Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[BH4-].[Na+].[OH-].[Na+]>>[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:10][C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[CH:15][CH:14]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1ccc(CNc2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (2.66 g; 20 mmol; 1 eq.), 4-dimethylaminobenzaldehyd (3.28 g; 22 mmol; 1.1 eq.), NaBH4 (1.14 g; 30 mmol; 1.5 eq.) and 5 N NaOH (20 ml; 100 mmol; 5 eq.) according to method 2; Yield: 3.24 g (61.0%); MS m/z: 166.3; 1H-NMR (500 MHz, DMSO d6): δ 2.83 (s, 6H); 4.13 (s, 2H); 5.83 (br s, 1H); 6.53 (br s, 1H); 6.60 (dd, 1H, 4J=2.1 Hz, 3J=8.5 Hz); 6.66-6.68 (m, 2H); 7.17-7.20 (m, 2H); 7.25-7.26 (m, 1H); 7.83 (s, 1H); 11.86 (br s, 1H)
Reaction SMILES: [CH2:1]([N:6]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=2[CH:21]=1)[C:7](=[O:19])[NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH2:1]([N:6]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]=2[CH:21]=1)[C:7](=[O:19])[NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN(C(=O)Nc1ccc(C(=O)OC)cn1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCN(C(=O)Nc1ccc(C(=O)O)cn1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
A solution of methyl 6-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-nicotinate (55) (37 mg) in 5 mL THF, 2 mL methanol and 2 mL water was treated with lithium hydroxide hydrate (50 mg), stirred at room temperature for two hours. The reaction mixture was diluted with 5 mL water, the pH adjusted to 2 with concentrated HCl and extracted with three 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, to give a pale yellow solid. The product was purified by flash chromatography (SiO2, 10% methanol/dichloromethane) followed by trituration in hexanes, yielding 17 mg 6-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -ureido]-nicotinic acid (49) as a white solid. M.P. 175-179.5° C.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1.[OH-].[Na+].[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29]Br)([CH3:24])([CH3:23])[CH3:22]>C(#N)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:21]([O:25][C:26]([NH:27][CH2:28][CH2:29][N:6]1[C:2]([Br:1])=[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5]1)=[O:31])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CCOC(=O)c1c[nH]c(Br)c1-c1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cn(CCNC(=O)OC(C)(C)C)c(Br)c1-c1cccc(F)c1
Yield: 74.4 %

Procedure:
To a solution of 39.6 g (127 mmol) of ethyl 5-bromo-4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate in 275 ml of acetonitrile are added 10.1 g (253 mmol) of powdered sodium hydroxide and 1.7 g (5.1 mmol) of tetrabutylammonium hydrogen sulfate, and the mixture is stirred vigorously for a few minutes, followed by adding 34.1 g (152 mmol) of tert-butyl(2-bromoethyl)carbamate (CAS 39684-80-5), and the mixture is then stirred for 17 hours at reflux. After cooling, the solvent is evaporated off under reduced pressure and the residue is taken up in ethyl acetate. The solution is washed with saturated aqueous sodium chloride solution, the organic phase is then dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a brown oil, which is crystallized from diisopropyl ether, to give 43 g of ethyl 1-(2-tert-butoxycarbonylaminoethyl)-5-bromo-4-(3-fluorophenyl)-1H-pyrrole-3-carboxylate in the form of a beige-coloured powder after filtering off and drying.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN(CCN(C)C)C.CN([CH:35]=[O:36])C>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:22]([CH3:23])=[CH:21][CH:20]=[C:7]2[C:6]=1[CH:35]([OH:36])[N:10]([C:11]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:8]2=[O:9]
Reactant: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1C
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1c(C)ccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 79.5 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-methoxymethoxy-4-methyl-N-(1-methyl-1-phenylethyl)benzamide (3.40 g, 10.9 mmol) was dissolved in THF (130 mL), and the solution was treated with TMEDA (5.20 mL, 34.5 mmol), sec-butyl lithium-hexane solution (0.95 mol/L, 36.5 mL, 34.7 mmol) and DMF (1.85 mL, 23.9 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=4/1 to 7/3 to 6/4). The obtained solid was purified by slurry using isopropylether and hexane to obtain 4-methoxymethoxy-5-methyl-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (2.96 g, yield 80%).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1([CH2:23][CH3:24])[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:18][CH3:19])[C:9]=2[CH:8]([C:20]([CH3:22])=[CH2:21])[CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:22][C:20]([CH:8]1[C:9]2[C:10]3[C:15](=[C:14]([CH2:18][CH3:19])[CH:13]=[CH:12][CH:11]=3)[NH:16][C:17]=2[C:5]([CH2:23][CH3:24])([CH2:4][C:3]([OH:25])=[O:2])[CH2:6][CH2:7]1)=[CH2:21]
Reactant: C=C(C)C1CCC(CC)(CC(=O)OC)c2[nH]c3c(CC)cccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C=C(C)C1CCC(CC)(CC(=O)O)c2[nH]c3c(CC)cccc3c21
Reaction time: 24 h
Yield: 91.5 %

Procedure:
The 4-(1-methylethenyl)-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid methyl ester (1.72 g, 5.08 mmol), prepared in Step (b), derived from the less polar ketone, and 7.11 mmol of K2CO3 (0.983 g) were refluxed under nitrogen in 40.6 ml of MeOH containing 5.1 ml of water. After 24 hours, most of the methanol was removed in vacuo and the residue was dissolved in 15 ml of water. It was acidified to pH~1 with 3M HCl (aq.) and extracted with 4×40 ml of ether. Drying (MgSO4) and flash chromatography afforded 1.51 g (4.65 mmol, 91%) of yellow oil. The compound was recrystallized from 2:1 petroleum ether/benzene to give 988 mg of white powder which was dried at 78° C. (high vacuum, phosphorous pentoxide) m.p. 133.5°-135° C.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.[OH-].[K+]>O>[N:12]1([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: c1cn[nH]c1
Reactant: Nc1nc2cccc(Br)n2n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cccc(-n3cccn3)n2n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A3); 1.06 g; 5.0 mmol; 1.0 eq.), pyrazole (3.40 g; 50.0 mmol; 10 eq.) and potassium hydroxide (842 mg; 15.0 mmol; 3.0 eq.) were melted and stirred overnight at 110° C. After this time, reaction mixture was cooled to rt poured into water and extracted with Et2O. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the title compound as a white solid (650 mg, 65%). HPLC, Rt: 1.22 min. (purity 96.6%). LC/MS, M+(ESI): 201.0.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]2[C:13]3[C:18]([O:19][CH2:20][C:3]=12)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=3.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[OH:21][C:16]1[CH:17]=[C:18]2[O:19][CH2:20][C:3]3[C:4](=[N:5][C:6]4[C:11]([C:2]=3[C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([O:23][CH3:22])[CH:29]=3)=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=4)[C:13]2=[CH:14][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1Br
Product: COc1cccc(-c2c3c(nc4ccc(O)cc24)-c2ccc(O)cc2OC3)c1
Yield: 87 %

Procedure:
This compound was prepared from 7-bromo-3,9-dihydroxy-6H-chromeno[4,3-b]quinoline (7) using 3-methoxyphenylboronic acid according to method M. Yellow powder; Yield: 87%; mp 155-158° C. (dec.); 1H-NMR (400 MHz, DMSOd-6) δ 3.82 (s, 3H), 4.99 (d, J=14.2 Hz, 1H), 5.04 (d, J=14.2 Hz, 1H), 6.35 (d, J=2.3 Hz, 1H), 6.60 (dd, J=8.6, 2.3 Hz, 1H), 6.71 (d, J=2.7 Hz, 1H), 6.90 (m, 1H), 6.92 (d, J=1.6 Hz, 1H), 7.12 (m, 1H), 7.24 (dd, J=9.1, 2.7 Hz, 1H), 7.52 (dd, J=8.2, 7.9 Hz, 1H), 7.89 (d, J=9.1 Hz, 1H), 8.15 (d, J=8.6 Hz, 1H), 9.80 (s, 1H), 9.96 (s, 1H); MS (ESI) m/z 370 ([M−H]−), 372 ([M+H]+); HRMS (ESI+) calcd for C23H17NO4372.1230 ([M+H]+). Found: 372.1223.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH:15]([N:18]=[C:19]=[O:20])([CH3:17])[CH3:16]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[O:20])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CC(C)N=C=O
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: CC(C)NC(=O)NCCSCc1ccc(CN(C)C)o1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
2-[[[5-(Dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and isopropylisocyanate (0.89 g) were dissolved in acetonitrile and allowed to stand overnight. Solvents were removed and the residue recrystallised from methanol:ether to give N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'-(1-methylethyl)urea as crystals m.p. 65°-67° (2.8 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C@:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12](=[O:16])[C@@H:13]([OH:15])[CH3:14])[N:10]=[C:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:8]1)=[N+:2]=[N-:3].[CH3:31]I.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[N:1]([CH2:4][CH2:5][CH2:6][C@:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12](=[O:16])[C@@H:13]([O:15][CH3:31])[CH3:14])[N:10]=[C:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:8]1)=[N+:2]=[N-:3]
Reactant: C[C@H](O)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN=[N+]=[N-])c1ccccc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a solution of (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-hydroxypropan-1-one (41 mg, 0.095 mmol) in DMF (2 mL) at 0° C. was added methyl iodide (50 μL, 0.48 mmol) followed by sodium hydride (10 mg, 60%). After stirring at 0° C. for 30 minutes and room temperature for 3 hours, the mixture was treated with saturated NH4Cl (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with water (6×10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the product (40 mg, 94%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#C)[C:5]2[O:9][C:8]([CH2:10][C:11]3[CH:16]=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)=[N:7][C:6]=2[CH:26]=1.BrC1[S:31][CH:32]=[CH:33][N:34]=1>C(N(CC)CC)C.[Pd](Cl)Cl.[Cu]I>[S:31]1[CH:32]=[CH:33][N:34]=[C:16]1[C:11]#[C:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][CH:2]=[CH:26][C:6]=2[N:7]=1
Reactant: C#Cc1cc(Cl)cc2nc(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc12
Reactant: Brc1nccs1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1nccs1)c1nc2ccccc2o1
Yield: 210.7 %

Procedure:
A suspension of 5-chloro-2-(3,5-di-t-butyl-4-hydroxy-benzyl)-7-ethynyl-benzoxazole (2.38 g, 6.0 mmol), 2-bromothiazole (1.13 ml, 95%, 12 mmol), bistriphenylphosphine)palladium(II) dichloride (21.1 mg, 30 μmol), and copper(I) iodide (1.2 mg, 6 μmol) in triethylamine (12 ml) was heated at 90EC, under argon, for 3 hours. The triethylanine was removed in-vacuo and the residue dissolved in ether (70 ml) and water (30 ml). The organics were washed with 1 N HCl (30 ml) and saturated sodium hydrogen carbonate (30 ml), dried (Na2SO4) and evaporated—to give 2.86 g (100%) of crude thiazolylethynylbenzoxazole, which was purified by flash chromatography (SiO2; dichloromethane). The product was crystallized and recrystallized from methanol to give 1.43 g (50.4%) of the title compound (mp 137-41EC).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.C(O)(C)C.S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=[N+]([O-])c1cccc(Cl)c1
Yield: 90 %

Procedure:
172.5 parts of 2-chloro-4-nitro-aniline are introduced into 180 parts of isopropanol and 300 parts of water, and 200 parts of concentrated sulfuric acid (98 percent strength by weight) are then added to the mixture. A solution of 125 parts of NaNO2 in 175 parts of water is run in at 50° C., as described in Example 1. The mixture is cooled, 400 parts of water are added and the product is filtered off. 142 parts (90% of theory) of 3-chloro-nitro-benzene, of melting point 40°-42° C., are obtained.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C(O)C.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([NH2:34])[C@@H:26]1[OH:35]>ClC(Cl)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][CH:17]([OH:18])[CH2:19][NH:34][C@@H:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH:26]3[OH:35])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: OC(CN[C@@H]1c2ccccc2CC1O)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, (1S, 2R)-(−)-cis-1-amino-2-indanol, and ethanol, essentially as described above in Example 57. Purity by LC/MS=100%, [M+H]+=435.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1([C:16]([CH3:18])=[CH2:17])[CH2:8][CH2:7][N:6]([CH2:9][C:10](OCC)=[O:11])[C:5]1=[O:15].[CH3:20][NH2:21]>CCO>[CH3:20][NH:21][C:10](=[O:11])[CH2:9][N:6]1[CH2:7][CH2:8][C:4]([CH2:3][CH:2]([CH3:19])[CH3:1])([C:16]([CH3:18])=[CH2:17])[C:5]1=[O:15]
Reactant: CN
Reactant: C=C(C)C1(CC(C)C)CCN(CC(=O)OCC)C1=O
Solvent: CCO
Product: C=C(C)C1(CC(C)C)CCN(CC(=O)NC)C1=O
Yield: 85 %

Procedure:
Ethyl 3-(2-methylpropyl)-2-oxo-3-(propen-2-yl)-1-pyrrolidineacetate (500 mg, 1.87 mmol) is stirred in a saturated solution of methylamine in EtOH (50 mL) at room temperature overnight. The solution is concentrated and purified by column chromatography (1:12:8 v/v CH2Cl2 :EtOAc:hexane) to give 401 mg (85%) of the title compound as an oil.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=O.C1(N=C=O)C=CC=CC=1.[C:15]([C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:24][N:25]=2)[N:22]=1)#[CH:16].C(N(CC)CC)C>C1C=CC=CC=1>[C:30]([O:29][C:28](=[O:34])[NH:27][CH2:26][C:23]1[N:21]2[N:22]=[C:17]([C:15]3[O:3][N:1]=[C:4]([CH3:5])[CH:16]=3)[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC[N+](=O)[O-]
Reactant: C#Cc1ccc2nnc(CNC(=O)OC(C)(C)C)n2n1
Solvent: c1ccccc1
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)on1
Temperature: 50 °C

Procedure:
To a solution of nitroethane (1.02 ml, 14.3 mmol) in benzene (50 mL) was added phenyl isocyanate (3.12 ml, 28.5 mmol). The mixture was stirred at 50° C. for twenty minutes followed by the addition of tert-butyl (6-ethynyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.00 g, 11.0 mmol) and triethylamine (0.0765 ml, 0.549 mmol). The mixture was stirred at 50° C. for six hours then at room temperature overnight. The mixture was cooled to room temperature, filtered and the resulting brown precipitate was washed with additional benzene. The filtrate was concentrated to yield the product as a black solid. MS m/z=331.1 [M+1]+. Calc'd for C15H18N6O3: 330.1.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([C:10](=[O:12])[CH3:11])[CH2:6][C:7]#[C:8][CH3:9])=[CH2:4].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]([C:10](=[O:12])[CH3:11])[CH2:6]/[CH:7]=[CH:8]\[CH3:9])=[CH2:4]
Reactant: [H][H]
Reactant: C=C(OC)C(CC#CC)C(C)=O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: C=C(OC)C(C/C=C\C)C(C)=O

Procedure:
A mixture of 9.96 g. (60 mmol.) of 2-methoxy-3-acetyl-1-hepten-5-yne, 0.50 g. of Lindlar catalyst, and 10 drops of synthetic quinoline in 100 ml. of ethyl acetate was stirred under one atmosphere of hydrogen until hydrogen absorption was complete, then filtered, concentrated and distilled to afford (Z)-2-methoxy-3-acetyl-1,5-heptadiene; b.p. 64°-66°, (2.0 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccn2)CC1
Yield: 87 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-pyridyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 87%). 1H NMR (300 MHz, CDCl3): δ 3.73 (m, 8H), 4.15 (s, 3H), 6.68 (d, J=8.4 Hz, 2H), 7.11-7.76 (m, 5H), 8.21 (dd, J=3.6 and 0.6 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH:15]=2)[CH:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:38][N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])[CH:15]=2)[CH:10]=1)[CH2:44][C:40]1[N:39]([CH3:38])[CH:43]=[CH:42][N:41]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCc1ccc2cc(CNCc3ncc[nH]3)ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCc1ccc2cc(CN(Cc3ncc[nH]3)Cc3nccn3C)ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (39.0 mg) obtained in Example 124-5 was dissolved in anhydrous methanol (1.0 ml) and then added with sodium cyanoborohydride (9.40 mg), acetic acid (1.00 ml), and 1-methyl-2-imidazole carboxaldehyde (12.0 mg), followed by stirring at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. The solution was added with a saturated aqueous sodium bicarbonate solution and stirred. The solution was subjected to extraction with chloroform and the extract was then washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (16.7 mg) of the subject compound as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17](S(C)(=O)=O)[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1>>[NH2:43][CH:40]1[CH2:41][CH2:42][N:37]([C:17]2[N:18]=[C:13]([C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=3[CH3:12])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:36])[C:14]3[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=4[F:35])[C:15]=3[N:16]=2)[CH2:38][CH2:39]1
Reactant: NC1CCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(N2CCC(N)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound is prepared from compound N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide and 4-piperidinamine by following the General Procedure for Sulfoxide/Sulfone/Sulfone Displacement, as disclosed above. The concentrated reaction mixture is precipitated with ethyl acetate/hexanes, and filtered. The desired product is obtained as a yellow solid (75 mg, 100%) 94% pure by HPLC: LC-MS m/z 531 (M+H)+, 1.65 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][O:11][C:6]=2[CH:5]=[C:4]([O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:3]=1>CO.[Pt](=O)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:3]=1
Reactant: O=C(O)COc1cc(Cl)c2c(=O)c(-c3ccccc3)coc2c1
Agent: O=[Pt]=O
Solvent: CO
Product: O=C(O)COc1cc(Cl)c2c(c1)OCC(c1ccccc1)C2=O
Yield: 39.8 %

Procedure:
One gram of {[5-chloro-4-oxo-3-phenyl-4H-1-benzopyran-7-yl]oxy}acetic acid was dissolved in 200 ml of methanol while heating, and 50 mg of platinum (IV) oxide was added to the solution. After an equimole of hydrogen was absorbed, the platinum catalyst was removed by filtration. The methanol in the filtrate was removed by distillation, and the residue was recrystallized from chloroform to obtain 0.4 g of the entitled compound having a melting point of 171° to 173° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]=[C:11]([CH3:13])[CH3:12]>>[C:11]([C:4]1[CH:3]=[C:2]([OH:1])[C:7]([C:11]([CH3:13])([CH3:12])[CH3:10])=[CH:6][C:5]=1[O:8][CH3:9])([CH3:13])([CH3:12])[CH3:10]
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C
Product: COc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Reaction time: 20 h
Yield: 6 %

Procedure:
A suspension of 124 parts of 4-hydroxyanisole and 3 parts of exchanger resin is prepared in a stirred reactor by stirring at 500 revolutions per minute at 100° C. under 1 bar, and 28 parts of isobutene are passed in. The exchanger resin is a sulfonated styrene-divinylbenzene copolymer resin which has been dehydrated for 20 hours at 100° C. under reduced pressure before being used; it has a gel structure and a particle size for from 20 to 150 micrometers. The suspension in the reactor is now stirred steadily at 500 revolutions per minute. After one hour, 80 parts of 4-hydroxyanisole and 20 parts of isobutene are fed in hourly, and correspondingly 100 parts of suspension are filtered through a suction take-off line fitted with a metal filter (pore diameter 10 micrometers) and are fed to a fractional distillation. After 100 hours' operation, 5,486 parts (85% of theory, based on starting material II) of a mixture of 2-tert.butyl-4-hydroxyanisole and 3-tert.-butyl-4-hydroxyanisole of boiling point 140°-145° C./14 millibars are obtained in addition to 490 parts (6% of theory, based on starting material II) of 2,5-di-tert.-butyl-4-hydroxyanisole. The conversion is 51 percent, based on 4-hydroxyanisole employed. The isobutene is consumed quantitatively.