Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=2[F:1])=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc(F)c1F
Product: Nc1ccc(C(=O)c2cccc(F)c2F)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 9.9 %

Procedure:
To stirred polyphosphoric acid (125 g) heated to 90° C. was added 2,3-difluorobenzoic acid (10.00 g, 63.3 mmol) followed by aniline (5.72 g, 61.7 mmol). The reaction mixture was heated at 180°-185° C. for 1 hour (solid dissolved at 135° C.), then the oil bath was removed and distilled water (35 mL) was cautiously added in small portions through the condenser. The oil bath was returned, and the reaction mixture heated at 135°-145° C. for 1 hour. The oil bath was again removed, 3N HCl (55 mL) was added to the solution, the reaction mixture was then poured into water (750 mL) and stirred for one hour. The aqueous solution was filtered through Celite and the filtrate basified with 15% NaOH to a pH of 8. A green solid was collected by filtration and purified by flash column chromatography (methylene chloride). Trituration with hexane yielded the title benzophenone (1.43 g, 10%) as a yellow solid; mp 104°-106° C. 1H-NMR (250 MHz, d6-DMSO): 6.41 (s, 2H, NH2) 6.60 (d, 2H, J=8.7 Hz, aromatic) 7.22-7.37 (m, 2H, aromatic) 7.50 (d, 2H, J=8.6 Hz, aromatic) 7.53-7.64 (m, 1H, aromatic). MS (CI, CH4): 234 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25].[CH2:27](I)[CH3:28]>CN(C=O)C.C(OCC)(=O)C>[NH2:7][C:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:27][CH3:28]
Reactant: CCI
Reactant: Nc1c(C(=O)c2ccccc2O)oc2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccccc1C(=O)c1oc2ccc(Cl)cc2c1N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of potassium carbonate (0.056 g, 0.4 mmol), 3-amino-5-chloro-2-(2-hydroxybenzoyl)-benzofuran (0.05 g, 0.4 mmol) and ethyl iodide (0.05 g, 0.34 mmol) in dry DMF is stirred at 60° C. for 2 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 114-115° C.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:31])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:31])[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:26][CH2:27][N:28]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:29][CH2:30]3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[N:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(C2CCNCC2)cc1
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)n1)c1ccc(C2CCN(S(C)(=O)=O)CC2)cc1

Procedure:
The title compound was produced in analogy to example 3, steps 1 and 2. Thus, reaction of (R)-6-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-2-methylpyridazin-3(2H)-one (example 25, step 1) with (1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide produced 4-{4-[(R)-3-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester, which after cleavage of the tert-butoxycarbonyl group led to (R)-2-methyl-6-(3-(4-(piperidin-4-yl)phenyl)-3-o-tolylpropanoyl)pyridazin-3(2H)-one. This compound was then reacted with methanesulfonyl chloride to afford the title compound. White solid, MS: 494.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14](=[O:20])[CH:15]=[C:16]([NH:18][CH3:19])[CH3:17].N1C=CC=CC=1.Cl.N1C=CC=CC=1>O1CCCC1>[CH3:12][O:13][C:14](=[O:20])[CH:15]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1)/[C:16](=[N:18]/[CH3:19])/[CH3:17]
Reactant: CNC(C)=CC(=O)OC
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-bromo-3-methyl-benzoyl chloride (40.0 mmol) in tetrahydrofuran (300 mL) wad added 3-methylamino-but-2-enoic acid methyl ester (5.12 g, 40.0 mmol), followed by pyridine (3.2 mL, 40.0 mmol), and the reaction was stirred overnight at room temperature. Solid pyridine hydrochloride coated the flask, so the mixture was decanted, and the solid was washed three times with EtOAc. The combined solutions were concentrated and diluted with EtOAc (500 mL), and the mixture was washed three times with water. The aqueous layer was separated and back-extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].CI.[CH2:17](OC(=O)C)C>CN(C=O)C.CCCCCC>[Br:1][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH3:17])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1cccc2[nH]cc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CI
Product: Cn1cc(Br)c2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Bromo-1H-indole-4-carbonitrile (I-146a: 500 mg, 2.272 mmol) was added dropwise to a stirred mixture of NaH (0.218 g, 9.0833 mmol) in dry DMF (15 mL) at 0° C. over a period of 10 minutes. This was followed by the addition of methyl iodide and the resulting mixture was stirred at 0° C. for 2 hours. The reaction was monitored by TLC (10% ethylacetate in hexane). The reaction mixture was quenched with ice water; the precipitate formed was collected and dried to afford 0.400 g of the crude product.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([CH2:8][OH:9])[CH2:4][CH:3]1[N+:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]C)=O)[CH:11]=1.[CH3:20][S:21]([O-:24])(=[O:23])=[O:22].[NH3:25]>CO>[C:16]([C:12]1[CH:11]=[N+:10]([CH:3]2[CH2:4][CH:5]([CH2:8][OH:9])[CH:6]([OH:7])[CH:2]2[OH:1])[CH:15]=[CH:14][CH:13]=1)(=[O:18])[NH2:25].[CH3:20][S:21]([O-:24])(=[O:23])=[O:22]
Reactant: N
Reactant: COC(=O)c1ccc[n+](C2CC(CO)C(O)C2O)c1
Agent: CS(=O)(=O)[O-]
Solvent: CO
Product: NC(=O)c1ccc[n+](C2CC(CO)C(O)C2O)c1
Reaction time: 2.5 h

Procedure:
Crude 1-(2,3-Dihydroxy-4-hydroxymethyl-cyclopentyl)-3-methoxycarbonyl-pyridinium-methansulfonate 118.3 g, 173.7 mmol) was dissolved in 100.0 ml methanol. After the addition of methanolic ammonia (7M, 350.0 ml, 2.45 mol) the reaction mixture was stirred for 2.5 h. After removing the solvent under reduced pressure a red-brown oil was obtained that was further dried for 3 h (40° C., 10 mbar). This crude product is pre-purified with activated charcoal and used directly for the synthesis of cNAD (WO 2007/012494).
Reaction SMILES: [NH2:1][C@@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([CH2:18][NH:1][C@@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
(1R,2S)-2-amino-1,2-diphenylethanol (2.10 g) was dissolved in dichloromethane (30 ml) and stirred at room temperature. Ethyl bromoacetate (2.00 g), dissolved in dichloromethane (15 ml), was added to the solution. The mixture was stirred at room temperature for 7 days, and then triethylamine (1.5 ml) was added and stirred at room temperature for an additional day. After the spot of the starting material in TLC disappeared, dichloromethane was evaporated under reduced pressure. Benzene (100 ml) was added to the remaining residue, and the triethylamine hydrobromide salt was washed out with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated. The residue (2.60 g, 88%) was recrystallized from hexane (ca. 300 ml). The crystals deposited were collected and dried under reduced pressure. Yield 2.20 g (75%); mp 123°-125° C.; [α]D18 +2.4° (c 1.00, EtOH). IR.(KBr): 3180, 1745, 765, 705 cm-1 . 1H-NMR (CDCl3): 1.17 (t, 3H, J=7 Hz), 2.35 (bs, 2H), 3.16 (pseudo s, 2H), 3.98 (q, 2H, J=7 Hz), 4.15 (d, 1H, J=6 Hz), 4.76 (d, 1H, J=6 Hz), 7.20 (s, 10H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=O)[N:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:21][CH3:22].[NH2:23][OH:24].Cl.C([O-])(=O)C.[Na+]>CCO>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:15]=[C:14]([CH:16]=[N:23][OH:24])[N:13]=[C:12]([CH3:18])[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(CNC(=O)c2cc(C=O)nc(C)n2)ccc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CNC(=O)c2cc(C=NO)nc(C)n2)ccc1F
Temperature: 100 °C
Yield: 79 %

Procedure:
To a stirred solution of N-(4-fluoro-3-methoxybenzyl)-6-formyl-2-methylpyrimidine-4-carboxamide (6.75 g, 22.28 mmol, Preparation #8) and NH2OH.HCl (3.09 g, 44.56 mmol, Sisco Research Labs) in aqueous EtOH (75%, 100 mL), was added sodium acetate (5.48 g, 66.84 mmol, Spectrochem). The reaction mixture was heated to reflux at about 100° C. for about 1 h. Then reaction mixture was cooled to RT and poured into ice cold water (140 mL). The resulting solids were filtered, washed with hexane (100 mL) and dried under vacuum to afford N-(4-fluoro-3-methoxybenzyl)-6-((hydroxyimino)methyl)-2-methylpyrimidine-4-carboxamide as a light yellow solid 5.60 g (80%), 1H NMR (400 MHz, DMSO): δ 12.40 (s, 1H), 9.463-9.432 (t, J=8.1 Hz, 1H), 8.10 (s, 1H), 8.08 (s, 1H), 7.17-7.11 (m, 1H), 6.89-6.86 (m, 1H), 4.477-4.461 (d, J=6.4 Hz, 2H), 3.81 (s, 3H), 2.72 (s, 3H), MS m/z: 318.8 (M+H)+.
Reaction SMILES: FC(F)(F)C(N[C@@H:6]1[C:14]2C(=CC=C(OC)C=2)C(=O)[CH2:7]1)=O.[CH3:20][O:21][C:22]1[CH:31]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[C:25]([OH:32])=[CH:24][CH:23]=1.C(Br)C=C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:14]([O:32][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])[CH:6]=[CH2:7]
Reactant: COC(=O)c1cc(OC)ccc1O
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)CC2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: C=CCBr
Product: C=CCOc1ccc(OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Step AS (1). A mixture of 10 g (55 mmol) of methyl 5-methoxysalicylate, 9.3 mL (110 mMol) of allyl bromide and 36 g (110 mmol) of cesium carbonate in 100 mL of acetonitrile was stirred at rt for 2 h. The reaction was filtered to remove cesium carbonate and concentrated under vacuum to yield 13.3 g (100%) of methyl 2-allyloxy-5-methoxybenzoate as a yellowish solid, which was used directly in the next reaction without purification. LC-MS (M+H)+=223; 1H NMR (400 MHz, CDCl3) δ ppm 3.77 (s, 3H) 3.88 (s, 3H) 4.49-4.58 (m, 2H) 5.20-5.29 (m, 1H) 5.39-5.50 (m, 1H) 5.96-6.11 (m, 1H) 6.89 (d, J=9.06 Hz, 1H) 6.98 (dd, J=9.07, 3.27 Hz, 1H) 7.32 (d, J=3.02 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[OH:5][CH:1]1[CH2:4][CH2:3][CH:1]([O:5][C:6](=[O:20])[NH:7][CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=3)[N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)[CH2:4][CH2:3]1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(C#N)cc2C1
Product: N#Cc1ccc2c(c1)CC(NC(=O)OC1CCC(O)CC1)CN2Cc1ccccc1

Procedure:
The title compound was prepared from (6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester, prepared as described in Example 1C, and benzaldehyde by procedures analogous to those described in Example 3A and 31.
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[C:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29](OC)=O)=[CH:27][CH:26]=1)#[N:24].[H-].[Na+]>CN(C=O)C>[OH:15][CH2:14][C@H:9]1[C@H:8]([C:7]2[C:6]([O:16][CH3:17])=[CH:5][C:4]([O:18][CH3:19])=[C:3]3[C:2]=2[O:1][C:29]([C:28]2[CH:33]=[CH:34][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[CH:21][C:20]3=[O:22])[CH2:12][CH2:11][N:10]1[CH3:13]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3ccc(C#N)cc3)oc2c1[C@@H]1CCN(C)[C@H]1CO

Procedure:
Compound of example 6 (1.5 g, 4.85 mmol) in dry DMF (15 mL) reacted with methyl 4-cyanobenzoate (2.57 g, 17.2 mmol) in the presence of NaH (50%, 1.2 g, 25 mmol), as described example 16, afforded the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(Cc1ccccc1[N+](=O)[O-])C(=O)OCC
Yield: 74.8 %

Procedure:
In the same manner as in Example 6 (1), a crude product was obtained using diethyl malonate (10.1 g) and 2-nitrobenzyl bromide (13.6 g). This was purified by silica gel column chromatography to give the title compound (13.9 g) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([CH2:16][C@H:17](O)[CH3:18])[C:9]=3[C:7]=2[N:8]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>O1CCCC1>[N:36]([C@@H:17]([CH3:18])[CH2:16][N:15]1[C:9]2[C:7]3[N:8]=[C:4]([CH2:3][O:2][CH3:1])[O:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=[N:14]1)=[N+:37]=[N-:38]
Reactant: COCc1nc2c(ccc3cnn(C[C@@H](C)O)c32)o1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCc1nc2c(ccc3cnn(C[C@H](C)N=[N+]=[N-])c32)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
A solution of the product from Step B (0.20 g, 0.77 mmol in tetrahydrofuran (10 mL) was cooled (ice bath), triethylamine (0.43 mL, 3.06 mmol) and methanesulfonic anhydride (0.24 g, 1.38 mmol) were added and the mixture was stirred at 0° C. for 20 minutes. Sodium azide (0.50 g, 7.66 mmol) was added to the reaction mixture, which was evaporated to a residue that was dissolved in dimethyl sulfoxide (10 mL) and heated at 90–100° C. for 2 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (magnesium sulfate), filtered, and evaporated to give a residue which was purified by chromatography (silica gel, hexane/ethyl acetate) to give a yellow oil (80 mg, 37%): LC/MS m/z 287.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])=[CH:14][C:13]=3[C:26]#[C:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.C(O)C>C(O)(=O)C.[C].[Pd]>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][C:22]([F:23])([F:24])[F:25])=[O:19])=[CH:14][C:13]=3[CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:11]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(C#CCCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NCC(F)(F)F)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(CCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
To a solution of N-cyclopropyl-1-(2-(4-phenylbut-1-yn-1-yl)-4-{[(2,2,2-trifluoroethyl)amino]carbonyl}phenyl)-1H-1,2,3-triazole-4-carboxamide (42.8 mg) obtained in Example 384 in acetic acid (7.0 ml)—ethanol (5.0 ml) was added palladium-carbon (20 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 days, and the insoluble material was filtered off. The solvent was evaporated, and the residue was purified by silica gel column (hexane/ethyl acetate=4/1 to 2/3). The resultant product was recrystallized from ethyl acetate/hexane to give the title compound as a colorless powder (4.3 mg, 10%).
Reaction SMILES: C(OCC)(=O)CC(C)=O.[C:10]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][NH2:21])[CH2:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11].[CH:22]1([C:25]2N(C(C)C)N=[CH:27][C:26]=2[CH:33]=[O:34])CC1>>[C:10]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[C:25]([CH3:22])=[C:26]([CH:33]=[O:34])[CH:27]=[N:21]2)[CH2:18][CH2:19]1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)N1CCC(NN)CC1
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Solvent: CCOC(=O)CC(C)=O
Product: Cc1c(C=O)cnn1C1CCN(C(C)(C)C)CC1

Procedure:
1-(1-tert-Butyl-piperidin-4-yl)-5-methyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl acetoacetate and (1-tert-butyl-piperidin-4-yl)-hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([NH2:25])[C:19](=[CH:23][CH:24]=3)[C:20]([OH:22])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[OH-].[Na+:28].O>C1COCC1>[Na+:28].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([S:13]([C:16]3[CH:17]=[C:18]([NH2:25])[C:19](=[CH:23][CH:24]=3)[C:20]([O-:22])=[O:21])(=[O:15])=[O:14])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)ccc1C(=O)[O-]

Procedure:
50 mg (0.13 mmol) of Compound 17 was suspended in approximately 1 ml of THF, then 126 μl of 1N sodium hydroxide aqueous solution was added dropwise. The solution was confirmed to have become uniform, then 30 ml of water was added and the mixture was freeze-dried to quantitatively obtain the above-identified compound in an amorphous state in an amount of 52 mg. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 7.11-7.22 (3H, m), 7.37 (1H, s), 7.83 (1H, d), 7.91 (1H, d).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[CH3:12][CH:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]1[C:28]([S:29][C:30]2[CH:35]=[C:34]3[O:36][CH2:37][O:38][C:33]3=[CH:32][C:31]=2I)=[N:27][C:21]2[C:22]([NH2:26])=[N:23][CH:24]=[N:25][C:20]1=2)[CH3:14].C([O-])(O)=O.[Na+].CN(C=O)C>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.O>[NH2:26][C:22]1[N:23]=[CH:24][N:25]=[C:20]2[C:21]=1[N:27]=[C:28]([S:29][C:30]1[C:31]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)=[CH:32][C:33]3[O:38][CH2:37][O:36][C:34]=3[CH:35]=1)[N:19]2[CH2:18][CH2:17][CH2:16][NH:15][CH:13]([CH3:12])[CH3:14]
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(C=O)cc2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 65.5 %

Procedure:
4-Formylphenylboronic acid (13 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1.2 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (8 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 2:2:1:0.5) to give 18.8 mg (66%) of DZ3-50. 1H NMR (500 MHz, MeOH-d4) δ 10.01 (s, 1H), 8.15 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.14 (s, 1H), 6.93 (s, 1H), 6.13 (s, 2H), 4.05 (t, J=6.8 Hz, 2H), 2.99 (septet, J=6.4 Hz, 1H), 2.62 (t, J=6.9 Hz, 2H), 1.99 (m, 2H), 1.24 (d, J=6.4 Hz, 6H); 13C NMR (125 MHz, MeOH-d4) δ 192.3, 154.1, 151.9, 151.0, 149.8, 148.8, 148.5, 146.4, 139.5, 135.3, 130.0, 129.4, 119.0, 117.7, 115.0, 110.8, 102.4, 49.9, 42.2, 40.3, 27.4, 20.2; HRMS (ESI) m/z [M+H]+ calcd. for C25H27N6O3S, 491.1865; found. 491.1877; HPLC: method A Rt=6.23, method B Rt=6.83.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([Cl:16])[C:6]=1[C:7]#[N:8]>C1COCC1.CCOC(C)=O>[Cl:16][C:9]1[C:6]([C:7]#[N:8])=[C:5]([NH:3][CH2:1][CH3:2])[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=1
Reactant: CCN
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A solution of ethylamine in THF (2 M, 13.8 mL, 27.6 mmol) was added slowly to a solution of 2,6-dichloro-3-nitrobenzonitrile (3.0 g, 13.8 mmol) in THF (30 mL) at −5° C. After 1.5 h, the solution was diluted with EtOAc (150 mL) and washed with 0.5 N HCl and brine. Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (8:1:1 hexanes/CHCl3/EtOAc) gave 2.57 g (82%) of the title compound as an orange solid. 1H NMR (400 MHz, CDCl3): δ 8.51 (br s, 1H), 8.30 (d, 1H, J=8.8 Hz), 6.78 (d, 1H, J=8.4 Hz), 3.89-3.97 (m, 2H), 1.41 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C9H8N3O2Cl, 226, 228; found 226, 228.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:9](=[O:28])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:24][C:23]([C:25]#[C:26][CH3:27])=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)(C)(C)C.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:36].[ClH:38].[NH2:7][CH:8]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:24][C:23]([C:25]#[C:26][CH3:27])=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)=[O:28]
Reactant: CC#Cc1cc2ncnc(N3CCN(C(=O)C(Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC#Cc1cc2ncnc(N3CCN(C(=O)C(N)Cc4ccc(Cl)cc4)CC3)c2s1
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-oxo-2-[4-(6-prop-1-ynyl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-prop-1-ynyl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 440.
Reaction SMILES: O=[C:2]([C:8]1[C:21]2[C:22]3=[C:23]4[C:18](=[CH:19][CH:20]=2)[CH:17]=[CH:16][CH:15]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].O.NN.[OH-].[K+].Cl>C(O)COCCO>[C:8]1([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:21]2[C:22]3=[C:23]4[C:18](=[CH:19][CH:20]=2)[CH:17]=[CH:16][CH:15]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1
Reactant: O=C(O)CCC(=O)c1ccc2ccc3cccc4ccc1c2c34
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: O=C(O)CCCc1ccc2ccc3cccc4ccc1c2c34
Yield: 71.1 %

Procedure:
1 g (2.78 mmol) of 4-oxo-4-(pyrene-1-yl)-butyric acid was dissolved in 30 ml diethylene glycol and 0.5 9 (10 mmol) of hydrazine hydrate as well as 0.56 g (10 mmol) of KOH added thereto. The reaction solution was heated under reflux for 2 hours and then poured onto iced hydrochloric acid (25%), forming a yellow precipitate. Filtration of the solid and recrystallization from EtOH yielded 570 mg (71%) of 4-(pyrene-1-yl)-butyric acid.