Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26](OC4C=CC([N+]([O-])=O)=CC=4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.Cl.[NH2:39][CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[NH2:39][CH:40]1[CH2:44][CH2:43][N:42]([C:26]([N:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[CH2:14][CH:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]=3)[CH2:10]2)=[O:27])[CH2:41]1
Reactant: NC1CCNC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Agent: Cl
Product: NC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(C4CC4)no3)C2)C1

Procedure:
90 mg (0.17 mmol) of the compound from Example 176A and 83 mg (0.52 mmol) of 3-aminopyrrolidine hydrochloride were reacted according to the General Method 6. Yield: 13 mg (15% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].FC(F)(F)C(O[C:29]1[C:34]([F:35])=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39])=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23][C:29]2[C:30]([F:39])=[C:31]([F:38])[C:32]([F:37])=[C:33]([F:36])[C:34]=2[F:35])=[O:22])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a stirred mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.30 g, 4.136 mmol), Et3 N (0.63 mL, 4.549 mmol) in DMF (20 mL) was added pentafluorophenyl trifluoroacetate at 0° C. The resulting mixture was stirred at room temp for 1 hr. The mixture was poured into water (60 mL) and precipitate was collected with suction. The crude solid was washed with 0.1 N HCl, H2O, n-hexane, and dried at 40° C. to afford 1.91 g (96%) pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetate as a pale brownish crystalline powder. IR (KBr) 1785, 1224, 1216 cm−1; 1H-NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 3.76 (s, 3H), 3.90 (s, 2H), 6.49 (s, 1H), 6.81 (d, J=1.5 Hz, 1H), 6.91 (dd, J=1.5, 8.3 Hz, 1H), 7.15 (t, J=7.3 Hz, 3H), 7.24 (m, 1H), 7.50 (d, J=7.8 Hz, 1H), 8.17 (d, J=7.8 Hz, 1H); MS (FAB) m/z 481 (M++1); Anal. Calcd for C30H33N3O5S.1/4H2O: C, 57.51; H, 3.57; N, 5.83. Found: C, 57.40; H, 3.75; N, 5:68.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[NH:16][N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O[CH:35]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:39]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Reactant: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 0 °C
Yield: 25.7 %

Procedure:
3-(4-Phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.5 g, 1.648 mmol), tert-butyl 3-{[(4-methylphenyl)sulfonyl]oxy}-1-pyrrolidinecarboxylate (1.12 g, 3.30 mmol) and cesium carbonate (1.07 g, 3.30 mmol) in N,N-dimethyl formamide (12 mL) was heated at 75° C. overnight. The reaction mixture was poured on to ice-water (100 mL). The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using ethyl acetate as mobile phase to give tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinecarboxylate (0.20 g, 28%). 1H NMR (DMSO-d6) δ 1.38 (m, 9H), 2.37 (m 2H), 3.32 (s, 3H), 3.44 (m, 1H), 3.59 (m, 1H), 3.65 (m, 1H), 3.75 (m, 1H), 5.44 (m, 1H), 7.16 (m, 5H), 7.43 (m, 2H), 7.65 (m, 2H), 8.26 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:9]1([C:15]#[C:16][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(I)cn1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(C#Cc2ccccc2)cn1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (320 mg, 0.45 mmol) was dissolved in 50 ml THF and 2-amino-5-iodopyrdine (2.0 g, 9.1 mmol) and phenylacetylene (2.0 ml, 18.2 mmol) were added at room temperature. Et3N (3.8 ml, 27 3 mmol), triphenylphosphine (72 mg, 0.27 mmol) and copper(I)iodide (52 mg, 0.27 mmol) were added and the mixture was stirred for 2 hours at 65° C. The reaction mixture was cooled and extracted once with saturated NaHCO3 solution and three times with ethyl acetate. The organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. The crude product was suspended in 5 ml of dichloromethane, stirred for 15 minutes and filtered. The crystals were washed with a small volume of dichloromethane and dried for 1 hour at 50° C. and <20 mbar. The desired compound was obtained as a light yellow solid (1.1 g, 63%), MS: m/e=195.3 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:26][N:25]=[N:24][N:15]=3)=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: CCCc1c(COc2ccc(C#N)cc2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(COc2ccc(-c3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.0 g. of 4-(4-acetyl-3-hydroxy-2-propylbenzyloxy)benzonitrile, 13.0 g. of sodium azide, and 10.9 g. of ammonium chloride in 250 ml. of dimethylformamide was heated to 115° C. for eight hours. An additional 13.0 g. of sodium azide and 10.9 g. of ammonium chloride were added every 2.5 hours during this period. The reaction was stirred overnight at room temperature and then heated an additional six hours with more reagents being added. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in 800 ml. of water. The solution was made acidic with hydrochloric acid and the resulting precipitate was filtered. The precipitate was dissolved in 1N sodium hydroxide and the solution was washed once with ethyl acetate. The basic solution was made acidic with hydrochloric acid and the precipitate was recovered by filtration. The precipitate was crystallized first from isopropyl alcohol/ethyl acetate/water and then recrystallized from isopropyl alcohol providing 10.3 g. of the desired title product, m.p. 203°-205° C. IR, NMR.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(Cl)(Cl)Cl>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCI)C(=O)OCc1ccccc1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a solution of N-t-butoxycarbonyl-(S)-2-amino-5-iodopentanoic acid benzyl ester(J.Org. Chem. 1998, 7875-7884)(100.8 mg, 0.23 mmol) in N,N-dimethylformamide (0.25 mL) was added piperidine (41.5 mg, 0.49 mmol) and the mixture was stirred for 3 hours at room temperature. To the reaction mixture was added chloroform (30 mL) and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution (3×3 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid benzyl ester(83.8 mg) as a colorless oily material.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[B:15]([OH:18])[O:16][CH2:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:22][CH3:23].CN(C)C=O.[H-].[Na+]>O>[CH2:22]([O:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:20]=[CH:19][C:14]3[B:15]([OH:18])[O:16][CH2:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH3:23]
Reactant: CCI
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
A solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.200 g, 0.749 mmol), iodoethane (0.182 mL, 2.25 mmol) and N,N-dimethylformamide (10 mL) under nitrogen balloon was put on an ice water bath. Sodium hydride (0.090 g, 2.25 mmol) was added and the mixture was stirred under nitrogen balloon at 0° C. for 15 minutes. The reaction was then stirred at room temperature for 2 hours. Water was added to quench the excess sodium hydride and the mixture was then neutralized using 1 M HCl. Water was added and the solution was extracted using ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was solidified by adding isopropylether. The precipitate was filtered and dried under reduced pressure to give 2-ethoxy-4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzonitrile (0.131 g, 59% yield). ES(−)MS m/z=294 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (t, J=6.9 Hz, 3H), 4.13 (q, J=7.0 Hz, 2H), 4.95 (s, 2H), 6.56 (dd, J=8.6, 1.9 Hz, 1H), 6.89 (d, J=1.9 Hz, 1H), 7.08 (dd, J=8.1, 1.6 Hz, 1H), 7.14 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 9.19 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:12])[CH2:8][CH:9]([CH3:11])[CH3:10].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl>CS(C)=O.O>[CH2:7]([NH:12][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: ClCCCCOc1ccc2ccccc2c1
Reactant: CC(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CCNCCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and isoamylamine (0.21 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(isoamyl)-(4-(naphthalen-2-yloxy)-butyl)amine, solid, m.p. 102° C., (yield 0.54 gm, 89.3%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:33])[CH:6]([O:11][CH:12]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([CH2:3][NH:4][C:5](=[O:33])[CH:6]([O:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:25][CH2:26]2)=[O:20])=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCNCC2)cc1)C(=O)NCC#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(S(C)(=O)=O)CC2)cc1)C(=O)NCC#N
Reaction time: 2 h

Procedure:
To a solution of N-(cyanomethyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamide from example 17, step 7 (102 mg, 0.23 mmol) in DMF (1 mL), was added methyl sulfonyl chloride (27 μL, 0.35 mmol) and cesium carbonate (91 mg, 0.28 mmol). The mixture was aged for 2 hours under nitrogen atmosphere and was diluted with dichloromethane. The resulting mixture was filtered over celite and concentrated under reduced pressure. The crude residue was chromatographed on silica gel using 1% NH4OH and 9% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([CH3:21])[C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[C:9]([NH:19][CH3:20])=[CH:8][N:7]=1)=[O:4].CCN(C(C)C)C(C)C.[F:33][C:34]([F:49])([F:48])[C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:38](Cl)=[O:39]>C1COCC1>[CH3:20][N:19]([C:9]1[CH:8]=[N:7][C:6]([N:5]([CH3:21])[C:3](=[O:4])[C:2]([F:1])([F:22])[F:23])=[CH:11][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:38](=[O:39])[C:37]1[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:35]([C:34]([F:33])([F:48])[F:49])[CH:36]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N(C)C(=O)C(F)(F)F)cc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N(C)C(=O)C(F)(F)F)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 60 h

Procedure:
2,2,2-Trifluoro-N-methyl-N-(5-(methylamino)-4-o-tolylpyridin-2-yl)acetamide (46 mg, 0.14 mmol) and DIPEA (61 μL, 0.35 mmol) in THF (1.5 mL) were treated with 3,5-bis-trifluoromethylbenzoyl chloride (51 μL, 0.28 mmol, CAS RN 1271-19-8). 3,5-Bis-trifluorobenzoyl chloride (25 μL, 0.14 mmol, CAS RN 1271-19-8) was added again at 90 min. and 4 hours. The reaction mixture was stirred for 60 hours and then evaporated to dryness. From the resulting residue, the product N-methyl-N-(4-o-tolyl-6-(2,2,2-trifluoro-N-methylacetamido)pyridin-3-yl)-3,5-bis(trifluoromethyl)benzamide was isolated by flash chromatography on silica gel (33-50% EtOAc in n-hexane) as a foam (70 mg, 87% over two steps). The compound was used in the next step without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:12])=[CH:8][CH:9]=[C:10]([OH:11])[C:4]2=[CH:3][CH:2]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S(=O)(=O)(O)O>C(OCC)(=O)C.O>[CH2:13]([O:12][C:7]1[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]([OH:11])=[CH:9][CH:8]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCO
Reactant: Oc1ccc(O)c2ccccc12
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCOc1ccc(O)c2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
112 g of naphthohydroquinone and 560 ml of n-decanol were placed in a 1 l three-necked flask and 56 ml of concentrated sulfuric acid was dropwisely added thereto for 30 minutes under nitrogen gas stream while stirring. Thereafter, the mixture was further stirred for 30 minutes and, then, heated at 50° C. for 1 hour and 30 minutes. After cooling, ethyl acetate-water was added to the reaction mixture and the precipitated crystals were filtered off. An aqueous sodium hydroxide solution was added to the filtrate so as to water layer reach pH of 5 to 6. Then, the ethyl acetate layer was washed with water and dried with MgSO4 overnight. The dried ethyl acetate solution was evaporated under reduced pressure to remove ethyl acetate and n-decanol. The residue was dissolved in 1 l of ethyl acetate and treated with 26 g of active carbon followed by concentration under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane and, further, recrystallized from benzene to obtain 73 g of white crystals having a melting point of 89° to 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[CH2:23]([CH2:25][NH2:26])[OH:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:26][CH2:25][CH2:23][OH:24])=[O:14])=[O:7]
Reactant: NCCO
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCCO)c1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)acetylamino]-benzoic acid (150 mg, 0.44 mmol) and ethanolamine (0.04 ml, 0.66 mmol) in DMF 3.0 mL was added EDC (126.5 mg, 0.66 mmol), HOBt (89.2 mg, 0.66 mmol) and DIPEA (0.11 ml, 0.66 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=15:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-(2-hydroxy-ethyl)-benzamide as a white solid (135 mg, 80% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH3:2].[CH2:15]([C:17]1[CH:22]=[C:21]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([CH2:32][CH3:33])[C:18]=1O)[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:15]([C:17]1[CH:22]=[C:21]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([CH2:32][CH3:33])[C:18]=1[O:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:12][CH2:13][CH3:14])[CH3:16]
Reactant: CCOC(COCCCCO)OCC
Reactant: CCc1cc(OC(=O)c2ccccc2)cc(CC)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(COCCCCOc1c(CC)cc(OC(=O)c2ccccc2)cc1CC)OCC
Yield: 97.9 %

Procedure:
To a mixture of 16.0 g of 4-(2,2-diethoxyethoxy)butanol, 18.9 g of 2,6-diehtyl-4-benzoyloxyphenol (which had been produced according to the method as described in JP-A 8-337549/1996), 20.2 g of triphenylphosphine, and 200 ml of tetrahydrofuran was slowly added dropwise 17.0 g of diisopropyl azodicarboxylate with stirring under ice cooling in a stream of nitrogen gas. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. This residue was subjected to silica gel chromatography, which afforded 31.4 g (yield, 88%) of 3,5-diethyl-1-benzoyloxy-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene, nD24.8 1.5129.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.Cl.O1CCOCC1>C(O)C>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Clc1ncc(CCc2cccnc2)c2ccccc12
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Clc1ccc(Nc2ncc(CCc3cccnc3)c3ccccc23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere, 250 mg (0.93 mmol) of 1-chloro-4-(2-pyridin-3-yl-ethyl)isoquinoline in 2.9 ml of abs. ethanol are mixed with 131 mg (1.02 mmol) of 4-chloro-aniline and 0.23 ml of 4 N HCl/dioxane, and stirred for 8 h at 80° C. The mixture is cooled to RT, filtered and the residue washed with acetonitrile. The residue is dissolved in 4 ml of water, then 0.9 ml of sat. NH3 solution are added, stirring is effected for 10 min, the precipitate is filtered off and washed with water. Recrystallisation from acetonitrile yields 1-(4chloroanilino)-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline; m.p.157-158° C.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH:46]1[CH:50]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:48]=[N:47]1>>[CH2:54]([O:53][C:51]([C:49]1[CH:50]=[N:46][N:47]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:48]=1)=[O:52])[CH3:55]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 65.3 %

Procedure:
By a procedure analogous to that of Example 32 Step A, t-butyl 4-hydroxypiperidine-1-carboxylate (0.79 g, 3.6 mmol) was reacted with triphenylphosphine (1.26 g, 4.8 mmol), diethyl azodicarboxylate (0.76 mL, 4.8 mmol) and ethyl 1H-pyrazole-4-carboxylate (0.50 g, 3.6 mmol) to afford the title compound (0.76 g) as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:64][N:65]1[C:69]([SH:70])=[N:68][N:67]=[N:66]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][C:18]([C@@H:15]1[C:14](=[O:35])[N:13]2[C@@H:16]1[CH2:17][C:11]([S:70][C:69]1[N:65]([CH3:64])[N:66]=[N:67][N:68]=1)=[C:12]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:34]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: Cn1nnnc1S
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nnnc1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.3 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.0386 ml) in methylene chloride (0.347 ml) was added to a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (100 mg) and 4-(N,N-dimethylamino)pyridine (2.3 mg) in methylene chloride (5 ml) at -30° C. A solution of trifluoromethanesulfonic anhydride (0.0326 ml) in methylene chloride (0.293 ml) was then added thereto at -30° C. After the mixture was stirred at the same temperature for an hour, a solution of N,N-diisopropyl-N-ethylamine (0.129 ml) in methylene chloride (1.16 ml) and a solution of 1-methyl-1H-tetrazole-5-thiol (42.9 mg) in methylene chloride (2.15 ml) were added successively at -30° C. The mixture was stirred at -30° C. for 30 minutes and allowed to warm to ambient temperature over a period of 30 minutes. After stirring at ambient temperature for 2 hours, the mixture was allowed to stand at 4° C. for 2 days. After removal of the solvent, the residue was dissolved in ethyl acetate. The solution was washed three times with water and an aqueous sodium chloride, dried over magnesium sulfate and then evaporated in vacuo. The residue was chromatographed on deactivated silica gel with 10% water (2 g), eluting with a mixture of benzene and acetone (50:1 to 10:1) to give 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-(1-methyl-1H-tetrazol-5-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (89 mg) as an oil.