Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](=[O:23])([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)OC1C=CC=CC=1.[N+]([O-])(O)=O.[O:28]([CH2:32][CH2:33][NH2:34])[N+:29]([O-:31])=[O:30]>C(#N)C>[O:28]([CH2:32][CH2:33][NH:34][C:8](=[O:23])[O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[N+:29]([O-:31])=[O:30]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Product: O=C(NCCO[N+](=O)[O-])Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
0.4 ml of triethylamine was added to a suspension of 0.5 g of diphenyl carbonate and 0.4 g of 2-nitroxyethylamine nitrate in 10 ml of acetonitrile. The mixture was stirred at room temperature for 2 hours and was then allowed to stand overnight at room temperature. The solvent was distilled off under reduced pressure, water was added to the residue, and it was extracted with ethyl acetate 3 times. The extracts were dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel (eluent; hexane: ethyl acetate=5:1) to give 0.22 g of the title compound as colorless powdery crystals.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]([N:34]1[CH2:39][CH2:38][CH:37]([C:40]([Cl:42])=[O:41])[CH2:36][CH2:35]1)(=[O:33])[CH3:32].C([O-])(O)=O.[Na+]>CCOC(C)=O>[ClH:42].[C:31]([N:34]1[CH2:35][CH2:36][CH:37]([C:40]([N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:41])[CH2:38][CH2:39]1)(=[O:33])[CH3:32]
Reactant: c1ccc(CC2CCN(CCCNc3cccnc3)CC2)cc1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2cccnc2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of N-[3-(4-Benzyl-1-piperidinyl)propyl]-3-pyridinamine (400 mg) in 6 ml of tetrahyfrofuran, triethylamine (0.719 ml) and 1-acetyl-4-piperidinecarbonyl chloride (180 mg) were added at 0° C., and the mixture was stirred for 2 h at 0° C. AcOEt (15 ml) and aq. NaHCO3 (15 ml) were added and the organic layer was separated. The aqueous layer was extracted with AcOEt (10 ml) twice. The combined AcOEt layer was washed with aq. NaHCO3 (10 ml) twice and brine (10 ml), dried over anhydrous MgSO4. After concentration, the residue was purified on Al2O3 column chromatography (hexane-AcOEt 1:1). After evaporation, to the residue 4N HCl in AcOEt (1.0 ml) was added and the resulting precipitate was collcted by filtration to give the title compound (251 mg, yield 39.0%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10](F)=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[CH:14]=2)[CH:3]=1.[Br:29][Si](C)(C)C>O1CCOCC1>[Br:29][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:10]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:9]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)Br
Reactant: Nc1cnc(Cl)cc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Solvent: C1COCCO1
Product: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 100 °C
Yield: 65.3 %

Procedure:
To a solution of 6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4′]bipyridinyl-3′-ylamine (1.6 g, 0.004 mol) in 1,4-dioxane (30 mL) was added bromotrimethylsilane (27 mL, 0.2 mol) which immediately produced a white precipitate. The reaction was heated at 100° C. for 48 h. The solid from the cooled reaction mixture was collected by filtration and washed with ethyl acetate (2×20 mL). The resultant solid was then purified by flash chromotagraphy (silica, 25 g column, Biotage, 0.10% methanol in (DCM containing 1% 2M ammonia in methanol)) to afford the title compound as an off-white solid (1.1 g, 45%). 1H NMR (DMSO-D6, 500 MHz): 8.62 (s, 1H), 8.25 (d, J=7.3 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=6.5 Hz, 2H), 7.42 (d, J=6.5 Hz), 7.35 (s, 1H), 5.57 (s, 2H), 3.47 (s, 2H), 2.34 (s, 4H), 1.51 (s, 4H), 1.40 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[F:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2([OH:60])[CH2:59][CH2:58][NH:57][CH2:56]2)=[CH:51][CH:50]=1>CN(C=O)C>[F:48][C:49]1[CH:50]=[CH:51][C:52]([C:55]2([OH:60])[CH2:59][CH2:58][N:57]([C:13]([C:9]3[CH:10]=[N:11][O:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[O:15])[CH2:56]2)=[CH:53][CH:54]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: OC1(c2ccc(F)cc2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(c3ccc(F)cc3)C2)cc1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (20 mg, 0.1 mmol), TBTU (39 mg, 0.12 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (35 μL, 0.2 mmol, 2 equ) in DMF (1 mL) was added to 3-(4-fluorophenyl)pyrrolidin-3-ol hydrochloride (22 mg, 0.1 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (30 mg). MS (ESI, pos. ion) m/z calcd for C21H19FN2O3: 366.1380, found 366.1380.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[C:49]1([CH2:55][C:56](Cl)=[O:57])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:28]2[N:24]([CH2:23][CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:56](=[O:57])[CH2:55][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=3)[C:25](=[O:41])[S:26][C:27]=2[CH:32]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)Cc1ccccc1
Reaction time: 8 h

Procedure:
500 mg of the compound obtained in Step A of Example 12 are dissolved in 10 ml of ethyl acetate; 0.353 ml of triethylamine is then added and the temperature is lowered to 0° C. 0.226 ml of phenylacetyl chloride is added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)Cn1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.2 %

Procedure:
A suspension of 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole (9.2 g, 37.2 mmol), ethyl bromoacetate (4.79 ml, 40.9 mmol) and cesium carbonate (36.4 g, 111.5 mmol) in DMF (140 ml) was stirred for 3 h at RT. Diethyl ether was added and the mixture was washed with 1N HCl and water, and dried over sodium sulfate. The ether phase was concentrated under reduced pressure to give 12.93 g (quant.) of [5-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid ethyl ester which was used in the next step without further purification.
Reaction SMILES: [Li]CCCC.CN(C)CCN(C)C.[CH3:14][O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[C:26](=[O:28])=[O:27].Cl>CCCCCC.C1CCCCC1.CCOCC>[CH3:14][O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26]([OH:28])=[O:27]
Reactant: COc1cccc2ccccc12
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1c(C(=O)O)ccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Reference: J. Organomet. Chem., 20 (1969) p. 251-252. n-BuLi (208.60 mmol, 83.44 ml of a 2.5 M solution in hexane, Aldrich) was stirred under argon in 42 ml of dry cyclohexane. This solution was cooled to 0° C. and treated dropwise (10 min.) with distilled tetramethylethylenediamine (TMEDA) (208.6 mmol, 24.24 g, 31.48 ml). The resulting slurry was stirred at 0° C. for 30 minutes, then treated dropwise (20 minutes) with a solution of 1-methoxynaphthalene (208.60 mmol, 33 g, 30.28 ml) (Aldrich Chem. Co., used without further purification) in 84 ml of dry cyclohexane. The resulting bright red homogeneous reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0° C. and added portionwise over 30 minutes via cannula to a -78° C. solution of dry Et2O (250 ml) saturated with CO2 (g) (CO2 pellets sublimed through drying tube containing SiO2, bubbled into dry Et2O at -78° C.). The resulting white slurry was warmed to ~0° over 45 minutes and then treated with 450 ml of 5% HCl (aqueous). The Et2O layer was separated and the aqueous layer extracted three times with Et2O. The organic extracts were combined and extracted with 3×150 ml saturated NaHCO3 (aqueous). The aqueous layer was filtered through a sintered glass funnel to remove insolubles and the filtrate was cooled to 0° C. and acidified slowly with concentrated HCl until pH=1. The resulting precipitate was filtered, azeotroped with 2× 150 ml of toluene, dried under high vacuum at 50° C. for 5 hours to afford 32.52 g (0.161 mol, 77% yield) of the 1-methoxy-2-naphthalene carboxylic acid as an off-white powder, m.p. 118-121.5° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:15])[CH:4]=1.[S:16]([O-:19])([O-:18])=[O:17].[Na+:20].[Na+].[CH2:22](O)C>O>[Cl:1][CH2:2][C:3]1([CH2:22][S:16]([O-:19])(=[O:18])=[O:17])[C:12]2[C:7](=[C:8]([CH3:14])[C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:15])[CH2:4]1.[Na+:20]
Reactant: O=S([O-])[O-]
Reactant: Cc1c(O)ccc2c(CCl)cc(=O)oc12
Reactant: CCO
Agent: [Na+]
Solvent: O
Product: Cc1c(O)ccc2c1OC(=O)CC2(CCl)CS(=O)(=O)[O-]
Temperature: 0 °C
Yield: 80 %

Procedure:
A solution of 1 g of the compound 5 dissolved in 90 mL of ethanol is introduced into a flask, and then a solution of sodium sulfite (1.1 equivalents, 617 mg) in 22 mL of water is added. The mixture is refluxed. After 20 hours of heating, the mixture is cooled to 0° C. The solution is filtered on a Büchner funnel, the obtained beige residue is washed with ethanol, as for the filtrate, it is evaporated under reduced pressure in order to obtain a yellow solid. This solid is washed with ethanol and diethyl ether. Both obtained solids are collected in order to obtain 1 g (80%) of the crude compound 6.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@H:29]1[CH3:34])([CH3:27])[CH3:26]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:31]3[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[C@H:29]([CH3:34])[CH2:30]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: CC(C)N1CCNC[C@H]1C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCN(C(C)C)[C@H](C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-isopropyl-2-methylpiperazine. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.93 (br. s., 3 H) 1.01 (br. s., 2 H) 1.16 (br. s., 5 H) 2.43 (s, 1 H) 2.47 (s, 3 H) 2.61 (d, J=12.20 Hz, 1 H) 2.75-2.98 (m, 1 H) 3.07 (br. s., 1 H) 3.29 (br. s., 2 H) 4.39 (br. s., 1 H) 7.47-7.62 (m, 3 H) 7.68 (s, 1 H) 7.95-8.11 (m, 2 H) 8.44 (s, 1 H); ESI-MS m/z [M+H]+ 445.3.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[O:28]>ClCCl>[OH:28][N:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH3:20])[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccccc1N=O
Reactant: O=Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1ccccc1N(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of benzaldehyde (106 mg, 1 mmol), 1-methyl-2-nitrosobenzene (121 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 60 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[CH:4][CH:3]=1.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 184 mg (1.0 mmol) of 4-methyl-2'-hydroxy-1,1'-biphenyl (Example 12, Step C) in 3 mL of dimethylformamide was treated with 55 mg of 60% sodium hydride (33 mg NaH, 1.4 mmol). The reaction mixture was stirred at room temperature for 30 minutes then treated with 169 mg (1.19 mmol) of 1-fluoro-4-nitrobenzene. The reaction mixture was heated at 100° C. for 2 hours. The reaction mixture was cooled, poured into 50 mL of water and the resultant mixture was extracted with ethyl ether. The combined extracts were washed with water, dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed on silica, eluting with hexanethyl acetate (10:1) to give 271 mg (0.89 mmol,88%) of the product. FAB-MS: calculated for C19 H15NO2 305: found 306 (M+H). 1H NMR (200 MHz,CDCl3): δ 2.28 (s,3H), 6.82 (d,2H), 7.19 (d,3H), 7.2-7.5 (m,5H), 8.05 (d,2H).
Reaction SMILES: [CH3:1][C:2]([O:37]C(=O)C)([CH3:36])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:35])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[N:13]=3)[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[OH:37][C:2]([CH3:36])([CH3:1])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:35])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[N:13]=3)[CH2:6]1)=[O:4]
Reactant: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A mixture of acetic acid 1,1-dimethyl-2-{3-[9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidin-1-yl}-2-oxoethyl ester (125 mg, 0.23 mmol) and LiOH (114 μL, 0.46 mmol, 4M solution) in THF (3 mL) and MeOH (1 mL) was allowed to stir at r.t. for 18 h. Further LiOH (343 μL, 1.37 mmol, 4M solution) and the mixture stirred at 50° C. for 5 days. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) then dissolved in a mixture of MeCN and H2O and allowed to freeze-dry affording 855 as a white solid (88 mg, 77%). LCMS (method I): RT 2.88 min, [M+H]+ 505.3. 1H NMR (DMSO, 400 MHz): δ 8.09-8.08 (1 H, m), 7.64-7.61 (1 H, m), 7.28-7.27 (2 H, m), 5.02 (1 H, brd s), 4.57 (1 H, t, J=8.94 Hz), 4.26 (4 H, brd s), 4.17 (1 H, dd, J=10.24, 5.60 Hz), 4.03 (1 H, t, J=8.97 Hz), 3.77 (4 H, t, J=4.64 Hz), 3.74 (3 H, s), 3.67 (1 H, dd, J=9.96, 5.41 Hz), 3.21-3.20 (3 H, m), 2.85 (3 H, s), 1.28-1.21 (6 H, m)
Reaction SMILES: [ClH:1].[OH:2][CH:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:7]=2[CH2:6][NH:5][CH2:4]1.CCOCC>C(O)C>[ClH:1].[OH:2][CH:3]1[CH2:9][C:8]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:7]=2[CH2:6][NH:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC(O)C2
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Nc1ccc2c(c1)CNCC(O)C2
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A suspension of 4-hydroxy-8-nitro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride (1.80 g, 7.36 mmol) (G. L. Grunewald and V. H. Dahanukar, J. Heterocycl. Chem., 1994, 31, 1609) and 5% Pd--C (0.2 g) in ethanol (100 ml) was hydrogenated at 50 psi for 2 h. The catalyst was filtered off and the solvent was concentrated to give a solid. This solid was dissolved in hot ethanol (50 ml) and ether (200 ml) was added slowly. The solid was collected, washed with ether (100 ml) and air-dried to give the title compound as a yellow solid (1.44 g, 91%), m.p. 232.5-4° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:18]([NH2:20])=[O:19])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.C(O)C.[CH3:24][C:25]([CH3:27])=O.[H][H]>[Pd].C(OCC)(=O)C>[CH:25]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:18]([NH2:20])=[O:19])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)([CH3:27])[CH3:24]
Reactant: [H][H]
Reactant: NCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Reactant: CC(C)=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)NCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
A solution of 6.7 g. of 9-(3-aminopropyl)-9-aminocarbonylfluorene (prepared as described in Example 29) in 90 ml. of ethanol containing 1.6 g. of acetone was stirred at 40° C. for sixteen hours. The reaction mixture was then hydrogenated for two hours at ambient temperature in the presence of 2.0 g. of 5% palladium on carbon and hydrogen at a pressure of 60 psi. The reaction mixture next was filtered and the solvent was removed from the filtrate by evaporation to provide a foam. The foam was dissolved in ethyl acetate and then extracted into 1 N hydrochloric acid. The aqueous acid layer was separated, make alkaline with 50% sodium hydroxide, and the product was extracted into fresh ethyl acetate. The organic extracts were combined, washed with water, dried, and the solvent was removed by evaporation under reduced pressure to provide 9-(3-isopropylaminopropyl)-9-aminocarbonylfluorene identical to that obtained in Example 27.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N+:15]#[C-:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=O>Cl(O)(=O)(=O)=O>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:23]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: O=Cc1ccccn1
Reactant: [C-]#[N+]c1c(C)cccc1C
Reactant: Nc1nccs1
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1cccc(C)c1Nc1c(-c2ccccn2)nc2sccn12

Procedure:
Compound 19 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-aminothiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) 2,6-dimethylphenylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-pyridinecarbaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: C(C1[C:4](=[O:24])[NH:5][CH:6]=[C:7]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:8]=1)#N.[OH-:25].[K+].Cl.[CH2:28]([OH:30])[CH3:29]>>[C:28]([C:29]1[C:4](=[O:24])[NH:5][CH:6]=[C:7]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:8]=1)([OH:25])=[O:30]
Reactant: N#Cc1cc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]c1=O
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)c1cc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]c1=O

Procedure:
A mixture of 3-(3-cyano-2-oxo-1,2-dihydropyridin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.60 g) and 85% potassium hydroxide (0.38 g) in 67% aqueous ethanol (6 ml) was refluxed for 4 hours. After cooling, the reaction mixture was added onto ice (12 g) and acidified with 5% hydrochloric acid. Precipitates were collected and recrystallized from a mixture of N,N-dimethylformamide and water twice to give 3-(3-carboxy-2-oxo-1,2-dihydropyridin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.36 g).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[F:5][C:6]1[CH:7]=[C:8]([C:12]2([OH:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:9]=[CH:10][CH:11]=1>>[C:1]([CH2:2][CH2:3][N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[CH:7]=2)([OH:22])[C:13]1=[O:21])#[N:4]
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(F)c1
Reactant: C=CC#N
Product: N#CCCN1C(=O)C(O)(c2cccc(F)c2)c2ccccc21

Procedure:
Reaction of acrylonitrile with 3 -(m-fluorophenyl)- 3-hydroxyindolin-2-one by a procedure analogous to that of Example 1 gives 1-(2-cyanoethyl)- 3-(m-fluorophenyl)- 3-hydroxyindolin-2-one. Hydrogenation of 1-(2-cyanoethyl)- 3-(m-fluorophenyl)-3-hydroxyindolin-2-one by a procedure analogous to that of Example 2 gives 1-(3-aminopropyl)- 3-(m-fluorophenyl)-3-hydroxyindolin-2-one. Cyclodehydration of 1-(3-aminopropyl)-3-(m-fluorophenyl)-3-hydroxyindolin-2-one by a procedure analogous to that of Example 3 gives 10-(m-fluorophenyl)- 2,3,4,10-tetrahydropyrimido[ 1,2-a] indol-10-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](=[N:7][OH:8])Cl)[CH3:2].[N:10]1([C:15]2[CH2:16][CH2:17][N:18]([C:21](=[O:23])[CH3:22])[CH2:19][CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[CH:20]2[CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16][C:15]2([N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[O:8][N:7]=1)=[O:9])[CH3:2]
Reactant: CCOC(=O)C(Cl)=NO
Reactant: CC(=O)N1CC=C(N2CCCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=NOC2(N3CCCC3)CCN(C(C)=O)CC12

Procedure:
A solution of 17.9 g (0.118 mol) of 2-chlorohydroxyiminoacetic acid ethyl ester in 20 mL of DCM was added to a solution of 16.3 g (84 mmol) of 1-(4-pyrrolidin-1-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (A) in 150 mL of DCM. On so doing, the solution warmed up and turned red. After cooling to 0° C. (ice bath), 16.4 g (0.118 mol) of triethylamine were slowly added dropwise with stirring. The mixture was stirred for 12 h at RT and then washed, firstly with 10% (weight percent) citric acid solution in water, and then with sat. aq. common salt solution. After removal of the solvent under a vacuum, the residue was purified by column chromatography (SiO2, EtOAc/EtOH 9:1). 18.5 g (71% of theoretical) of the desired product 5-acetyl-7a-pyrrolidin-1-yl-3a,4,5,6,7,7a-hexahydro-isoxazolo[4,5-c]pyridine-3-carboxylic acid ethyl ester (B) were obtained in the form of a brown oil.