Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH:27](=O)[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH2:27][CH3:28])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: COC(=O)c1cc(Cl)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To a stirred solution of tert-butyl 4-{[5-chloro-3-(methoxycarbonyl)-2-methylphenyl]amino}piperidine-1-carboxylate (2.40 g, 6.28 mmol) in dichloromethane (50 mL) and acetic acid (1.8 mL) was added acetaldehyde (830 ul, 12.6 mmol) and sodium triacetoxyborohydride (4.00 g, 18.8 mmol). The reaction mixture was stirred at rt for 18 hours. Then aq. NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 heptane/ethylacetate=10/1) to give the titled compound as oil (2.40 g, 89% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.56 (s, 1H), 7.21 (d, J=1.6 Hz, 1H), 4.04 (m, 2H), 3.89 (s, 3H), 3.02 (q, J=7.0 Hz, 2H), 2.88 (m, 1H), 2.68 (m, 2H), 2.44 (s, 3H), 1.71 (m, 2H), 1.48-1.61 (m, 2H), 1.45 (s, 9H), 0.83-0.89 (t, J=7.0 Hz, 3H); MS (ES) [M+Na] 433.0.
Reaction SMILES: C(O)C.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>O>[CH2:27]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCCBr
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
To 400 ml ethanol is added 21.5 g of 4-hydroxy-4'nitrobiphenyl, and the mixture heated to reflux. A solution of 7.1 g KOH in 30 ml of water is added dropwise at reflux temperatures. After complete addition, 18 g of 5-bromo-1-pentene is added and the reaction medium is heated at reflux temperature for about 15 hours. Ethanol is removed under vacuum from the cooled mixture, and the solid residue is slurried with water in a blender, filtered, washed with water, and air dried. The product then is recrystallized from 90/10 hexane/toluene, mp 74°-76° C.
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ClCCl>CN(C)C=O>[CH2:20]([O:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2]([CH:1]=[O:13])=[CH:3][C:4]=1[O:5][CH3:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(OC)c1OCc1ccccc1
Reaction time: 25 h
Yield: 87.6 %

Procedure:
To a stirring suspension of syringaldehyde (25.19 g, 138 mmol) and potassium carbonate (38.14 g, 276 mmol, 2 equ) in N,N-dimethyl formamide (500 ml) was added benzyl bromide (20 ml, 168 mmol, 1.2 equ). The reaction was stirred for 25 hours, then poured into dichloromethane. The organic solvent was washed with water (5×) then dried (MgSO4) and concentrated in vacuo to give a pink oil. This was recrystallised from hexane to give 31 (32.9 g, 87 %).
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:9]>C1C=CC=CC=1>[NH:5]1[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:9][N:7]=[N:6]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)C#N
Solvent: c1ccccc1
Product: CCOC(=O)c1nnn[nH]1
Reaction time: 96 h
Yield: 41.9 %

Procedure:
A solution of trimethylsilylazide (0.58 g) and ethyl cyanoformate (0.5 g) in dry benzene (20 ml) was heated at reflux for 48 hours. The solution was allowed to stand at room temperature for 4 days, and the resulting white solid was filtered off to give ethyl tetrazole-5-carboxylate (0.3 g), m.p. 88°-93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>CN(C=O)C>[C:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[CH2:30][N:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:47]([N:46]([CH3:50])[CH3:45])=[O:48])=[CH:3][CH:4]=1)[CH:9]1[CH2:10][CH2:11][N:12]([CH:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]2[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:26])[CH2:13][CH2:14]1)#[N:38]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(N)cc2)CC1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(NC(=O)N(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 76 h
Yield: 76 %

Procedure:
A mixture of COMPOUND 142 (61 mg, 0.12 mmol), K2CO3 (50 mg, 0.36 mmol) and dimethylcarbamoyl chloride (23 μL, 0.24 mmol) in DMF (1 mL) was stirred at room temperature for 76 hours to afford COMPOUND 155 as a white solid (53 mg, 76%) following work-up and purification. 1H NMR (CDCl3) δ 0.93-1.17 (m, 2H), 0.99 (d, 3H, J=6.0 Hz), 1.49-1.59 (m, 1H), 1.69-1.78 (m, 3H), 2.14 (t, 1H, J=11.1 Hz), 2.31 (s, 6H), 2.54 (t, 1H, J=10.8 Hz), 2.73-2.85 (m, 3H), 2.98 (s, 6H), 3.27 (t, 1H, J=10.5 Hz), 3.52 (m, 1H), 3.73 (s, 2H), 3.90 (m, 1H), 6.04 (s, 1H), 6.50 (d, 2H, J=8.1 Hz), 6.94-6.99 (m, 3H), 7.09 (d, 2H, J=8.1 Hz), 7.39-7.58 (m, 4H), 8.44 (br s, 1H). 13C NMR (CDCl3) δ 13.81, 19.54, 29.38, 30.74, 31.29, 36.79, 40.28, 43.97, 48.67, 52.61, 57.72, 61.01, 112.75, 115.27, 119.44, 122.87, 127.66, 128.76, 129.49, 130.39, 130.59, 130.76, 131.54, 134.46, 139.03, 142.81, 144.99, 156.69, 170.24. ES-MS m/z 581 (M+H). Anal. Calcd. for C35H44N6O2.0.2CH2Cl2: C, 70.73; H, 7.49; N, 14.06. Found. C, 70.74; H, 7.57; N, 13.74.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:6]2.[H-].[Na+].F[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1)=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:6]2
Reactant: CCCCCCCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 93 %

Procedure:
6-(Methyloxy)-3-octyl-2-phenyl-1-naphthalenol (193) (0.60 g, 1.66 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.72 g (93%) of the title compound (194) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.84 (t, J=7.0 Hz, 3H), 1.05-1.30 (m, 10H), 1.40-1.50 (m, 2H), 2.54 (t, J=7.9 Hz, 2H), 3.94 (s, 3H), 6.67 (d, J=8.4 Hz, 2H), 7.03-7.14 (m, 3H), 7.16-7.26 (m, 4H), 7.56-7.64 (m, 3H), 7.67 (d, J=9.1 Hz, 1H), 9.79 (s, 1H). LCMS (APCI): m/z 467 (M+H)+.
Reaction SMILES: O[C:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[F:15])[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.Cl.O.N>C(O)(=O)C>[F:15][C:9]1[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=1[C:2]1[CH2:7][CH2:6][S:5][CH2:4][CH:3]=1
Reactant: Nc1ccc(C2(O)CCSCC2)c(F)c1
Agent: Cl
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(C2=CCSCC2)c(F)c1
Reaction time: 18 h
Yield: 95.7 %

Procedure:
4-Hydroxy-4-(2-fluoro-4-aminophenyl)tetrahydrothiopyran (11.35 g, 50 mM) and butylated hydroxytoluene (50 mg) as antioxidant were suspended in a mixture of concentrated hydrochloric acid (37%, 200 ml) and water (50 ml), and stirred at 80° under nitrogen for 18 hours. Glacial acetic acid (150 ml) was added, and reaction continued at 80° for a further 5 hours. After cooling, the reaction was made basic by the cautious addition of concentrated ammonia and ice. The mixture was extracted with diethyl ether (400 ml), the extract washed with water (100 ml), brine (100 ml), dried (magnesium sulfate), filtered and evaporated to give the title product (10 g) as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.CN(C)C=O.[Br:19]N1C(=O)CCC1=O>O>[Br:19][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[OH:13]
Reactant: COc1ccc2cc(O)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Br)c(O)ccc2c1
Reaction time: 0.75 h
Yield: 87.8 %

Procedure:
Add 6-methoxynaphthalene-2-ol (20 g, 114.8 mmol) to dimethylformamide (DMF, 250 mL) at ambient temperature followed by N-bromosuccinimide (NBS, 21.5 g, 120 mmol) over a 30 minute period. After 45 minutes, dilute with water (800 mL), collect and dry the precipitate to provide 25.5 g (87%) of 1-bromo-6-methoxy-naphthalen-2-ol.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:3]=2[CH2:2]1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>CO.O>[N:8]1[C:3]2[CH2:2][CH2:1][CH2:11][C:9](=[N:13][OH:14])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2ncccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: ON=C1CCCc2ncccc21
Temperature: 25 °C

Procedure:
A mixture of 1.0 eq of 5,6,7,8-tetrahydroquinolinone-5 (93) (Tyger Scientific, T11850), 3.0 eq of hydroxylamine hydrochloride (Aldrich, 37,992-1), and 3.0 eq of sodium acetate in 50 mL of MeOH and 15 mL of H2O was refluxed for 4 hrs. The mixture was allowed to cool to rt. After rotary evaporation of the MeOH, 100 mL of H2O was added. The solid formed was collected by vacuum filtration. The solid collected was triturated with hexanes and dried under vacuum to give 94.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9]1)(=O)=O.[C:19]1(=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[NH:20]1.[K]>CN(C)C=O>[O:29]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:20]1[CH2:6][CH2:7][C:8]1([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH2:9]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC1(CCOS(C)(=O)=O)CC1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 150 °C
Reaction time: 18 h
Yield: 49.1 %

Procedure:
To a solution of 2-{1-[(tert-butoxycarbonyl)amino]-cyclopropyl}ethyl methanesulfonate (9.5 g, 344.3 mmol) in anhydrous N,N-dimethylformamide (20 ml) was added potassium 2,3-dihydro-1H-isoindole-1,3-dione (7.0 g, 37 mmol). After being stirred at 150° C. for 18 hours, the resulting mixture was then filtered and washed with diethyl ether (50 mL). The filtrate was washed with brine (50 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was heated with stirring in water and the precipitate was collected by filtration and dried in vacuo to afford 6.0 g of the pure product as an orange solid (yield was 53%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][CH:42]=[O:43])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][CH:42]([OH:43])[CH2:41][CH:38]2[CH2:37][CH2:36][N:35]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:40][CH2:39]2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)CC(O)CC2CCN(Cc3ccccc3)CC2)cc1
Yield: 62.7 %

Procedure:
50 ml of tetrahydrofuran was added to 3.80 g of N-t-butoxycarbonyl-4-acetylaniline, and 19.0 ml of a 1.7M t-butyl lithium·pentane solution was added dropwise thereto under an argon stream at -78° C. Subsequently, a solution of 3.50 g of (1-benzylpiperidin-4-yl)acetaldehyde dissolved in 10 ml of tetrahydrofuran was added to the mixture, and the resulting mixture was stirred until its temperature was returned to room temperature. Then, a saturated ammonium chloride aqueous solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 4.57 g of the title compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:12]([O:24][CH2:25][CH2:26]Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:26][CH2:25][O:24][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCCOCCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOCCOc1ccc(C(=O)OC)cc1

Procedure:
A mixture of 20.4 g (0.134 mol) of 4-hydroxybenzoic acid methylester, 200 ml of dimethyl formamide, 40 g (0.160 mol) of 2-dodecyloxy ethylchloride (from 2-dodecyloxy ethanol and thionyl chloride) and 8.6 g (0.160 mol) of sodium methylate was heated for 7 hours to boiling temperature and, after cooling and removal of the sodium chloride by filtration, was evaporated to dryness. The residue was dissolved in methylene chloride and subjected to column chromatography (silica gel, Merck using methylene chloride as the eluent). After recrystallization from methanol, the combined fractions after TLC gave 30 g (61% of the theoretical) of pure 4-(2-dodecyloxyethoxy)-benzoic acid methylester melting at 40° to 42° C.
Reaction SMILES: CI.[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]2[C:29]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=S)=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][CH:12]=1)#[N:4].Cl>C(O)C>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:19]3[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=[CH:28][C:29]=3[N:30]=[C:31]2[NH:33][CH2:34][CH3:35])=[CH:13][CH:12]=1)#[N:4]
Reactant: CCNC(=S)Nc1cccc(C(=O)OCC)c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Solvent: CI
Solvent: CCO
Product: CCNc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
Methyl iodide (4.5 g) was added to a solution of ethyl 2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]-3-(ethylthioureido)benzoate (1.8 g) in ethanol (50 ml), and the mixture was heated under reflux for 12 hours. To the reaction mixture was added 1N-HCl (60 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and water and dried. The solvent was evaporated to dryness and the residue was purified by column chromatography on silica gel to afford yellow syrup (0.96 g, 58%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH:13]=O)[CH:4]=[N:3]1.[H-].[Na+].C(OP([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(OCC)=O)C.CN(C)C=O>O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5](/[CH:13]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:4]=[N:3]1
Reactant: Cn1ncc(C=O)c1-c1cccnc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnn(C)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-carbaldehyde (750 mg), sodium hydride (60% in oil, 176 mg), ethyl diethylphosphonoacetate (1.08 g) and N,N-dimethylformamide (8 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl (2E)-3-[1-methyl-5-(3-pyridinyl)-1H-pyrazol-4-yl]acrylate (770 mg, 75%) as pale-yellow prism crystals. melting point: 159-160° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]>>[CH2:27]([O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]2=[N:3][C:2]=3[NH2:1])=[CH:19][CH:18]=1)[CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: CC(C)CCBr
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCC(C)C)cc3)cc12

Procedure:
2-(4-(Isopentyloxy)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 136, but using 1-bromo-3-methylbutane. 1H NMR (Acetone-d6): δ 8.72 (s, 1H), 8.69 (s, 1H), 8.26 (d, 1H), 7.43 (s, 1H), 7.12-7.18 (m, 3H), 6.84 (d, 2H), 6.50 (br, 2H), 3.98 (t, 2H), 3.21 (t, 2H), 3.06 (t, 2H), 2.46 (s, 3H), 1.78-1.87 (m, 1H), 1.61-1.67 (dd, 2H), 0.96 (s, 3H), 0.95 (3H). LRMS [M+H]=400.2
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:13])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C1C[O:17][CH2:16]C1.[Li]CCCC.CN(C=O)C>CCOC(C)=O>[CH3:10][C:7]1([CH3:11])[C:6]2[CH:12]=[C:2]([CH:16]=[O:17])[CH:3]=[C:4]([CH3:13])[C:5]=2[O:9][CH2:8]1
Reactant: C1CCOC1
Reactant: Cc1cc(Br)cc2c1OCC2(C)C
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C=O)cc2c1OCC2(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a nitrogen flushed 50 mL round bottom flask were added 5-bromo-3,3,7-trimethyl-2,3-dihydro-1-benzofuran (0.11 g, 0.46 mmol) and THF (3 mL). A solution of n-BuLi (0.20 mL, 2.5 M solution in hexanes) was added via a syringe at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, then DMF (0.053 mL, 0.68 mmol) was added. The reaction mixture was allowed to warm to room temperature. EtOAc (20 mL) and wet silica gel (5 g silica gel/0.5 mL of water) were added. The resulting mixture was stirred at room temperature for 10 minutes and then filtered. The resulting solid was rinsed with EtOAc. The filtrate was concentrated. The residue was purified on a silica gel column eluting with a gradient of 100% hexanes to 10% EtOAc/hexanes to give the title intermediate (40 mg) as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1.ClCCl>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)c1sccc1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate (0.55 g; 3.5 mmol) in pyridine (2 mL) and dichloromethane (2 mL) was added 4-tert-butylbenzenesulfonyl chloride (0.98 g; 4.2 mmol). The resulting mixture was warmed to 40° C. to aid in solubility, then stirred at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane and washed with aqueous hydrochloric acid (2N). The aqueous layer was separated and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, decanted, and filtered through a and of silica. The silica was washed with dichloromethane. The eluant was combined with hexanes and allowed to stand. After 24 hours the resulting solid product was collected by filtration to give the desired product as a white solid (817 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:24])=[C:8]([NH:10][C:11]2[O:12][C:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:14][N:15]=2)[CH:9]=1)(=[O:3])[CH3:2].[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>C(O)C>[CH3:24][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH2:2][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:9][C:8]=1[NH:10][C:11]1[O:12][C:13]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:14][N:15]=1
Reactant: CC(=O)c1ccc(C)c(Nc2ncc(-c3ccc(C#N)cc3)o2)c1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C(=O)CCc2ccccc2)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-[2-(5-Acetyl-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile (100 mg, 0.315 mmol) and benzaldehyde (0.035 mL, 0.35 mmol) in ethanol, was added dropwise at 0° C., 1 mL of aqueous NaOH 30%. After the mixture was stirred at room temperature for 16 h and poured into ice water (ca. 10 mL). The precipitate was filtered, washed diethyl ether and dried under vacuum.
Reaction SMILES: C([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:15]2)[N:7]=1)(C)(C)C.C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:8]2[NH:7][C:6](=[O:5])[CH:11]=[N:10][CH:9]=2)[CH2:15]1
Reactant: CC(C)(C)Oc1cncc(CCN2CCCC(COc3ccccc3F)C2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1cncc(CCN2CCCC(COc3ccccc3F)C2)[nH]1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
After dissolving 160 mg of 2-tert-butoxy-6-[2-[3-(2-fluorophenoxymethyl)piperidino]ethyl]pyrazine in 2 ml of ethyl acetate, 2 ml of 4N hydrogen chloride/ethyl acetate was added, and the mixture was allowed to stand at room temperature for 30 minutes. Aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, active carbon was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (108 mg, 79% yield).