Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.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>[CH3:16][N:14]1[CH:15]=[C:11]([C:4]2[N:3]=[C:2]([C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:12]=[N:13]1
Reactant: Cn1cc(-c2cc3nccn3c(Cl)n2)cn1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a mixture of 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation J, 132 mg, 0.565 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (164 mg, 0.847 mmol) in DME (4 mL) was added 1M K2CO3 (1.69 mL, 1.69 mmol) and the resulting solution was purged with N2 for 15 minutes. Pd(PPh3)4 (65.3 mg, 0.0565 mmol) was added, the flask sealed, and the mixture stirred at 90° C. for 15 hours. The reaction mixture was cooled to ambient temperature and diluted with H2O (10 mL). The aqueous mixture was extracted with EtOAc, the extracts were combined and diluted with hexanes (1 vol). After standing for 15 minutes, the resulting precipitate was collected by vacuum filtration and washed with 50% EtOAc-hexanes to afford desired product. The EtOAc filtrate was extracted with 1M NaOH and the extracts were combined with the previous aqueous portion. The aqueous mixture was treated with 6M HCl to pH 4 then with NaCl to saturation. The mixture was extracted with DCM and the combined extracts were dried over Na2SO4, filtered through a Celite pad and concentrated. The residual product was combined with the previous batch and dried in vacuum to provide the title compound (133 mg, 89% yield) as a light yellow solid. MS (apci) m/z=266.2 (M+H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:54]1([CH2:60][CH2:61][CH2:62][NH:63][C:64](=[O:79])[C@H:65]([CH2:68][CH2:69][CH2:70][NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[NH:66][CH3:67])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>O1CCCC1>[C:54]1([CH2:60][CH2:61][CH2:62][NH:63][C:64](=[O:79])[C@H:65]([CH2:68][CH2:69][CH2:70][NH:71][C:72]([O:74][C:75]([CH3:77])([CH3:76])[CH3:78])=[O:73])[N:66]([C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:67])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Reaction time: 8 h
Yield: 66.3 %

Procedure:
A cold solution (0° C.) of N-Boc-homophenylalanine (221 mg), diisopropylethylamine (228 μl), and anhydrous tetrahydrofuran (4 ml) was treated with PyBrop (398 mg), followed by the addition of a solution of Nδ-Boc-Nα-methylornithine 3-phenylpropylamide (228 mg) in tetrahydrofuran (3 ml). The resulting solution was stirred for overnight. The precipitate was filtered and the solid was washed with ethyl acetate. The filtrate was concentrated in vacuo and the product purified by silica gel chromatography (hexane/ethyl acetate) to give N-Boc-homophenylalanyl-Nδ-Boc-Nα-methylornithine 3-phenylpropylamide (260 mg): 1H NMR (400 MHz, CDCl3) δ1.43 (s, 18H), 1.7-2.0 (m, 8H), 2.58 (t, J=6.4 Hz, 2H), 2.6-2.85 (m, 5H), 3.0-3.4 (m, 4H), 4.4-4.5 (m, 1H), 4.9-5.0 (m, 1H), and 7.1-7.3 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[N:5][N:6]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([NH:1][C:2]1[NH:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[N:5][N:6]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1nnc(N)[nH]1
Product: COC(=O)c1nnc(NC(C)=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 5-amino-4H-1,2,4-triazole-3-carboxylate (1.42 g, 10.0 mmol) in acetic anhydride (30 mL) was refluxed for 30 min until a clear solution was formed. The solution was evaporated to dryness and H2O (40 mL) was added. The resulting suspension was stirred at rt overnight. H2O was evaporated to afford the titled compound as a white powder (1.85 g), which was used without further purification.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15]4[C:16]5[N:33]=[CH:32][S:31][C:17]=5[N:18]=[C:19]([C:21]5[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=5)[C:24]([O:26]C)=[O:25])[N:20]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:5]2)[CH2:3][O:2]1.[OH-].[Na+]>C1COCC1.CO>[CH2:3]1[C:4]2([CH2:7][N:6]([C:8]3[CH:9]=[C:10]([NH:14][C:15]4[C:16]5[N:33]=[CH:32][S:31][C:17]=5[N:18]=[C:19]([C:21]5[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=5)[C:24]([OH:26])=[O:25])[N:20]=4)[CH:11]=[CH:12][CH:13]=3)[CH2:5]2)[CH2:1][O:2]1
Reactant: COC(=O)c1cccc(-c2nc(Nc3cccc(N4CC5(COC5)C4)c3)c3ncsc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2nc(Nc3cccc(N4CC5(COC5)C4)c3)c3ncsc3n2)c1
Reaction time: 15 h
Yield: 15 %

Procedure:
To a stirred solution of methyl 3-(7-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoate (70 mg, 0.15 mmol) in 5 mL of THF and 5 mL of methanol was added a solution of 1N NaOH (2 mL) at room temperature. After the addition, the reaction was stirred at this temperature for 15 hours. The solvent was evaporated and the residue was diluted with water and adjusted to pH=2 by HCl (aq.). The precipitate was filtered, the cake was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 70% acetonitrile/30% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (10 mg, 15%). 1H NMR (300 MHz, DMSO): δ 10.13 (s, 1H), 9.41 (s, 1H), 9.00 (s, 1H), 8.66 (d, 1H, J=8.1 Hz), 8.12-8.10 (m, 1H), 7.70 (t, 1H, J=7.9 Hz), 7.45 (s, 1H), 7.24-7.18 (m, 2H), 6.23 (d, 1H, J=7.5 Hz), 4.75 (s, 4H), 4.03 (s, 4H). LC-MS: 446 [M+H]+, tR=1.59 min. HPLC: 97.95% at 214 nm, 100% at 254 nm, tR=7.31 min.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[C:5]([CH3:12])([CH3:11])[S:4]1)[OH:2].[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:13][NH:14][C:15]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[C:5]([CH3:11])([CH3:12])[S:4]1)=[O:16]
Reactant: CCCC1=NC(=NO)SC1(C)C
Reactant: CN=C=O
Product: CCCC1=NC(=NOC(=O)NC)SC1(C)C

Procedure:
2-oxo-4-propyl-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-propyl-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 112°-114° C. The 2-oxo-4-propyl-5,5-dimethyl-3-thiazoline-oxime starting material melts at 145°-147° C.
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].[CH2:7]=[C:8]([CH3:10])[CH3:9]>C(O)C>[C:8]([NH:2][C:1](=[O:6])[O:3][CH2:4][CH3:5])([CH3:10])([CH3:9])[CH3:7]
Reactant: C=C(C)C
Reactant: CCOC(N)=O
Solvent: CCO
Product: CCOC(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
A stirred mixture of 89 g of ethyl carbamate, 5 g of ethanol, 10 g of ®LEWASORB AC-10 and 70 g of isobutene was heated to 70° C. in a stirred autoclave, and stirring was continued at this temperature for 4 hours. After the reaction was complete, the catalyst was separated off and the mixture was worked up by distillation. 136 g (93% of theory) of ethyl N-tert.-butylcarbamate of boiling point 70°-71° C./20 mbar were obtained. Gas chromatography showed that the crude product contained 0.2 percent by weight of diisobutene, but not diethyl carbonate was detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([O:20][CH3:19])[CH:22]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: COc1cccc(N)c1
Product: COc1cccc(NC(=O)c2ccncc2Nc2ccc(I)cc2F)c1

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(3-methoxyphenyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.31 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.46 mmol of 3-methoxyaniline. LC/MS [6.40 min; 464 (M+1)]
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[CH2:11][C:12]#[N:13])=[CH:2]1.O.[NH2:16][NH2:17]>CCO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:11]=[C:12]([NH2:13])[NH:16][N:17]=2)=[CH:2]1
Reactant: N#CCC(=O)c1c[nH]c2ccccc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2c[nH]c3ccccc23)n[nH]1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To a solution of 3-(1H-indol-3-yl)-3-oxo-propionitrile (6.4 g, 34.7 mmol, 1.0 eq), in absolute EtOH (40 mL), hydrazine monohydrate (5.0 mL, 104.1 mmol, 3.0 eq) was added and the reaction was heated at reflux for 24 hours. The reaction mixture was allowed to cool to room temperature; the solid was filtered and washed with Et2O/EtOAc 10/1 to give 3.0 g of title product (yield 74%).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:56])/[CH:48]=[CH:49]/[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH:43]=[CH:44][CH:45]=2)=[N:8]1>Cl.O1CCOCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:47](=[O:56])/[CH:48]=[CH:49]/[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(/C=C/c1ccccc1)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccccc1)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
(2E)-N-(3-{1-Perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)-3-phenylprop-2-enamide was dissolved in 4 mL of 4.0 N HCl in 1,4-dioxane and the reaction was stirred at room temperature overnight. After neutralization with aqueous NaHCO3, the compound precipitated out of solution. The solid was collected by filtration and was purified by preparative HPLC. (0.036 g, 33% yield over 2 steps): 1H NMR (CD3OD) δ 8.7 (s, 1H), 8.3 (br s, 1H), 8.1 (br d, 1H), 7.8-7.6 (m, 6H), 7.54 (t, 1H), 7.45-7.4 (m, 3H), 6.85 (d, 1H); ES-MS (m/z) 407 [M+H]+.
Reaction SMILES: C([O-])(=O)C.[Na+:5].C(O)C.[CH3:9][S:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[CH:22]([NH:23][C:24](=[O:34])[C:25]([C:28]3[N:29]=[C:30]([NH2:33])[S:31][CH:32]=3)=[N:26][OH:27])[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19]>CN(C)C=O>[CH3:9][S:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[CH:22]([NH:23][C:24](=[O:34])[C:25]([C:28]3[N:29]=[C:30]([NH2:33])[S:31][CH:32]=3)=[N:26][OH:27])[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([O-:20])=[O:19].[Na+:5]
Reactant: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CSCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1

Procedure:
3.5 ml of a methanolic solution of sodium acetate and 30 ml of ethanol were added to a solution of 1 g of the syn isomer of 3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid in 2 ml of dimethylformamide and the mixture was vacuum filtered. The product was rinsed with ethanol and then with ether to obtain 0.804 g of syn isomer of sodium 3-methylthiomethyl-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[N:6]=1.[CH3:17][O-:18].[Na+]>CO>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[N:6]=[C:7]([C:11](=[NH:12])[O:18][CH3:17])[CH:8]=[CH:9][CH:10]=1
Reactant: N#Cc1cccc(Cc2ccccc2Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cccc(Cc2ccccc2Cl)n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
2-(o-Chlorobenzyl)-6-cyanopyridine (5.0 g, 0.022 moles) was added to a solution of sodium methoxide in methanol [prepared by dissolving sodium metal (0.55 g, 0.024 g atoms) in methanol (50 ml)] and the mixture stirred at 20° C. for 5 hours. The methanol was evaporated, the residue taken up in dichloromethane and the precipitate filtered off through a silica bed. Removal of the solvent from the filtrate gave methyl 6-(o-chlorobenzyl)-2-picoline imidate (5.5 g, 100%) as a brown oil which was used in the next stage without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[C:27]([F:31])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>O1CCOCC1>[CH2:11]([N:3]([CH2:1][CH3:2])[CH:4]=[C:5]([C:23](=[O:24])[C:22]1[CH:26]=[C:27]([F:31])[C:28]([Cl:30])=[CH:29][C:21]=1[Cl:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:12]
Reactant: CCOC(=O)C=CN(CC)CC
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(=CN(CC)CC)C(=O)c1cc(F)c(Cl)cc1Cl
Yield: 80.2 %

Procedure:
First 17.1 g of ethyl 3-diethylaminoacrylate are added dropwise and then 10.5 g of triethylamine are added to a solution of 22.75 g of 2,4-dichloro-5-fluorobenzoyl chloride in 80 ml of anhydrous dioxane, while cooling in ice and stirring. The mixture is stirred at room temperature for one hour, heated to boiling under reflux for 45 minutes, and the solvent is removed by distillation in vacuo, and the oily residue is taken up in methylene chloride/water. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. 29 g of ethyl 3-diethylamino-2-(2,4-dichloro-5-fluorobenzoyl)acrylate are obtained as a brown oil.
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:26][C:27]1[CH:28]=[C:29]([CH2:34][CH2:35][NH2:36])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH2:34][CH2:35][NH:36][CH2:24][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CCCCCCCCCCCCOc1ccc(C=O)c2ccccc12
Product: CCCCCCCCCCCCOc1ccc(CNCCc2ccc(Cl)c(Cl)c2)c2ccccc12

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-(dodecyloxy)-1-naphthaldehyde and 2-(3,4-dichlorophenyl)ethylamine gave the title compound as an oil. HPLC (Condition A), Rt: 5.72 min (HPLC purity: 82.0%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl>[C:16]([N:13]1[CH2:14][CH2:15][C:10]2([CH2:9][C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2]2=[O:1])[CH2:11][CH2:12]1)(=[O:18])[CH3:17]
Reactant: O=C1c2ccccc2CC12CCNCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)Cc1ccccc1C2=O
Reaction time: 1 h

Procedure:
To a solution of 1.13 g (5.6 mmoles) 1,3-dihydro-1-oxospiro[2H-indene-2,4'-piperidine] in 15 ml methylene chloride cooled to 0° C. was added 1.23 g (12.0 mmoles) acetic anhydride. The solution was stirred at 0° for 1 hour and the solvent was removed in vacuo to give crude 1'-acetylspiro[2H-indene-2,4'-piperidine]-1(3H)-one.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=O)[CH2:5][CH:4]([CH3:8])[O:3]1.CC([O-])=O.[Na+].[NH2:14][OH:15].Cl>CCO>[CH3:1][CH:2]1[C:6](=[N:14][OH:15])[CH2:5][CH:4]([CH3:8])[O:3]1
Reactant: NO
Reactant: CC1CC(=O)C(C)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1CC(=NO)C(C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2,5-dimethyldihydrofuran-3(2H)-one (20 g, 0.175 mol) and NaOAc (43 g, 0.526 mol) in EtOH (300 mL), NH2OH.HCl (15.8 g, 0.228 mol) was added portion in the mixture at 0° C. After addition, the reaction was stirred at rt for 3 h. Filtered, the filtrate was concentrated and the residue was dissolved in DCM, filtered, the filtrate was concentrated to give 2,5-dimethyldihydrofuran-3(2H)-one oxime. 1H NMR (ppm, 300 MHz, CDCl3) δ 3.7-4.9 (m, 2H), 2.0-3.0 (m, 2H), 1.2-1.4 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][O:18][CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[NH:14][N:13]=[C:12]([CH2:17][O:18][CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: N=C(N)NN
Reactant: COCc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: COCc1n[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 91 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methoxymethyl-4,5,6,7-tetrahydroindazol-4-one (0.1 g), aminoguanidine hydrochloride (0.046 g), concentrated hydrochloric acid (0.086 ml), water (0.086 ml) and ethanol (10 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was dissolved in 1N hydrochloric acid (1ml), and the solution was concentrated. The resulting crystals were recrystallized from ethanol-ethyl acetate to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methoxymethyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 148) (0.06 g) as colorless crystals.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:35])([O:28]C3CCCCO3)[CH3:27])[CH:17]=2)=[CH:10][C:9]=1[CH2:36][OH:37]>C1COCC1.O>[OH:37][CH2:36][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]2[CH:17]=[C:18]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:35])([OH:28])[CH3:27])[CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:13][C:8]=1[CH2:7][OH:6]
Reactant: CC(C)(CCCCc1cccc(C=Cc2ccc(CO)c(CO)c2)c1)OC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)CCCCc1cccc(C=Cc2ccc(CO)c(CO)c2)c1
Temperature: 40 °C

Procedure:
0.09 ml of concentrated sulphuric acid are added to 44 mg (0.1 mmol) of [2-hydroxymethyl-5-(2-{3-[5-methyl-5-(tetrahydropyran-2-yloxy)hexyl]-phenyl}vinyl)phenyl]methanol in 1 ml of THF and 1 ml of water. The solution is heated at 40° C. for 48 hours. Water is added and the mixture is extracted with ether. The organic phase is dried over magnesium sulphate and concentrated. The product is triturated in an ether-hexane mixture and is then filtered and dried.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([O:7][C:8]([O:10][C:11]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:12]=1)=[O:9])([CH3:6])[CH3:5].[I-].[CH4:30].O>CN(C)C=O>[CH3:6][C:4]([O:7][C:8]([O:10][C:11]1[CH:16]=[C:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:14]=[C:13]([CH:23]([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:12]=1)=[O:9])([CH3:3])[CH3:5]
Reactant: C
Reactant: CCOC(=O)Cc1nc(OC(=O)OC(C)(C)C)cc(N2CCOCC2)n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1nc(OC(=O)OC(C)(C)C)cc(N2CCOCC2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
84 mg of sodium hydride are added to a solution of 700 mg of ethyl [4-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)-6-(morpholin-4-yl)pyrimidin-2-yl]acetate in 8 ml of N,N-dimethylformamide under argon. The reaction mixture is then stirred for 15 minutes at 0° C. 0.130 ml of methane iodide is then added and the resulting mixture is stirred at ambient temperature overnight. 0.5 ml of water is added and the reaction mixture is concentrated to dryness under reduced pressure. After purification by silica column chromatography, elution being carried out with a gradient of heptane/ethyl acetate eluent of 0% to 50% and then with ethyl acetate at 100%. 150 mg of ethyl 2-[4-({[(2-methylpropan-2-yl)oxy]carbonyl}oxy)-6-(morpholin-4-yl)pyrimidin-2-yl]propanoate are obtained in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH2:11][CH3:12])[N:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][C:24]([C:27]([C:34]3[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:37]4[CH:47]=[CH:48][CH:49]=[CH:50][C:36]=4[N:35]=3)=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)O1.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.C1COCC1>[CH2:11]([N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([C:34]3[N:38]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:37]4[CH:47]=[CH:48][CH:49]=[CH:50][C:36]=4[N:35]=3)=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=2)=[N:3]1)[CH3:12]
Reactant: CCn1nc(Br)c2ncccc21
Reactant: CCOC(=O)C=C(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C
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: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(-c2nn(CC)c3cccnc23)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C
Temperature: 150 °C
Yield: 88.9 %

Procedure:
A mixture of 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (300 mg), ethyl 3-{4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl}-3-(1-[{2-(trimethylsilyl)ethoxy}methyl]-1H-benzo[d]imidazol-2-yl)acrylate (1456 mg), Pd(PPh3)4 (77 mg), 2 M Na2CO3 aqueous solution (1.991 mL) and THF (4 mL) was heated at 150° C. for 30 min under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/AcOEt) to give the title compound (670 mg).