Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=1)[CH3:2].Cl.N([O-])=O.[Na+].[N-:26]=[N+:27]=[N-].[Na+]>O.C(O)(=O)C.C(OCC)(=O)C.CCCCCC>[CH2:1]([NH:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N+:26]=[N-:27])=[C:7]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(N)c(OCc2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCNC(=O)c1ccc(N=[N+]=[N-])c(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
N-Ethyl-4-amino-3-benzyloxybenzamide (1.52 g, 5.62 mmol) obtained in Example 312c) was dissolved in water (20 ml) and acetic acid (10 ml), 1N hydrochloric acid (5.62 ml, 1.0 eq.) was added. An aqueous solution (5 ml) of sodium nitrite (394 mg, 5.62 mmol, 1.0 eq.) was added at 0° C., and the mixture was stirred for 30 min. An aqueous solution (5 ml) of sodium azide (373 mg, 5.62 mmol, 1.0 eq.) was further added, and the mixture was stirred at 0° C. for 1.5 hr. The reaction mixture was diluted with ethyl acetate-hexane (3:1, 80 ml), washed sequentially with water, 0.1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness to give N-ethyl-4-azido-3-benzyloxybenzamide as a yellow powder (1.64 g). This powder (1.64 g) and ethyl 4-benzyloxy-3-oxobutyrate (1.35 g, 5.71 mmol) were dissolved in ethanol (40 ml), sodium ethoxide (454 mg, 6.00 mmol) was added, and the mixture was stirred at room temperature for 30 min and at 60° C. for 14 hr. 1N sodium hydroxide (5.71 ml) was added to the reaction mixture, and the mixture was stirred for 2 hr. The reaction mixture was diluted with water (30 ml), ethanol was evaporated, and the residue was diluted with water (40 ml) and washed with ethyl acetate-hexane (2:1, 90 ml). The organic layer was extracted with 1% aqueous sodium carbonate solution (50 ml). The aqueous layers were combined, acidified (pH<3) with 6N hydrochloric acid and extracted with ethyl acetate (90 ml and 50 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give a pale-brown solid (purity about 90%, 2.10 g, 3.9 mmol, 69%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:35][O:36][C:37]([C:39]1[N:40]([CH2:60][CH2:61][F:62])[CH:41]=[C:42]([C:44]2([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[C:54](Br)[CH:53]=3)[C:48](=[O:49])[N:47]([CH3:50])[C:46]([NH2:51])=[N:45]2)[CH:43]=1)=[O:38]>C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.CCOC(C)=O.CCOC(C)=O.C1(C)C=CC=CC=1.CO>[CH3:35][O:36][C:37]([C:39]1[N:40]([CH2:60][CH2:61][F:62])[CH:41]=[C:42]([C:44]2([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[C:54]([C:24]4[CH:25]=[N:20][CH:21]=[N:22][CH:23]=4)[CH:53]=3)[C:48](=[O:49])[N:47]([CH3:50])[C:46]([NH2:51])=[N:45]2)[CH:43]=1)=[O:38]
Reactant: OB(O)c1cncnc1
Reactant: COC(=O)c1cc(C2(c3ccc(F)c(Br)c3)N=C(N)N(C)C2=O)cn1CCF
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C2(c3ccc(F)c(-c4cncnc4)c3)N=C(N)N(C)C2=O)cn1CCF
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.2 %

Procedure:
In a pressure tube was put 2 mL of MeOH and 2 mL of toluene. The solution was degassed with argon and 7.5 mg (0.008 mmol) of Pd2(dba)3 and 8.6 mg of triphenylphosphine was added under an argon atmosphere. After 15 min stirring at room temperature, 47.0 mg (0.38 mmol) of 5-pyrimidyl-boronic acid, 83 mg (0.78 mmol) of Na2CO3, and 125 mg (0.27 mmol) of 4-[2-Amino-4-(3-bromo-4-fluoro-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-1-(2-fluoro-ethyl)-1H-pyrrole-2-carboxylic acid methyl ester was added and the reaction sealed heated to 110° C. for 18 h. The reaction mixture was cooled, diluted with 100 mL of CHCl3, filtered through celite and the solvent removed at reduced pressure. Chromatography on silica gel using a gradient of EtOAc to 2%-8% MeOH-EtOAc yielded 0.08 gm (64% yield) of a white solid (mp 88-90° C.). 1H NMR (500 MHz, CDCl3) δ: 3.15 (s, 3H), 3.73 (s, 3H), 4.50 (m, 1H), 4.58 (m, 2H), 4.68 (m, 1H), 6.96 (s, 2H), 7.16 (t, 1H, J=8.66 Hz), 7.65 (m, 2H), 8.88 (m, 2H), 9.15 (s, 1H). MS (ESI) m/z 455.1 ([M+H])+; MS (ESI) m/z 453.1 ([M−H])−.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([OH:31])=O)=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][C:54]=1[C:60]([N:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:32])[CH2:28][C:29]([N:65]2[CH2:66][CH2:67][N:62]([C:60](=[O:61])[C:54]3[CH:55]=[C:56]([Cl:59])[CH:57]=[CH:58][C:53]=3[Cl:52])[CH2:63][CH2:64]2)=[O:31])=[CH:24][CH:25]=1
Reactant: O=C(c1cc(Cl)ccc1Cl)N1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
HOBt (25 mg, 0.185 mmol) and DIPEA (22 mg, 0.175 mmol) were added to a stirred solution of N-biphenyl-4-yl-malonamic acid (50 mg, 0.175 mmol) in DMF (3 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (50 mg, 0.26 mmol) was added followed by the addition of (2,5-dichloro-phenyl)-piperazin-1-yl-methanone hydrochloride (55 mg, 0.187 mmol). The reaction mixture was stirred at room temperature overnight. Water was then added and the resulting precipitate was filtered and purified by column chromatography using silica gel 60-120 mesh and 50% ethyl acetate in hexane as eluant to afford 35 mg (41%) of N-biphenyl-4-yl-3-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 497.11 M+1)+, 95.5%. 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.64 (m, 2H), 7.58 (m, 4H), 7.44 (m, 3H), 7.38 (d, 2H), 7.32 (m, 2H), 3.95 (m, 2H), 3.8 (m, 1H), 3.75 (m, 4H), 3.65 (m, 1H), 3.52 (d, 3H), 3.34 (m, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[N:12]1([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>>[N:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH2:2][N:15]1[CH2:14][CH2:13][N:12]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]#[N:21])[CH2:17][CH2:16]1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (680 mg, 3.7 mmol), 2-(1-piperazinyl)benzonitrile (823 mg, 4.4 mmol), and DIEA (1.3 mL, 7.4 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.80 (m, 4H) 3.23 (m, 4H) 4.09 (s, 2H) 7.13 (m, 1H) 7.21 (d, J=8.14 Hz, 1H) 7.59 (m, 2H) 7.71 (dd, J=7.80, 1.70 Hz, 1H) 8.34 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 336 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[C:7]3[N:8]([C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][N:13]=3)C=[N:10][C:5]=2[S:4][CH:3]=1.CNCCN>CO.[Cl-].[NH4+]>[Cl:1][C:2]1[C:6]([C:7]2[NH:13][N:12]=[C:11]([CH:14]([CH3:16])[CH3:15])[N:8]=2)=[C:5]([NH2:10])[S:4][CH:3]=1
Reactant: CC(C)c1nnc2c3c(Cl)csc3ncn12
Agent: CNCCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)c1n[nH]c(-c2c(Cl)csc2N)n1
Reaction time: 0.25 h

Procedure:
9-chloro-3-isopropylthieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (300 mg, 1.19 mmol) and N-methylethane-1,2-diamine (0.50 ml, 5.67 mmol) in methanol (10 ml) was placed into a preheated oil bath at 60° C. After stirring for 15 min, the solution was diluted with saturated ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 4-chloro-3-(3-isopropyl-1H-1,2,4-triazol-5-yl)thiophen-2-amine. Method [7] Retention time 1.39 min by HPLC (M+=243 and 245).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:22]([O:24]CC)=[O:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:22]([OH:24])=[O:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(c1ccccc1C)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1C(C(=O)O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
To 4-(Ethoxycarbonyl-o-tolyl-methyl)-piperazine-1-carboxylic acid tert-butyl ester (152) (0.83 g, 2.27 mmol) in EtOH (10 mL) was added NaOH (0.46 g, 11.38 mmol) and the mixture stirred at room temperature for 18 h. The reaction mixture was then concentrated to dryness. The resulting residue was taken up in H2O (100 mL) and acidified (pH=4–6) with 25% KHSO4, and the desired acid was extracted into EtOAc (100 mL). The organic phase was washed with H2O (100 mL) and brine (100 mL) and concentrated to dryness yielding 0.66 g (86%) pure product.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][CH2:33][O:34][CH3:35])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:38]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][CH2:33][O:34][CH3:35])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)([F:38])[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: COCCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: COCCc1nnc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 153), using 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride salt (compound 11.2 HCl salt) instead of 4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5). m/z (ES+) 501.8 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 11.46 (br s, 1H), 7.75-7.45 (m, 3H), 7.49 (d, J=8.4 Hz, 2H), 7.32 (s, 1H), 4.89 (br d, J=13.2 Hz, 1H), 4.28-4.15 (m, 1H), 3.79 (t, J=6.0 Hz, 2H), 3.70-3.45 (m, 2H), 3.46 (s, 3H), 3.31-3.17 (m, 1H), 3.13 (t, J=6.0 Hz, 2H), 2.45 & 2.38 (2 br singlets, amide rotamers, Ar—CH3, 3H), 2.30-1.68 (m, 10H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][P:11](=[O:15])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:16]>C(O)C.[Pd]>[ClH:16].[CH3:14][P:11]1(=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CP1(=O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CP1(=O)CCNCC1
Reaction time: 4 h

Procedure:
1-Benzyl-4-methyl-[1,4]azaphosphinane 4-oxide was dissolved in ethanol (100 mL). 1 M HCl (100 mL) was added, along with palladium on carbon (10%, 2.6 g). The mixture was hydrogenated on a Parr shaker for 4 hours at 50 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure. The product was triturated in hot ethanol (50 mL) and cooled, and the solution was diluted with ether (300 mL). The white crystalline solid was filtered, washed with ether (2×50 mL), hexane (2×50 mL), and dried in vacuo. 4-methyl-[1,4]azaphosphinane 4-oxide hydrochloride was obtained as a white crystalline solid (9.46 g, 94%). 1H NMR (400 MHz, DMSO) δ 3.07 (m, 2H); 2.68 (m, 2H); 1.78 (m, 2H); 1.61 (m, 2H), 1.39 (3H, d, JH-C—P=13.6 Hz.); 31P NMR: δ 29 ppm; ESMS (m/z): (M+1)+ found, 134.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[BrH:11].BrBr>C(O)(=O)C>[BrH:11].[Br:11][CH2:9][C:8]([C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(C)nc1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)CBr)cn1

Procedure:
500 mg (3.59 mmol) of 1-(6-methylpyrid-3-yl)ethanone, 590 μl (3.59 mmol) of hydrobromic acid, 204 μl (3.95 mmol) of bromine and 10 mL of glacial acetic acid were used in the reaction. After precipitation with ethyl ether and filtration, 1.02 g of 2-bromo-1-(6-methylpyrid-3-yl)ethanone hydrobromide are obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)=[O:9])([CH3:6])[CH3:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:31])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][OH:23])=[O:9])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To 112 mg 2-({1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester in 1 ml abs. THF at −10° C. 0.25 ml tetra-butylammonium fluoride (1 M in THF) was added, and the reaction was stirred at 0° C. for 3 h. It was then poured onto ice-water and extracted with ethyl acetate three times. The combined organic layers were then washed with water, dried over sodium sulphate, concentrated in vacuo and crystallized from n-pentane to yield 67 mg 2-{[1-(2-hydroxy-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.ClCCl.[OH-].[OH-].[Pd+2]>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([OH:19])=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cc1ccccc1OCCCN1CCCC1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)Cc1ccccc1OCCCN1CCCC1
Temperature: 50 °C
Yield: 73.4 %

Procedure:
0.8 g of 10% palladium hydroxide on carbon is added to a solution of 5.3 g of benzyl {2-[3-(1-pyrrolidinyl)propoxy]phenyl}acetate in 50 cm3 of ethyl acetate and 50 cm3 of dichloromethane, and the mixture is heated to 50° C. and then purged with nitrogen. After hydrogen has been bubbled through for 20 hours, the suspension is cooled to room temperature and purged with a stream of nitrogen, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is chromatographed on an alumina column (particle size 100 mesh, height 30 cm, diameter 4.5 cm), eluting under a pressure of 0.7 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (75:25 by volume) and collecting fractions of 100 cm3. Fractions 1 to 6 are concentrated to dryness under reduced pressure (2.7 kPa). 2.9 g of {2-[3-(1-pyrrolidinyl)propoxy]phenyl}acetic acid are obtained in the form of a thick oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([F:25])=[C:20]([CH3:26])[CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([F:25])=[C:20]([CH3:26])[CH:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: COC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)Nc1cc(C)c(F)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](CCCCN)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.2 %

Procedure:
To a solution of (R)-6-tert-butoxycarbonylamino-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid methyl ester (2.000 g, 5.232 mmol) in 10 mL of dichloromethane, was added trifluoroacetic acid (10 mL). After stirring at room temperature for 19 h, the reaction mixture was concentrated under reduced pressure, and dried in vacuum for overnight. The crude product (1.200 g, 81% yield) was used directly in the next step without further purification. LC-MS: tR=4.8 min; m/z 283 (M+H)+.
Reaction SMILES: [C:1]([O-])(=[O:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH3:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[CH2:1]([OH:12])/[CH:2]=[CH:3]/[CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCC=CCC=C/C=C/C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CCCC=CCC=C/C=C/CO
Yield: 78 %

Procedure:
To a solution of ethyl trans, trans, trans-2,4,7-undecatrienoate (4.7 g) in dry ether (200 ml) was added with stirring lithium aluminum hydride (1 g) under ice-cooling little by little. The mixture was stirred for an hour at the same temperature. To the resultant mixture was added ether containing water to give insoluble materials, which were removed by filtration. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give colorless oily trans, trans, trans-2,4,7-undecatrien-1-ol (3.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](SC)[N:12]=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:11]2[N:12]=[N:13][C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)[CH2:28][CH2:27]1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2nnc(SC)nc2-c2ccc(OC)cc2)cc1
Solvent: O
Product: COc1ccc(-c2nnc(N3CCN(C)CC3)nc2-c2ccc(OC)cc2)cc1

Procedure:
Ten grams of 5,6-bis(4-methoxyphenyl)-3-methylthio-1,2,4-triazine and 40 ml. of N-methylpiperazine were refluxed for 12 hours. The reaction mixture was poured into water and the solid product was collected. The product was crystallized twice from 75 ml. of ethanol and twice from ethyl acetate to yield 1.8 g. of 3-(4-methylpiperazino)-5,6-bis(4-me;thoxyphenyl)-1,2,4-triazine, mp about 158°-160°C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([CH2:11][CH:12]=O)=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O1CCCC1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[O:10][C:9]([CH2:11][CH2:12][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: O=CCc1ccc(C2OCCO2)o1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(NCCc2ccc(C3OCCO3)o2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 20.3 %

Procedure:
Next, the resulting (5-[1,3]dioxolan-2-yl-furan-2-yl)-acetaldehyde (1.57 g), aniline (0.94 mL, 10.3 mmol) and triacetoxy sodium borohydride (3.76 g, 17.2 mmol) were suspended in a mixture solution of tetrahydrofuran (30 mL) and acetic acid (1 mL) at 0° C., and the mixture was stirred at room temperature for 19 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), and the title compound (453 mg, 1.75 mmol, 14%) was obtained as a brown oil.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]1[CH:20]=[CH:19][CH2:18][C:17]2[C:10]=1[CH:11]=[C:12]1[C:16]=2[CH:15]=[N:14][N:13]1[CH2:21][CH:22](O)[CH3:23])[CH3:7].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([CH:22]([CH3:23])[CH2:21][N:13]1[C:12]2=[CH:11][C:10]3[C:17]([CH2:18][CH:19]=[CH:20][C:9]=3[O:8][CH2:6][CH3:7])=[C:16]2[CH:15]=[N:14]1)=[N+:33]=[N-:34]
Reactant: CCOC1=C2C=c3c(cnn3CC(C)O)=C2CC=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Yield: 94.4 %

Procedure:
1.2 ml (15.5 mmol) of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 2 g (7.7 mmol) of (RS)-1-(7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 4.3 ml (31 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 50 minutes. The reaction mixture was subsequently diluted with 130 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 1 g (15.5 mmol) of sodium azide and the reaction mixture was heated to 75° for 15 hours while stirring. After cooling the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The is combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate). 2.06 g (94%) of (RS)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][NH:12][C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>[Cu](I)I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[N:13][N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Brc1ccccn1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2C)cc1
Agent: I[Cu]I
Product: COc1ccc(-c2cc(=O)n(-c3ccccn3)nc2C)cc1

Procedure:
5-(4-Methoxy-phenyl)-6-methyl-2-pyridin-2-yl-2H-pyridazin-3-one was prepared from 5-(4-methoxy-phenyl)-6-methyl-2H-pyridazin-3-one and 2-bromopyridine in the presence of copper iodide using the procedure described in Example 98 Step 2; Mp 156-7° C.; MS m/z 294 (M+H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: [N-]=[N+]=NCc1nc2ccccc2o1
Agent: [Pd]
Solvent: CCO
Product: NCc1nc2ccccc2o1
Reaction time: 0.67 h

Procedure:
A mixture of 8.28 g (47.5 mmol) of 2-(azidomethyl)benzoxazole (PREPARATION 5) and 0.526 g of 10% Palladium on charcoal in absolute ethanol (150 ml) is shaken under hydrogen at 36 psi for 40 min. The catalyst is then filtered off and the filtrate is concentrated. The crude product is chromatographed on silica gel (700 ml) eluting with methanol/dichloromethane (2/98), the appropriate fractions are pooled and concentrated to give the product. Crystallization from ethyl ether/hexane gives the title compound, mp 46.5°-47.5°; MS (m/z) at 148; NMR (CDCl3) 1.70, 4.14, 7.33, 7.51, 7.70 δ.