Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.I[CH2:26][C@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:34]=[CH:35][C:36]3[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=3[CH:43]=2)[CH2:28]1.CCN(C(C)C)C(C)C.Cl>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:26][C@H:27]5[O:31][C:30](=[O:32])[N:29]([C:33]6[CH:34]=[CH:35][C:36]7[S:41][CH2:40][C:39](=[O:42])[NH:38][C:37]=7[CH:43]=6)[CH2:28]5)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C1CSc2ccc(N3C[C@@H](CI)OC3=O)cc2N1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSc2ccc(N3C[C@@H](CN4CCN(c5cc6c(cc5F)c(=O)c(C(=O)O)cn6C5CC5)CC4)OC3=O)cc2N1
Temperature: 80 °C

Procedure:
A mixture of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxo-3-quinoline carboxylic acid (commercial; 331 mg), 6-((S)-5-iodomethyl-2-oxooxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one (prepared according to WO 2008/126034; 395 mg) and DIPEA (0.5 ml) in DMSO (6 ml) was heated at 80° C. for 24 h. The reaction mixture was allowed to reach rt, poured on 0.1N HCl (50 ml) and filtered. The resulting solid was purified by CC (DCM/MeOH 19:1 to 9:1 to 4:1, followed by DCM/MeOH 19:1+1% AcOH), affording after concentration under reduced pressure and subsequent stirring in MeOH/EA a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][CH:13]=[N:12][C:11]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:20])[CH:13]=[N:12][C:11]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cc(C)cc(Sc2[nH]cnc2C(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2c(C(C)C)ncn2C)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
In 10 ml of dry N,N-dimethylformamide was dissolved 1.0 g (4.1 mmol)of 5-(3,5-dimethylphenylthio)-4-isopropyl-1H-imidazole (X=Y=Me)(9), followed by addition of 330 mg (8.3 mmol)of 60% sodium hydride under ice-cooling. After 5 minutes, 690 mg (4.9 mmol)of methyl iodide was added and the mixture was stirred for 10 minutes. This reaction mixture was poured in ice-water and extracted with diethyl ether. The organic layer was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was fractionated by alumina chromatography (ethyl acetate:n-hexane,=1:1). From the first fraction, 833 mg (yield 79%)of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-methyl-1H-imidazole (X=Y=Me) (10)was recovered as oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:16](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.[CH2:31]1[CH2:35]OC[CH2:32]1>C(O)(=O)C>[CH2:16]([N:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)[CH2:15][CH2:14]1)[CH:31]([CH3:32])[CH3:35]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7 g (34 mmol) 1-(5-nitro-pyridin-2-yl)-piperazine (commercially available), 3.15 g (44 mmol) isobutytraldehyde, 10.7 g (50 mmol) sodium trisacetoxyborohydride in 140 ml THF and 3 ml acetic acid was stirred at room temperature for 16 h. After addition of 50 ml water, THF was removed under vacuum. The residue was taken up in 300 ml water and 400 ml ethyl acetate and made alkaline by addition of 2M aq. Na2CO3 solution. The mixture was afterwards extracted two times with 300 ml ethyl acetate each. The combined organic phases were washed two times with 200 ml water each, dried with MgSO4 and evaporated to dryness. The residue was used without further purification in the synthesis of intermediate 9. (m/e): 265.0 (MH+; 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:5][N:4]=1.O=S(Cl)[Cl:29]>C(#N)C.O1CCOCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][Cl:29])=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(Nc2ncnc3[nH]c(-c4ccc(CO)cc4)cc23)ccn1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC#N
Product: COc1cc(Nc2ncnc3[nH]c(-c4ccc(CCl)cc4)cc23)ccn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
At 0° C., a suspension of 1.23 g (3.5 mMol) of {4-[4-(2-methoxy-pyridin-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol in 18 ml of acetonitrile, 18 ml of dioxane and 1.5 ml of SOCl2 is prepared at 0° C. and then stirred for 4.5 h at RT. The mixture is diluted with 0.2 I of EtOAc and 0.1 I of saturated NaHCO3-solution, stirred and the title compound filtered off; MS-ES+: (M+H)+=366. More product can be obtained by extraction of the filtrate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:14]([F:16])[F:15])=[C:7]([CH:13]=1)[C:8]([N:10]=[C:11]=[O:12])=O)#[N:2].[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH:26]C(OC(C)(C)C)=O)=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:15][CH:14]([F:16])[C:6]1[C:7]([C:8]2[NH:10][C:11](=[O:12])[N:25]([C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:35])[F:34])=[CH:20][CH:21]=3)[N:26]=2)=[CH:13][C:3]([C:1]#[N:2])=[CH:4][N:5]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cnc(C(F)F)c(C(=O)N=C=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 25.3 %

Procedure:
The title compound was prepared by following the procedure as described in Example-83 by using 5-cyano-2-(difluoromethyl)nicotinoyl isocyanate (Intermediate-145, 0.900 g, 4.03 mmol), tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.0 g, 3.63 mmol), TFA (10 mL), DCM (40 mL) to afford 0.350 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.45-7.56 (t, J=53.4 Hz, 1H), 7.90 (d, J=9.3 Hz, 2H), 8.20 (d, J=8.7 Hz, 2H), 8.77 (s, 1H), 9.32 (s, 1H), 13.01 (s, 1H); MS (m/z): 382.15 (M+H)+.
Reaction SMILES: CCC([O-])(C)C.[Na+].[C:8](OC)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.S(=O)(=O)(O)O>C1(C(C)C)C=CC=CC=1>[C:8]([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][C:18]1=[O:24])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1ccccc1
Agent: CCC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)c1ccccc1
Product: O=C1CCCCC1C(=O)c1ccccc1
Temperature: 100 °C
Yield: 76 %

Procedure:
Cumene (dry, 180 mL), sodium tert-pentoxide (35.8 g; 0.326 mol), and methyl benzoate (68.1 g; 0.50 mol) were placed into a four-necked, round bottom, half-liter flask equipped with a stirrer, a thermometer, and a reflux condenser. The mixture was heated to 100° C. and kept at that temperature under a blanket of nitrogen. Cyclohexanone (24.5 g; 0.250 mol) was added slowly over a period of 15 minutes by means of a syringe pump. After 20 minutes from the beginning of the addition of the ketone, the mixture was cooled with an ice water bath to room temperature. Aqueous sulfuric acid (10%) was added with stirring, keeping the temperature below 25° C., until the pH of the aqueous layer was acidic. The organic layer was washed in a one liter separation funnel with aqueous sodium bicarbonate and then with water. The solvents were evaporated on a Rotovap and the residue was crystallized from heptane, affording BCH (38.43 g, 76% yield) having a purity of 99% (GC).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][NH:13][CH3:14]>CO>[CH3:12][N:13]([CH3:14])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: ClCCCOc1cccnc1
Reactant: CNC
Solvent: CO
Product: CN(C)CCCOc1cccnc1
Temperature: 100 °C
Yield: 92.9 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (2.00 g, 11.65 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of dimethylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue. The pH of the solution was adjusted to 6, and the mixture was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4×50 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated to give 1.95 g (92.9%) of an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7]2.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[ClH:26].[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[C:3]3[C:4](=[O:18])[CH:5]=[C:6]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[O:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:30][CH2:29]1
Reactant: OC1CCNCC1
Reactant: ClCCCCCCBr
Reactant: O=c1cc(-c2ccccc2)oc2cccc(O)c12
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2cccc(OCCCCCCN3CCC(O)CC3)c12

Procedure:
The compound was prepared by the method of Example 21 from 5-hydroxyflavone, 1-bromo-6-chlorohexane, and 4-hydroxypiperidine: mp 210°-211° C.
Reaction SMILES: C(C1(O)C[CH2:7][C@@H:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])C1)C=C.I([O-])(=O)(=O)=O.[Na+].[CH:26]([OH:29])([CH3:28])[CH3:27].[C:30]([O:33]CC)(=[O:32])[CH3:31]>O.[Ru](=O)=O>[CH2:12]([O:11][C:9]([CH:6]1[CH2:7][CH2:28][C:26]([CH2:31][C:30]([OH:33])=[O:32])([OH:29])[CH2:27]1)=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(C)=O
Reactant: C=CCC1(O)CC[C@@H](C(=O)OCc2ccccc2)C1
Reactant: CC(C)O
Agent: O=[Ru]=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: O=C(O)CC1(O)CCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of benzyl 3-allyl-3-hydroxycyclopentanecarboxylate (from step A, 150 mg, 0.576 mmol) in ethyl acetate (5 mL) was added ruthenium(IV) oxide hydrate (104 mg, 0.691 mmol) followed by 10% wt. aqueous sodium periodate solution (˜3 mL). The resulting mixture was stirred at room temperature for 4 hours. Isopropyl alcohol (3 mL) was added to quench the reaction. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to yield 2-(3-(benzyloxycarbonyl)-1-hydroxycyclopentyl)acetic acid (130 mg, 0.467 mmol, 81% yield) as an oil. It was used as such for the next step without further purification. MS (ESI+) m/z 301 (M+Na)+
Reaction SMILES: C(OC[O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:35])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1)C.FC(F)(F)C(O)=O>ClCCl>[OH:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([NH:17][C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[C:20]([CH3:35])=[N:21][N:22]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:16])=[CH:13][N:14]=[C:8]2[CH:7]=1
Reactant: CCOCOc1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(O)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
7-(Ethoxymethoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11.2 mg, 0.02 mmol) was dissolved in dichloromethane (0.9 mL) and treated with trifluoroacetic acid (0.1 mL). The mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated and dried under high vacuum to give 7-hydroxy-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (8 mg). MS m/z 413.2 (M+1, APCI+).
Reaction SMILES: NC(=O)CO[CH2:5][C:6]1[N:10]=[C:9]([C@H:11]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][C:13]([NH:15][OH:16])=[O:14])[O:8][N:7]=1.C1(CCCC(C2ON=C(C[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])N=2)CC(O)=O)CCCCC1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)ON>O1CCCC1.CO>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:11]([C:9]2[O:8][N:7]=[C:6]([CH2:5][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[N:10]=2)[CH2:12][C:13]([NH:15][OH:16])=[O:14])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)CCc1noc(C(CCCC2CCCCC2)CC(=O)O)n1
Reactant: NC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Agent: CC(C)COC(=O)Cl
Agent: C[Si](C)(C)ON
Solvent: C1CCOC1
Solvent: CO
Solvent: CN1CCOCC1
Product: CCOC(=O)CCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3R)-6-cyclohexyl-3-[3-(3-ethoxy-3-oxopropyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 94) (110 mg, 0.30 mmol) and N-methylmorpholine (60 μl, 0.54 mmol) in anhydrous tetrahydrofuran (6 ml) was cooled to 0° C., treated with isobutyl chloroformate (42 μl, 0.32 mmol) and stirred under a nitrogen atmosphere for 2.5 hours. O-(Trimethylsilyl)hydroxylamine (120 μl, 1.00 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol) to afford the title compound as a yellow oil (94 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][C:12]2[N:16]3[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[C:9]([F:24])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:25].Cl.[NH:27]([C:29]([NH2:31])=[O:30])[NH2:28]>CO>[F:1][C:2]1[C:10]([CH2:11][C:12]2[N:16]3[N:17]=[C:18](/[C:21](=[N:28]/[NH:27][C:29]([NH2:31])=[O:30])/[CH3:22])[CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[C:9]([F:24])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:25]
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Yield: 62.6 %

Procedure:
A solution of 1-(3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (45 mg, 0.099 mmol, 75% pure) and hydrazinecarboxamide hydrochloride (22 mg, 0.198 mmol) in 10 mL MeOH was stirred at room temperature overnight. Solvent was evaporated and the residue was dissolved in a small amount of MeOH. Precipitates formed and was filtered to give the title compound as a white solid (25 mg, 0.062 mmol). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.95 (s, 1H), 8.62 (d, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 8.0 (s, 1H), 7.54 (d, 1H), 6.85 (broad, 2H), 4.48 (s, 2H), 4.0 (s, 3H), 2.3 (s, 3H). LCMS (method B): [MH]+=398.9, tR=2.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6](I)[C:5]2=O.[C:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)#[CH:15].C(N(C(C)C)CC)(C)C.[OH:32][CH2:33][CH2:34][NH:35][NH2:36]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CC#N>[NH2:20][C:19]1[CH:21]=[CH:22][C:16]([C:14]#[C:15][C:6]2[C:5]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=3[OH:8])=[N:36][N:35]([CH2:34][CH2:33][OH:32])[CH:7]=2)=[CH:17][CH:18]=1
Reactant: NNCCO
Reactant: C#Cc1ccc(N)cc1
Reactant: O=c1c(I)coc2ccc(Cl)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1ccc(C#Cc2cn(CCO)nc2-c2cc(Cl)ccc2O)cc1
Yield: 22.9 %

Procedure:
To a mixture of 6-chloro-3-iodo-chromone (1A, 30.65 g, 0.1 mol), 4-ethynylaniline (14.05 g, 0.12 mol), PdCl2(PPh3)2 (1.404 g, 2.0 mmol) and CuI (190 mg, 1.0 mmol) was added anhydrous CH3CN (500 mL). Upon stirring, diisopropylethylamine (DIPEA, 69.7 mL, 0.4 mol) was added slowly to the above mixture. The reaction mixture was stirred at rt for 5 h. LCMS indicated all of 1A was consumed. 2-Hydroxyethylhydrazine (22 mL, 0.325 mol) was then added. The mixture was stirred at rt overnight. The mixture was filtered and the solid was washed with small amount of CH3CN, and dried under high vacuum to give 2A (8.1 g). Silica (˜100 mL) was added to the filtrate, and the solvent was removed with rotavapor. The resultant powder was load on a silica column and eluted with hexanes-ethyl acetate (v/v 2/1, 2/3, 1/1, 1/2) and then pure ethyl acetate. The fractions containing 2A were combined and solvent was removed. The residua were recrystallized from hexanes-ethyl acetate to give 2A (16.5 g). Total 24.6 g of the title compound 2A was obtained, and the yield is 69.5%. 1H NMR (CDCl3/CD3OD=5/1, 500 MHz) δ 8.71 (d, 1H, J=1.5 Hz), 7.80 (s, 1H), 7.39 (d, 2H, J=7.5 Hz), 7.19 (dd, 1H, J=8.0, 1.5 Hz), 6.95 (d, 1H, J=8.5 Hz), 6.70 (d, 2H, J=7.5 Hz), 4.28 (t, 2H, J=5.0 Hz), 3.98 (t, 2H, J=5.0 Hz). LCMS (ESI) m/z 354.17 (MH+, 100); HPLC: tR=4.05 min.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][C:17]1[C:21]([S:22](Cl)(=[O:24])=[O:23])=[C:20]([CH3:26])[O:19][N:18]=1.[CH3:27][O:28][CH2:29][C:30]([C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)([CH3:32])[CH3:31]>>[CH3:16][C:17]1[C:21]([S:22]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:39]([C:36]4[CH:35]=[CH:34][C:33]([C:30]([CH3:32])([CH3:31])[CH2:29][O:28][CH3:27])=[CH:38][CH:37]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)(=[O:24])=[O:23])=[C:20]([CH3:26])[O:19][N:18]=1
Reactant: COCC(C)(C)c1ccc(N)cc1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: COCC(C)(C)c1ccc(N2CCC3(CCN(S(=O)(=O)c4c(C)noc4C)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 476.22 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 3,5-dimethyl-isoxazole-4-sulfonyl chloride, 4-(2-methoxy-1,1-dimethyl-ethyl)-phenylamine.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19].[K+].[Br-]>C(O)C>[CH2:1]([O:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1ncn2OCc1ccccc1
Reactant: N
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: Nc1ncnc2c1ncn2OCc1ccccc1

Procedure:
A solution of 9-benzyloxy-6-chloropurine (38.4 g; 0.147 mmol) in ethanol (300 ml) saturated with ammonia was heated at 100° C. in an autoclave for 16 hours. After cooling the suspension was evaporated to dryness and the residue partitioned between chloroform (750 ml) and water (500 ml). The separated aqueous phase was washed with chloroform (200 ml). The combined organic phases were washed with water, dried (MgSO4) and evaporated, affording an orange solid homogeneous on t.l.c. (31.1 g, 87%). IR: υmax (KBr) 3372, 3300, 3187, 3038, 1660, 1637, 1600, 1581 cm-1 ; 1H NMR: δH [(CD3)2SO] 5.3(2H, s, CH2Ar), 6.8(2H, br.s, D2O exchangeable, NH2), 7.3(6H, s, H-8, Ar), 7.7(1H, s, H-2). Found: C, 59.39; H, 4.60; N, 29.07%; m/e 241.0949. C12H11N5O requires: C, 59.73; H, 4.60; N, 29.03%; m/z 241.0964.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C[NH:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1.[OH-].[Na+].O.O1CCOC[CH2:39]1>C(Cl)Cl>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([N:18]([CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH3:39])[N:3]=[C:2]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CNC1CCN(C)CC1
Reactant: C1COCCO1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Nc2nc(NC3CCN(C)CC3)nc(N(C)C3CCCCCC3)n2)cc1Cl
Yield: 30.9 %

Procedure:
To 133 (10.014 g, 26.2 mmol) in 1,4-dioxane (80 mL) was added slowly methyl-(1-methyl-piperidin-4-yl)-amine (3.8 mL, 26.2 mmol) dissolved in 1,4-dioxane (15 mL) by addition funnel. Then aqueous sodium hydroxide (10.5 mL, 2.5 N, 26.2 mmol) was added by addition funnel followed by water (26 mL). The reaction mixture was heated at reflux for about 2.5 hours under a nitrogen atmosphere. The reaction was cooled and diluted with methylene chloride. The reaction mixture was filtered using vacuum and the white solid 147 removed. The filtrate was then washed 1 time with brine. The aqueous layer was back extracted 1 time with methylene chloride. The organic layers were combined and dried over potassium carbonate. The organic solution was filtered and concentrated in vacuo to afford the crude product (5.89 g). The crude reaction product was purified by flash column chromatography (silica gel) eluting with 96:3:1 methylene chloride:methanol:15 M ammonium hydroxide. The fractions were combined, dried over sodium sulfate/potassium carbonate, filtered, and concentrated in vacuo to afford 137 as a white solid (3.84 g, 30.9%), mp 104-105° C.; HPLC: YMC Pack Pro C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 13.8 min, 97% purity); MS (ESI): m/z 474 (M+H, 41), 408 (2.3), 364 (2.8), 258 (13), 239 (14), 239 (47.5), 238 (100), 127 (5.3).
Reaction SMILES: C([C@@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@@H:5]1[OH:13])(O)=O.[N:14](C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[NH2:14][C@H:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[OH:13]
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(O)[C@@H]1c2ccccc2C[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@H]1c2ccccc2C[C@H]1O

Procedure:
One gram of the hydroxamic acid of (1R,2S)-1-carboxy-2-hydroxyindane is reacted with equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in tetrahydrofuran at room temperature using the procedure of Bittner, Grinberg and Kartoon (Tet. Lett. 23, 1965-8 (1974)). The product is isolated by acidification and extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2R)-1-amino-2-indanol is isolated as a light yellow oil.