Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([F:10])=[C:4]([F:11])[N:3]=1.[C:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)#[N:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:8][C:7]1[C:2]([O:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]#[N:13])=[N:3][C:4]([F:11])=[C:5]([F:10])[C:6]=1[CH3:9]
Reactant: N#Cc1cccc(O)c1
Reactant: Cc1c(F)c(F)nc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1c(F)c(F)nc(Oc2cccc(C#N)c2)c1F
Temperature: 45 °C

Procedure:
To 2,3,5,6-tetrafluoro-4-methylpyridine (0.71 g, 4.3 mmol) dissolved in acetonitrile (5 mL) was added 3-cyanophenol (0.5 g, 4.2 mmol) and cesium carbonate (1.44 g, 4.4 mmol). The reaction was heated in an oil bath at 45° C. for 16 hours and partitioned with ether and water. The organic layer was separated, washed with brine, dried (Na2SO4), and the solvent removed in vacuo. Chromatography on silica gel with methylene chloride/hexane (7/3) gave 3-[(3,5,6-trifluoro-4-methylpyridin-2-yl)-oxy]benzonitrile; NMR (CDCl3) 7.55 (m, 2), 7.45 (m, 2), 2.24 (s, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]([C:17]([OH:19])=O)=[CH:15][C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[N:13]2)=[O:10])=[N:6][CH:7]=1.Cl.[CH:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)([CH3:31])[CH3:30].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[CH:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:17]([C:16]2[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[N:13]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)=[O:19])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: COCCOCCOc1cc(C(=O)O)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOCCOc1cc(C(=O)NC2CCN(C(C)C)CC2)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reaction time: 16 h

Procedure:
To 310 mg 2-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-[2-(2-methoxy-ethoxy)-ethoxy]-2H-pyrazole-3-carboxylic acid in 5 ml DCM and 0.3 ml NEt3, 110 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 197 mg BOP-CL were added at RT and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[C:18]([C:22]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=2[C:24]#[N:25])[CH:19]=[N:20][CH:21]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]([C:18]2[CH:19]=[N:20][CH:21]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:17]=2)=[C:23]([CH:26]=1)[C:24]#[N:25]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: N#Cc1cc(F)ccc1-c1cncc(Br)c1
Product: CC(C)(O)c1ccn2c(-c3cncc(-c4ccc(F)cc4C#N)c3)cnc2c1F
Yield: 51.9 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (145 mg, 0.75 mmol) and 2-(5-bromopyridin-3-yl)-5-fluorobenzonitrile (208 mg, 0.75 mmol) were coupled following the procedure in Example 23 to afford 5-fluoro-2-{5-[8-fluoro-7-(2-hydroxyprop-2-yl)imidazo[1,2-α]pyridin-3-yl]pyridin-3-yl}benzonitrile (152 mg, 52%) as a white solid: δH (500 MHz, DMSO) 1.59 (6H, s), 5.57 (1H, s), 7.23 (1H, dd, J 7 and 7), 7.80 (1H, ddd, J 9, 9 and 3), 7.91-7.94 (1H, m), 7.99 (1H, s), 8.08 (1H, dd, J 9 and 3), 8.41 (1H, dd, J 2 and 2), 8.58 (1H, d, J 7), 8.82 (1H, s), 9.01 (1H, s); m/z (ES+) 391 (100%, [MH]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:12]#[N:13])=[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[N+]([CH3:18])([O-])=O.N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1([C:12]#[N:13])[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:18]1)=[O:14])[CH3:2]
Reactant: CCOC(=O)C(C#N)=C1CCCCC1
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(C#N)CC12CCCCC2
Reaction time: 2.5 h
Yield: 74.9 %

Procedure:
To a solution of cyano-cyclohexylidene-acetic acid ethyl ester (1.37 g, 7.09 mmol) in 30 mL acetonitrile was added nitromethane (1.92 mL, 35.5 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.06 mL, 7.09 mmol) resulting in an orange solution. The reaction was stirred for 2.5 hours, then partitioned between ethyl ether (Et2O) and 1N hydrochloric acid (HCl) (aq). The phases were separated, and the organic phase washed with brine, dried over magnesium sulfate (MgSO4), and concentrated. Flash chromatography of the residue (5% ethyl acetate (EtOAc)/hexanes) afforded 1.1 g (75%) of 1-cyano-spiro[2.5]octane-1-carboxylic acid ethyl ester as a colorless oil. 1H NMR (CDCl3) δ 4.22 (m, 2H), 1.77 (d, J=5.1 Hz, 1H), 1.42–1.72 (m, 10H), 1.40 (d, J=5.1 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H). 13C NMR δ 166.40, 118.60, 62.72, 40.20, 34.67, 29.01, 28.75, 25.69, 25.54, 25.28, 24.66, 14.38. LRMS: m/z 208.0 (M+1). IR: 2239, 1732 cm−1. Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.41; H, 8.33; N, 6.75.
Reaction SMILES: [CH3:1][C:2]1([CH:17]=O)[CH2:6][CH:5]2[CH:7]([CH3:16])[C:8]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:12])[C:10]([CH3:11])=[C:4]2[O:3]1.[CH2:19]1[C:31]2[NH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH2:22][CH2:21][NH:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[N+:13]([C:8]1[CH:7]([CH3:16])[CH:5]2[CH2:6][C:2]([CH2:17][N:20]3[CH2:21][CH2:22][C:23]4[C:24]5[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=5)[NH:30][C:31]=4[CH2:19]3)([CH3:1])[O:3][C:4]2=[C:10]([CH3:11])[C:9]=1[CH3:12])([O-:15])=[O:14]
Reactant: CC1=C2OC(C)(C=O)CC2C(C)C([N+](=O)[O-])=C1C
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1=C2OC(C)(CN3CCc4c([nH]c5ccccc45)C3)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
2.0 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde, 1.52 g of 2,3,4,9-tetrahydro-1H-beta-carboline, 50 ml of methylene chloride, 0.8 ml of acetic acid and 2.04 g of sodium triacetoxyborohydride were added, followed by stirring overnight at room temperature. The mixture was poured into ice-water and an aqueous sodium hydroxide solution was added. The reaction solution was extracted with chloroform, washed with saturated saline and dried over anhydrous magnesium sulfate and, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=50:1) to obtain 1.49 g of the objective product.
Reaction SMILES: CS(O[C@@H:6]1[CH2:10][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[N:8]([C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27](=[O:47])[N:28]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=4)[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[C:20]3[CH:19]=2)[CH2:7]1)(=O)=O.[C-:48]#[N:49].[K+]>CS(C)=O>[C:48]([C@@H:6]1[CH2:7][N:8]([C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]([N:28]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[CH2:38][C:39]4[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=4)=[O:47])=[C:20]3[CH:19]=2)[C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH2:10]1)#[N:49]
Reactant: [C-]#N
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@H](OS(C)(=O)=O)C[C@@H]4c4cccc(F)c4)cc23)cc1
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](C#N)C[C@@H]4c4cccc(F)c4)cc23)cc1
Temperature: 90 °C

Procedure:
A mixture of (3R,5R)-1-(3-(bis(4-methoxybenzyl)carbamoyl)pyrazolo[1,5-a]pyridin-5-yl)-5-(3-fluorophenyl)pyrrolidin-3-yl methanesulfonate (I-34) (0.17 g, 0.26 mmol), potassium cyanide (20 mg, 0.31 mmol) and DMSO (anhyd, 1 mL) was heated at 90° C. for 3 hours. After cooling, the reaction mixture was partitioned in EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica chromatography eluting with an EtOAc/Hex gradient to yield 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-35). 1H NMR (400 MHz, CDCl3) δ 8.15-8.11 (m, 1 H), 7.80 (s, 1 H), 7.37-7.28 (m, 1 H), 7.22-7.15 (m, 5 H), 7.02-6.93 (m, 2 H), 6.93-6.86 (m, 5 H), 6.15 (dd, J=2.7, 7.7 Hz, 1H), 5.08 (dd, J=2.6, 7.9 Hz, 1 H), 4.72 (d, J=15.7 Hz, 2 H), 4.54 (d, J=15.8 Hz, 2 H), 4.20-4.14 (m, 1 H), 3.91-3.83 (m, 1 H), 3.82 (s, 6 H), 3.37-3.24 (m, 1 H), 2.82 (ddd, J=8.1, 10.1, 12.4 Hz, 1 H), 2.41 (ddd, J=2.8, 6.4, 12.4 Hz, 1 H). MS m/z 590.2 (M+1)+
Reaction SMILES: N.Cl.C[NH:4]C.[O:6]=[C:7]1[C:15]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[CH2:27][C:28]1[O:29][CH:30]=[C:31]([C:33](O)=[O:34])[N:32]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1OC(C(O)=O)=CC=1>O1CCOCC1>[O:6]=[C:7]1[C:15]2([CH2:19][O:18][C:17]3[CH:20]=[C:21]4[C:25](=[CH:26][C:16]2=3)[CH2:24][CH2:23][O:22]4)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]1[CH2:27][C:28]1[O:29][CH:30]=[C:31]([C:33]([NH2:4])=[O:34])[N:32]=1
Reactant: O=C(O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1
Reactant: CNC
Agent: Cl
Agent: N
Agent: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Solvent: C1COCCO1
Product: NC(=O)c1coc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)n1

Procedure:
Following the procedure as described in EXAMPLE 13.1 and making non-critical variations using 4 M ammonia solution in dioxane to replace dimethylamine hydrochloride, 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid to replace 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid, 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxamide was obtained (19%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 7.53 (d, J=10.2 Hz, 2H), 7.33-6.99 (m, 4H), 6.54 (s, 1H), 6.38 (s, 1H), 5.22-5.01 (m, 2H), 4.75 (ABq, 2H), 4.46 (t, J=8.8 Hz, 2H), 2.92 (t, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ177.3, 161.9, 161.6, 160.9, 159.2, 143.2, 142.2, 136.8, 132.5, 129.2, 124.1, 123.8, 120.8, 120.4, 119.7, 109.6, 92.8, 80.0, 72.5, 57.3, 37.4, 28.7; MS (ES+) m/z 403.8 (M+1).
Reaction SMILES: C=CC[C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([OH:17])=[C:15]([OH:18])[CH:14]=[C:13]([CH2:19][CH:20]=[CH2:21])[CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[CH3:22][CH2:23][CH2:24]CCC>CO.C(OC(=O)C)C.[Pd](Cl)Cl>[CH:22](/[C:5]1[CH:4]=[CH:9][C:8]([O:10][C:11]2[CH:12]=[C:13](/[CH:19]=[CH:20]/[CH3:21])[CH:14]=[C:15]([OH:18])[C:16]=2[OH:17])=[CH:7][CH:6]=1)=[CH:23]\[CH3:24]
Reactant: CCCCCC
Reactant: C=CCc1cccc(Oc2cc(CC=C)cc(O)c2O)c1
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C/C=C/c1ccc(Oc2cc(/C=C/C)cc(O)c2O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of obovatol (1 g) in methanol was added palladium chloride (PdCl2) (10 mg), followed by stirring at room temperature for 5 hours. After completion of the reaction, the organic layer containing the active material was collected and concentrated in a vacuum. The concentrate (1.1 g) was dissolved in methylene chloride (30 ml) and loaded onto a silica gel (Merck, Art No. 9385) so as to adsorb the active material thereonto. Purification through silica gel column chromatography eluting with a gradient of a mixture of ethylacetate and hexane from 10:90 to 20:80 afforded colorless 3-(4-((E)-prop-1-enyl)phenoxy)-5-((E)-prop-1-enyl)benzene-1,2-diol (0.91 g, yield 90%)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](O)[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.C1(C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:26]>C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:26])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)N1Cc2nc(N)nc(O)c2C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)N1Cc2nc(N)nc(Cl)c2C1
Yield: 57.1 %

Procedure:
Intermediate (h) (11 g, 49 mmol) was azeotroped×2 with toluene. Anhydrous acetonitrile (250 mL) and POCl3 (25 mL, 270 mmol) were added and the mixture was refluxed for about 2.5 h. Additional POCl3 (50 mL) was added and the mixture was refluxed for an additional 2 h. The volatile components were concentrated under vacuum at 40° C. to give a red solution. A minimum amount of dry acetonitrile was added until the solution was readily transferable whereupon it was poured onto ice in a large beaker. The flask was further rinsed with a small amount of acetonitrile which was added to the ice. Water (about 50 mL) was added to the ice mixture to help it with stirring. Concentrated NH4OH (25 mL) was added slowly with stirring until the ice slurry mixture was strongly basic, then 50% aqueous NaOH (25 mL) was also added to the still stirring slurry of ice. Additional ice was added. After about 5 minutes stirring as ice slurry, EtOAc was added. After stirring in the beaker for several more minutes, water was added to help melt the ice. The mixture was poured into a separatory funnel and the layers were allowed to partition. The aqueous layer was extracted with EtOAc×3. The combined EtOAc extracts were washed ×2 with saturated aqueous KHSO4, ×2 with saturated aqueous NaHCO3, ×1 with brine, dried over Na2SO4, filtered and evaporated to afford a pale pink powder which was triturated with ethyl acetate to give compound I(C) as pale pink solids (6.8 g, 28 mmol) in 57% yield. HPLC/LCMS purity was greater than 90%. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.20 (s, 2H), 4.48 (s, 2H), 4.45 (s, 2H), 4.17-4.08 (m, 2H), 1.24 (t, 3H). LCMS (M+H)+: 243.2, 245.2.
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].N1C=CC=CC=1.Cl[C:12]([O:14][CH:15]([Cl:17])[CH3:16])=[O:13]>>[C:12](=[O:13])([O:4][CH:2]([CH3:3])[CH3:1])[O:14][CH:15]([Cl:17])[CH3:16]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)O
Solvent: c1ccncc1
Product: CC(C)OC(=O)OC(C)Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 2-propanol (2.66 mL, 34.97 mmol) and pyridine (3.39 mL, 41.96 mmol), pre-cooled in a dry-ice/acetone bath was slowly added 1-chloroethyl chloroformate. The resulting mixture was allowed to slowly warm to 25° C. overnight, with stirring. After concentration under reduced pressure the mixture was dissolved in ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1-chloroethyl isopropyl carbonate as a pink/orange oil (5.11 g, 88% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[CH3:13][NH2+:14][CH3:15].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O>C1COCC1>[CH3:13][N:14]([CH3:15])[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: C[NH2+]C
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
1H-indazole-3-carboxylic acid (45.2 g, 279 mmol) was suspended in THF (500 mL), and to the suspension were added 1-hydroxybenzotriazole dimethylammonium salt (55.7 g, 308 mmol) obtained in a similar manner to the known method [for example, Synthesis, page 285 (1992)] and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58.9 g, 307 mmol), followed by stirring at room temperature overnight. The reaction mixture was added with water, was extracted with ethyl acetate, and the organic layer was sequentially washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from mixed solvent of acetone/water to obtain N,N-dimethyl-1H-indazole-3-carboxamide (37.7 g, 71%).
Reaction SMILES: [H][H].[O:3]=[C:4]1[CH:9]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21]C=O)[N:12]=[C:11]2[CH3:24])[CH2:8][CH2:7][C:6](=[O:25])[NH:5]1>C(O)=O>[NH2:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[N:10]([CH:9]1[CH2:8][CH2:7][C:6](=[O:25])[NH:5][C:4]1=[O:3])[C:11]([CH3:24])=[N:12]2
Reactant: Cc1nc2cccc(NC=O)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: [H][H]
Solvent: O=CO
Product: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In certain embodiments, when the hydrogen donor is formic acid, the transfer hydrogenation further comprises the step of hydrolyzing N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione as described herein elsewhere.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([CH3:24])=[CH2:23]>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:23][C:22]([CH3:24])=[CH2:21])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C(=O)OC)cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of methyl 4-hydroxy-3-methoxybenzoate (100 g, 0.55 mol) and K2CO3 (92 g, 0.66 mol) in DMF (800 ml) was added drop wise 3-chloro-2-methyl-propene (55 g, 0.60 mol). The mixture was stirred at 60° C. overnight. TLC (EtOAc/petroleum ether=1/3) showed no starting material was present. The reaction mixture was filtered and the filtrate was added water (400 ml). The mixture was extracted with EtOAc (400 ml×3). The combined organic phase was washed with brine (400 mL), dried (Na2SO4) and concentrated to give the product (130 g, 100%) as yellow oil. The oil was used directly to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 1H), 7.19 (s, 1H), 6.80 (d, 1H), 5.00(d, 2H), 4.50 (s, 2H), 3.83 (d, 6H), 1.76 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:7][CH:6]=[CH:5]2.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Br[CH2:25][CH2:26][O:27][Si:28]([CH3:34])([CH3:33])[C:29]([CH3:32])([CH3:31])[CH3:30].S([O-])([O-])(=O)=O>CN(C=O)C.C1(C)C=CC=CC=1>[C:29]([Si:28]([CH3:34])([CH3:33])[O:27][CH2:26][CH2:25][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[C:10]([N+:11]([O-:13])=[O:12])[CH:9]=2)[CH:5]=[CH:6]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cc2cc[nH]c2cc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc2ccn(CCO[Si](C)(C)C(C)(C)C)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 352 mg of 5-methyl-6-nitroindole in 10 mL DMF was added drop wise 2.2 ml of 1M toluene solution of lithium hexamethyldisilazide. The solution was stirred for five minutes and 0.5 ml (1.1 equivalents) bromoethoxy dimethyl-t-butyl silane was added. The mixture was stirred at 0° C. for 30 minutes and then stirred for 4 hours at room temperature. Sulfate buffer (pH2) was added and the mixture was extracted with ethyl acetate. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to yield 300 mg of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-6-nitro-1H-indole.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>C(Cl)Cl>[C:38]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(C(C)=O)CC2)cn1
Reaction time: 12 h

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide (200 mg, 4.8 mmol) was dissolved in 5 mL of methylene chloride, charged with 0.08 mL of triethylamine, and 0.03 mL of acetylchloride at 0° C. The reaction was stirred for 12 h, quenched with sodium bicarbonate, extrated with methylene chloride and concentrated. The compound was purified by silica gel chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.9, 21.6, 32.8, 33.7, 36.0, 40.7, 43.0, 45.4, 53.1, 55.5, 102.6, 102.8, 103.1, 105.6, 105.7, 112.3, 112.4, 112.5, 131.5, 137.8, 169.1, 169.3, 169.5; MS 462.25 m/z (M+1).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCCCC)=[N+:2]=[N-:3].[I:22]C1C=CC=CC=1C(Cl)=O.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[I:22])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: O=C(Cl)c1ccccc1I
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCCNC(=O)c1ccccc1I
Yield: 74 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 2-iodobenzoyl chloride (0.312 g, 1.17 mmol) was reacted with 2-azidoethanamine (0.101 g, 1.17 mmol) and triethylamine (0.237 g, 2.34 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-2-iodobenzamide (0.272 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, 1H), δ 7.33 (m, 2H), δ 7.08 (t, 1H), δ 6.51 (s, 1H), δ 3.54 (s, 2H), δ 3.53 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 169.9, 141.9, 140.0, 131.5, 128.4, 128.4, 92.7, 50.8, 39.6 ppm; HRMS (ESI) calcd for C9H9IN4O (M+) 315.9821. found 315.9820.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][N:23]=1>ClCCl.N1C=CC=CC=1>[N:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)=[O:13])=[N:23][CH:24]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccncn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccncn1)c1ccccc1SSc1ccccc1C(=O)Nc1ccncn1
Yield: 2 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (3.00 g, 8.74 mmol) in 75 mL of dichloromethane and 4-aminopyrimidine (1.66 g, 17.5 mmol) in 14 mL of pyridine. The crude product was triturated with a hot mixture of acetonitrile and DMF, filtered, and recrystallized from water-DMF to yield 0.08 g of the title compound, mp 234°-235° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[CH:11]([N:14]([CH:18]([CH3:20])[CH3:19])[C:15](Cl)=[O:16])([CH3:13])[CH3:12].N1C=CC=CC=1.Cl>>[CH:11]([N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:16])[O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH3:13])[CH3:12]
Reactant: OCCc1ccccc1F
Reactant: CC(C)N(C(=O)Cl)C(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)N(C(=O)OCCc1ccccc1F)C(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 8.0 g (57.1 mmol) of 2-(2-fluorophenyl)ethanol, 9.34 g (57.1 mmol) of diisopropylcarbamoyl chloride and 6.93 ml (85.7 mmol) of pyridine was heated to 90° C. and stirred overnight. After cooling to room temperature, the mixture was treated with 1 N—HCl, extracted 3 times with ethyl acetate, washed with water, saturated NaHCO3, water and brine and then dried over sodium sulfate. After the solvent was distilled off, purification of the residue by silica gel chromatography gave 14.0 g of the title compound. (Yield: 98%).