Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[S:9].[C:23](=O)([O-])[O-].[K+].[K+].IC.CS(C)=O>C(OCC)(=O)C>[CH3:23][S:9][C:8](=[N:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)Nc2ccccn2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CS(C)=O
Product: CSC(=Nc1ccccn1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
Part B: A mixture of tert-butyl 4-(pyridin-2-ylcarbamothioyl)piperazine-1-carboxylate (15.30 g, 47.5 mmol), potassium carbonate (13.10 g, 95.0 mmol), iodomethane (3.00 mL, 47.5 mmol), and DMSO (200 mL) was stirred at 25° C. for 24 h. The reaction mixture was diluted with ethyl acetate, washed with water (×4) and brine, dried over anhyd. sodium sulfate, filtered, and concentrated to provide tert-butyl 4-(methylthio(pyridin-2-ylimino)methyl)piperazine-1-carboxylate (12.00 g) as a waxy solid; 1H NMR (300 MHz, CDCl3) δ 8.25 (m, 1H), 7.63 (m, 1H), 6.88 (m, 2H), 3.70 (m, 4H), 3.52 (m, 4H), 2.04 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:6][NH:7][CH2:8][CH:9]([NH:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4]1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.CN1CCOCC1>CO.CN(C)C=O>[CH:3]1([CH2:6][N:7]2[C:19](=[O:21])[CH2:18][CH2:17][NH:16][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8]2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)CCNC(CNCC1CC1)c1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1CCNC(c2ccccc2)CN1CC1CC1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Sodium hydroxide (1M; 6.53 mL, 6.53 mmol) was added to a solution of ethyl N-{2-[(cyclopropylmethyl)amino]-1-phenylethyl}-beta-alaninate (1.81 g, 6.22 mmol) in methanol (10 mL). After 1 h, the mixture was concentrated and azeotroped with toluene (3×) to give the crude acid. Diphenylphosphoryl azide (2.68 ml, 12.43 mmol) was added to a solution of the crude acid (1.77 g, 6.22 mmol) and 4-methylmorpholine (1.37 mL, 12.4 mmol) in N,N-dimethylformamide (124 mL). After 18 h, the reaction was concentrated and diluted with water. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane→90% dichloromethane/10% (10% ammonium hydroxide/methanol)] gave the title compound (1.38 g). MS 245 (M+1). 1H NMR (500 MHz, CDCl3) δ 7.47–7.30 (m, 5H), 3.89–3.88 (m, 2H), 3.65 (dd, J=13.9, 6.6 Hz, 1H), 3.31–3.26 (m, 1H), 3.24–3.21 (m, 1H), 3.02–2.93 (m, 3H), 2.70–2.65 (m, 1H), 1.02–0.97 (m, 1H), 0.58–0.49 (m, 2H), 0.28–0.21 (m, 2H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][CH:14]=1.[CH2:22]([O:24][C:25](=[O:31])[C:26](OCC)=[O:27])[CH3:23].Cl>C(#N)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:20]#[N:21])[C:26](=[O:27])[C:25]([O:24][CH2:22][CH3:23])=[O:31])=[CH:15][CH:14]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(=O)C(C#N)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
A 542 μL (3.63 mmol) sample of DBU was added to a solution of 500 mg (3.30 mmol) of 4-chlorophenylacetonitrile and 493 μL (3.63 mmol) of diethyloxalate in 1.6 mL of acetonitrile. After ca. 10 min, the mixture was diluted with ethyl acetate and acidified with dilute HCl. The organic phase was washed with three portions of water, dried and stripped to an oily solid. Trituration with hexane/butyl chloride yielded 414 mg, m. p. 135-136° C. A second crop of 35 mg gave a total yield of 54% of ethyl 3-(4-chlorophenyl)-3-cyano-2-oxopropanoate.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[C:7](B(O)O)[CH:8]=1.[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH2:39][CH2:38][CH2:37][C:36]=2Br)[CH:30]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH2:39][CH2:38][CH2:37][C:36]=2[C:7]2[CH:8]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=[CH:5][C:6]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:30]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1ccnc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccc(F)cc1F
Product: CCOC(=O)c1ccnc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using [5-trifluoromethyl-2-(2,4-diflurobenzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)-boronic acid and 2-(bromocyclopent-1-enyl)pyridine-4-carboxylic acid ethyl ester instead of 3-(2-bromo-cyclopent-1-enyl)-6-methyl benzoic acid ethyl ester
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])=[O:7])(C)(C)C.Cl.[C:23]([NH:26][C@H:27](C(O)=O)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]([C:58](=[O:66])[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([O:44][CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=[C:31]([CH2:67][CH3:68])[CH:30]=1)(=[O:25])[CH3:24].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCOCC1.CN(C)C=O.C(OCC)(=O)C>[C:23]([NH:26][CH:27]([C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:14])[O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]([C:58](=[O:66])[C:59]([O:61][C:62]([CH3:64])([CH3:65])[CH3:63])=[O:60])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([O:44][CH:45]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:43])=[C:31]([CH2:67][CH3:68])[CH:30]=1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)OCC[Si](C)(C)C
Reactant: CCc1cc(C[C@H](NC(C)=O)C(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)OCC[Si](C)(C)C)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 55.5 %

Procedure:
2-(trimethylsilyl)ethyl 5-[(tert-butoxycarbonyl)amino]pentanoate (317 mg, 1.0 mmol) was treated with 4N HCl in dioxane at room temperature for 30 minutes, then concentrated under reduced pressure. The residue (665 mg, 1.0 mmol), N-acetyl-4-{2-[(benzhydryloxy)carbonyl][tert-butoxy(oxo)acetyl]anilino}-3-ethylphenylalanine (665 mg, 1.0 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (321 mg, 1.0 mmol) and diisopropylethylamine (521 μL, 3.0 mmol) in N,N-dimethylformamide (2 mL) was stirred at ambient temperature overnight, diluted with ethyl acetate and washed with aqueous NaHCO3 (1×30 mL), brine (1×30 mL), dried (MgSO4), filtered and concentrate under reduced pressure. The residue was purified on silica gel eluting with ethyl acetate to provide of titled compound 480 mg. MS (APCI(+)) m/e 864 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].[H-].C([Al+]CC(C)C)C(C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C@H:30](N)[CH3:31])[CH:27]=[CH:28][CH:29]=1.[BH4-].[Na+]>>[CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][NH:4][C@@H:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1)[CH3:31]
Reactant: CC(C#N)=Cc1ccccc1
Reactant: COc1cccc([C@@H](C)N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Product: COc1cccc([C@@H](C)NCC(C)=Cc2ccccc2)c1

Procedure:
In a similar fashion, α-methylcinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-(2-methyl-3-phenylprop-2-enyl)-1-(3-methoxyphenyl)ethylamine, 25G, as a clear, colorless oil; m/z (rel. int.) 281 (M+, 5), 266 (18), 190 (12), 146 (78), 135 (82), 131 (100), 115 (21), 105 (21), 91 (62), 77 (19).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][CH:5]=1.[NH2:33][CH2:34][CH2:35][CH2:36][NH2:37].[C-]#N.[Na+].O>CO>[NH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(CN(Cc2ccccn2)C(c2ccccn2)c2ccccn2)nc1
Reactant: NCCCN
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NCCCNC(=O)c1ccc(CN(Cc2ccccn2)C(c2ccccn2)c2ccccn2)nc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A solution of 15 (473 mg, 1.11 mmol), 1,3-diaminopropane (1.1 ml, 13.1 mmol) and NaCN (7 mg, 0.14 mmol) in methanol (15 ml) was heated under reflux for 24 hours under an Argon atmosphere. After cooling to room temperature the mixture was poured into water (100 ml) and the aqueous layer was washed with ether (2×125 ml), followed by extraction with dichloromethane (3×75 ml). The combined dichloromethane layers were washed with water (50 ml), brine (50 ml) and dried (Na2SO4). Evaporation of the solvent afforded 16 (418 mg, 81%) as a slightly yellow sticky solid. 1H-NMR (CDCl3) δ1.71 (m, 2H), 2.91 (m, 2H), 3.54 (m, 2H), 3.91 (s, 2H), 3.96 (s, 2H), 5.29 (s, 1H), 7.09 (m, 3H), 7.60 (m, 7H), 8.03 (m, 1H), 8.43 (d, 1H, J=4.4 Hz), 8.52 (d, 2H, 4.8 Hz), 8.85 (s, 1H); 1H-NMR (CDCl3) δ30.41 (t), 39.34 (t), 40.51 (t), 56.79 (t), 57.14 (t), 71.86 (d), 121.81(d), 122.07 (d), 122.35 (d), 122.86 (d), 123.82 (d), 128.36 (s), 135.39 (d), 136.23 (d), 136.29 (d), 147.42 (d), 148.95 (d), 149.18 (d), 159.27 (s), 159.58 (s), 162.58 (s), 165.33(s); MS (CI): m/z 468 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH:15]3C(=O)OC(C)(C)[O:17][C:16]3=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C1(OC)C(C(O)=O)=CC=CC=1.[OH-].[Na+].C(S)CCCCCCCCCCC>CN1CCCC1=O.O>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][C:16]([OH:24])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(C3C(=O)OC(C)(C)OC3=O)CCCCC2)c1
Agent: CCCCCCCCCCCCS
Agent: COc1ccccc1C(=O)O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)CC1(c2cccc(O)c2)CCCCC1
Temperature: 120 °C
Reaction time: 60 h
Yield: 145.6 %

Procedure:
5-(1-(3-Methoxyphenyl)cyclohexyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (105.B) (985 mg, 2.96 mmol) was dissolved in N-methylpyrrolidinone (6.0 mL) and water (53.4 μL, 2.96 mmol) was added. The solution was heated at 120° C. for three hours and LCMS indicated conversion to the anisole carboxylic acid intermediate. The reaction was cooled and NaOH (530 mg, 13.3 mmol) and commercially available dodecane-1-thiol (2.47 mL, 10.4 mmol) were added and the mixture was reheated to 120° C. and stirred for 2.5 days. The reaction was cooled and then diluted with water (75 mL). The mixture was extracted with ether (2×75 mL). The aqueous layer was then acidified with hydrochloric acid and extracted with EtOAc (3×75 mL). The combined EtOAc layers were washed with water (2×100 mL) and brine (1×75 mL) and dried over magnesium sulfate. The filtrate was concentrated to give 2-(1-(3-hydroxyphenyl)cyclohexyl)acetic acid 105.C (1.01 g, 145% yield) with acceptable purity (contains residual N-methylpyrrolidone) to take to the next reaction. MS ESI (neg.) m/e: 233.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([OH:20])=O)[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:20])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNCC1
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added piperidine (0.13 ml, 1.29 mmol) and T3P (50 wt % solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (113 mg, 46% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C21H29ClN2O2, 376.9, found, 377.1 (M+1) APCI; 400 MHz 1H NMR (CDCl3) δ 7.47 (d, J=2.1 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.34 (dd, J=7.9, 1.7 Hz, 1H), 3.70 (s, 2H), 3.54-3.48 (m, 2H), 3.32-3.26 (m, 2H), 3.02-2.93 (m, 1H), 2.75-2.67 (m, 2H), 2.65-2.51 (m, 6H), 1.78-1.71 (m, 4H), 1.63-1.44 (m, 6H); 100 MHz 13C NMR (CDCl3) δ 173.5, 146.3, 135.4, 133.9, 130.8, 126.5, 123.7, 72.9, 56.7, 54.3, 46.8, 43.5, 41.0, 28.4, 26.8, 25.8, 24.7, 23.7.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[NH:9][N:10]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27].O>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[N:10]([CH2:25][C:26](=[O:27])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOCCOCc1cc(C(=O)OC(C)(C)C)[nH]n1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCOCc1cc(C(=O)OC(C)(C)C)nn1CC(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 350 mg 5-[2-(2-Methoxy-ethoxy)-ethoxymethyl]-2H-pyrazole-3-carboxylic acid tert-butyl ester in 5 ml of DMF and 46 mg of sodium hydride (60% in mineral oil) were added at RT. After stirring for 20 min at room temperature 290 mg of 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added. The reaction was stirred at room temperature for 3 h. Then 10 ml of water were added and the mixture was filtered through a Chem Elut® cartridge by elution with DCM. After concentration under reduced pressure the crude was subjected to the next reaction without further purification. Yield: 400 mg.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6](=[O:22])[N:7]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])[CH:8]=1)#[N:2].N.[OH:32]O.O>CO>[CH:15]1([NH:14][C:12]([C:11]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:9]([N:7]3[C:6](=[O:22])[C:5]([NH:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:4][C:3]([C:1]([NH2:2])=[O:32])=[CH:8]3)[CH:10]=2)=[O:13])[CH2:16][CH2:17]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C#N)nc(NCc2ccccc2)c1=O
Reactant: OO
Agent: N
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C(N)=O)nc(NCc2ccccc2)c1=O
Reaction time: 12 h

Procedure:
To a stirred solution of 3-[5-cyano-2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 104, 100 mg) in methanol (1 mL) was added conc. ammonia solution (1 mL) followed by 30% hydrogen peroxide solution (1 mL). After 12 h, water was added and the mixture was extracted with dichloromethane. The pooled organics were washed with brine, dried (MgSO4), filtered and the solvent removed. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound (31 mg).
Reaction SMILES: C(OC([N:8]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=O)=[CH:22][CH:21]=1)[CH2:9][CH2:10][NH:11][CH2:12][C:13](OCC)=[O:14])=O)(C)(C)C.Cl.O1CCOCC1.CC[N:38](C(C)C)C(C)C>>[N:26]1[O:28][N:38]=[C:24]2[CH:25]=[C:20]([CH2:19][CH2:18][N:8]3[CH2:9][CH2:10][NH:11][CH2:12][C:13]3=[O:14])[CH:21]=[CH:22][C:23]=12
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CNCCN(CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CNCCN1CCc1ccc2nonc2c1
Temperature: 120 °C

Procedure:
To a flask charged with ethyl [(2-{(tert-butoxycarbonyl)[2-(4-nitrophenyl)ethyl]amino}ethyl)amino]acetate (500 mg, 1.3 mmol) and a stir bar was added 4N HCl in dioxane (3.2 mL, 13 mmol). When LC indicated the reaction was done, solvents were removed under reduced pressure. The resulting residue was dissolved in ethanol (20 mL), and Hunig's base (1.1 mL, 6.4 mmol) was added to the solution. The reaction was heated to 120° C. for 16 hours. LC showed formation of the desired product, which was purified by silica gel chromatography to provide 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one. LC-MS (IE, m/z): 247 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH2:29][CH2:28][C:27]5([CH2:33][CH2:32][CH2:31][CH2:30]5)[CH:26]=4)=[C:19]([O:34][CH3:35])[CH:18]=3)[CH2:14]2)=[O:12])[CH:6]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O>C(Cl)(Cl)Cl>[CH3:43][S:44]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]4[CH2:29][CH2:28][C:27]5([CH2:30][CH2:31][CH2:32][CH2:33]5)[CH:26]=4)=[C:19]([O:34][CH3:35])[CH:18]=3)[CH2:14]2)=[O:12])[CH:6]=1)(=[O:46])=[O:45]
Reactant: COc1cc(C2CN(C(=O)c3cc(OCCO)ccn3)C2)ccc1OCC1=CC2(CCCC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C2CN(C(=O)c3cc(OCCOS(C)(=O)=O)ccn3)C2)ccc1OCC1=CC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [4-(2-hydroxyethoxy)-pyridin-2-yl]-{3-[3-methoxy-4-(spiro[4.4]non-1-en-2-ylmethoxy)phenyl]-azetidin-1-yl}-methanone (0.040 g) prepared in Example 11 (3) in chloroform (3.0 mL) were added triethylamine (0.028 mL) and methanesulfonyl chloride (0.014 mL). The reaction mixture was stirred at RT for 30 minutes. Water was added to the reaction mixture. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure to give the crude title compound.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]1([C:15]2[C:23]([CH:24]=[CH:25][C:26](O)=[O:27])=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[CH2:36]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][NH:39]1)[CH3:37]>C(Cl)Cl.O1CCCC1>[C:9]1([C:15]2[C:23]([CH:24]=[CH:25][C:26]([N:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH:38]3[CH2:36][CH3:37])=[O:27])=[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]3[N:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC1CCCCN1
Reactant: O=C(O)C=Cc1c(-c2ccccc2)nn2ccccc12
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Yield: 47.8 %

Procedure:
Isobutyl chloroformate (1.04 g) was added dropwise to a mixture of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acrylic acid (trans isomer) (2.0 g) and triethylamine (0.766 g) in methylene chloride (40 ml) and tetrahydrofuran (10 ml) at -20° C. with stirring. After being stirred at the same temperature for 30 minutes, a solution of 2-ethylpiperidine (0.942 g) in tetrahydrofuran (10 ml) was added thereto dropwise at -20° C. and the mixture was stirred at -20° C. to 10° C. for 2 hours. The mixture was warmed to room temperature and evaporated in vacuo. A saturated sodium bicarbonate solution was added to the residue and extracted twice with chloroform (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (40 g) with chloroform as an eluent. The fractions containing the object compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5 -a]pyridin-3-yl)acryloyl]-2-ethylpiperidine (trans isomer) (1.30 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CC(C)=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1O
Yield: 45.2 %

Procedure:
A solution of methyl 2,4-dihydroxybenzoate (6.73 g) in acetone (250 mL) is treated with potassium iodide (2.66 g), tetrabutylammonium chloride (0.05 g), potassium carbonate (5.53 g), and 4-chlorobenzyl chloride (7.08 g), and stirred at reflux for 24 hours. The mixture is filtered, and the filtrate evaporated. The residue is taken up in ethyl acetate, washed with water, dried, and evaporated. The residue is recrystallized from ethyl acetate to yield methyl 2-hydroxy-4-(4-chlorobenzyloxy)benzoate as colourless crystals (5.3 g, 45%), m.p. 119-121° C. 1H NMR (DMSO) 3.9(3H,s), 5.2(2H,s), 6.6(2H,m), 7.5(4H,m), 7.7(1H,d).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].Cl[CH2:11][C:12]([NH:14][C:15]1[C:16]2[C:21]([N:22]=[C:23]3[C:28]=1[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13].[Cl-].[NH4+]>CN(C)C=O>[NH:3]1[CH2:7][C:6](=[O:8])[N:5]([CH2:11][C:12]([NH:14][C:15]2[C:16]3[C:21]([N:22]=[C:23]4[C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:4]1=[O:9]
Reactant: O=C(CCl)Nc1c2c(nc3ccccc13)CCCC2
Reactant: O=C1CNC(=O)N1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)CNC1=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
In 20 ml of dimethylformamide was suspended 0.8 g (content: 60%) of sodium hydride, and then 3 g of 2,4-imidazolidinedione was added to the suspension and the mixture was stirred at room temperature for 30 minutes. Then, 2.75 g of 9-chloroacetylamino-1,2,3,4-tetrahydroacridine (described in "Chem. listy, Vol. 51, p. 1906 (1957)") was added to the mixture and reaction was carried out by heating to 80° C. for 30 minutes. After cooling to 10° C., the mixture was poured into 100 ml of an aqueous solution containing 8 g of ammonium chloride. Precipitated crystals were collected by filtration, washed with water and dried. These crystals were recrystallized from methanol-chloroform to give 2.5 g of the title compound. Melting point: 302° to 304° C. (decomposed).