCCc1cnc(-c2cnc(Cl)c(F)c2)nc1
Temperature: 100 °C

Procedure:
65 mmol of 2-iodo-5-propylpyrimidine and 65 mmol of 2-chloro-3-fluoro-5-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)pyridine are dissolved in 155 ml of dioxane, and 130 mmol of tripotassium phosphate and 2 mmol of tetrakis(triphenylphosphine)palladium catalyst are added. The mixture is heated at 100° C. for 17 hours with stirring. Water and methyl tert-butyl ether are added to the reaction solution, and the organic phase is washed with water, dried using sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with dichloromethane/MTB ether 90/10, giving 2-(6-chloro-5-fluoropyridin-3-yl)-5-propylpyrimidine.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([C:30]4[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:32][CH:31]=4)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ccc(OC(F)(F)F)cc4)nc3C)c(C)nc12
Temperature: 160 °C
Yield: 70.5 %

Procedure:
To a microwave pressure tube is added 0.100 g (0.254 mmol) of 8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine, 0.157 g (0.762 mmol) of 4-(trifluoromethoxy)benzene boronic acid, 0.147 g (0.127 mmol) of Pd(PPh3)4, 0.381 mL (0.762 mmol) of 2 M aqueous sodium carbonate, and 2 mL Ethanol. The reaction mixture is heated in the microwave at 160° C. for up to 1 hour. The reaction mixture is partitioned between 50 mL of ethyl acetate and 50 mL of water. The layers are separated and the aqueous is extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using 2% methanol in dichloromethane as a solvent system. The product containing fractions are combined to obtain 0.085 g of the product, 70% yield. MS, ES+=475.2 (M+1); 1H-NMR (DMSO-d6)=8.134-8.112 (d, 2H); 7.553-7.532 (d, 2H); 7.059 (s, 1H); 3.142-3.113 (m, 1H); 2.500 (s, 3H); 2.399 (s, 3H); 2.330 (s, 3H); 1.907-1.782 (m, 4H); 0.827-0.791 (m, 6H) ppm.