Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[C:3]([C:6]#[N:7])[C:4]#[N:5].[CH:21](OC)(OC)OC>>[CH3:21][O:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)=[C:3]([C:4]#[N:5])[C:6]#[N:7]
Reactant: COC(OC)OC
Reactant: N#CC(C#N)=C(O)c1ccc(Oc2ccccc2)cc1
Product: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Yield: 47.5 %

Procedure:
A solution of 2-(hydroxy(4-phenoxyphenyl)methylene)malononitrile (50 g, 190.8 mmol) in CH(OMe)3 (500 mL) was heated to 75° C. for 16 hr. Then the mixture was concentrated to a residue and washed with MeOH (50 mL) to give 25 g (47.5%) of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile as a yellow solid. 1H NMR (DMSO-d6) δ 7.70 (d, J=8.4 Hz, 2H), 7.52-7.45 (m, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.22-7.06 (m, 4H), 3.93 (s, 3H). MS (ESI) m/e [M+1]+ 276.9.
Reaction SMILES: [NH2-].[Na+].N.[CH:4]([N:7]([CH:19]([CH3:21])[CH3:20])[CH2:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:11]#[N:12])([CH3:6])[CH3:5].[CH3:22][C:23]([CH3:27])=[CH:24][C:25]#[N:26]>CCOCC.O>[CH:19]([N:7]([CH:4]([CH3:6])[CH3:5])[CH2:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)([C:23]([CH3:27])([CH3:22])[CH2:24][C:25]#[N:26])[C:11]#[N:12])([CH3:21])[CH3:20]
Reactant: CC(C)N(CCC(C#N)c1ccccn1)C(C)C
Reactant: CC(C)=CC#N
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)N(CCC(C#N)(c1ccccn1)C(C)(C)CC#N)C(C)C
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
The mixture of 4.7 g of sodium amide and 400 ml of liquid ammonia is cooled to -40° C., then the solution of 24.5 g of 4-diisopropylamino 2-(2-pyridyl) butane nitrile (Example 1a) in 30 ml of anhydrous ether is added, the temperature being maintained between -40° C. and -33° C. The mixture is stirred for 15 mins. at this temperature then the solution of 9 g of 3,3-dimethyl acrylonitrile in 40 ml of ether is added, still at the same temperature. The temperature is allowed to rise slowly up to ambient temperature (duration: about 5 hrs.). 200 ml of ether are added then water is added drop by drop. The ethereal phase is separated and the aqueous phase is re-extracted with ether. The ethereal extracts are collected and dried over sodium sulfate. The solvent is evaporated to dryness and the residue is chromatographed over a column of alumina with the eluting ethyl acetate-pentane (2.5-100) vol/vol mixture.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:53]=[C:54]2[C:59](=[CH:60][CH:61]=1)[CH:58]=[C:57]([C:62]1[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=1)[CH:56]=[CH:55]2>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:53]=[C:54]2[C:59](=[CH:60][CH:61]=1)[CH:58]=[C:57]([C:62]1[CH:63]=[C:64]([NH:68][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:65]=[CH:66][CH:67]=1)[CH:56]=[CH:55]2
Reactant: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(OC)c5oc4=O)c3)ccc2c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
DIEA (0.0115 mL, 0.067 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.013 g, 0.06 mmol) and HATU (0.025 g, 0.067 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-naphthalen-2-yl)-phenylamine (0.015 g, 0.06 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 83% yield: LCMS (ESI) m/z 452 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:25]([O:18][C:15]1[CH:16]=[CH:17][C:12]([S:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[NH2:1])=[CH:13][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
A slurry containing of the product from Example 85A (0.2 g, 0.763 mmole) and cesium carbonate (0.25 g, 0.763 mmole) in dimethylformamide (5 ml) was treated with benzyl bromide (0.091 ml, 0.763 mmole) and the resulting slurry was stirred 18 hours at room temperature. Afterwards ice water (50 mL) was added to the solution and to the resultant slurry was added ethyl acetate (50 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a yellow solid as the title compound (0.24 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH:26]C(OCC1C=CC=CC=1)=O)[CH:20]=[CH:19]2>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([NH2:26])[CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Oc3ccc4cc(NC(=O)OCc5ccccc5)ccc4c3)c2cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N-[6-(6,7-dimethoxy(4-quinolyloxy))(2-naphthyl)](phenylmethoxy)carboxamide (Step b, 170 mg, 0.35 mmol) and Pd/C (17 mg, 10%, Aldrich) in 60 mL of EtOAc was stirred at RT under H2 balloon for 16 h. The mixture was filtered through a Celite® pad. The filtrate was concentrated in vacuo to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 347.0 (M+1). Mass Calc'd for C21H18N2O3: 346.13.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[N:10]1[NH:11][N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:8]#[C:4][CH2:5][CH2:6][N:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]3=[N:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: c1ccc2n[nH]nc2c1
Product: FCc1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 75.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (111 mg, 0.58 mmol, Example 190(E)) and 2-but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol, Example 109(D)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 61 mg (0.22 mmol, 37%) of 2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][O:12][C:13](=[O:16])[CH2:14]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:12][C:13](=[O:16])[CH2:14][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)cc1C=O
Yield: 99.4 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (35 g, 220 mmol), bromo-acetic acid methyl ester (43 g, 282 mmol), K2CO3 (60 g, 434 mmol) and in DMF (300 mL) was heated at 140° C. for 10 min. Then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water 4 times, dried over anhydrous Na2SO4, concentrated to give crude product as yellow solid (50 g).
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)Nc2ccc(OC)c(-c3c(F)cnn3C)c2)cc1
Yield: 29 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 4-methoxyphenylisocyanate, in a similar manner as described in Example 1.68. Additionally the residue was washed with CH2Cl2, providing 18 mg (29% yield) of Compound 87: LCMS m/z (%)=371 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.06 (s, 1H), 7.95 (s, 1H), 7.63 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 7.49 (d, J=2.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.37 (d, JH,F=4.4 Hz, 1H), 7.11 (d, J=9.2 Hz, 1H), 6.85 (d, J=9.2 Hz, 2H), 3.82 (s, 3H), 3.75 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.41 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([F:19])[CH:11]=1.N12CCCN=C1CCCCC2>C(#N)C>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:15])=[C:12]([F:19])[CH:11]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl bromide (0.86 g, 5.0 mmol, 1.1 eq.) was added neat to a solution of 4-bromo-2-fluorobenzoic acid (1.0 g, 4.6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.36 mL, 9.2 mmol, 2.0 eq.) in anhydrous acetonitrile (20 mL). The reaction was stirred at room temperature for 18 hours before removing the solvent in vacuo. The residue was diluted with ether and washed with water, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, and brine. The organic layer was dried (MgSO4) and concentrated in vacuo to provide the title compound as a pale yellow oil that crystallized into long needles upon standing (1.4 g, 99%): 1H NMR (300 MHz, CDCl3) δ7.82 (t, 1 H), 7.42-7.31 (m, 7 H), 5.35 (s, 2 H); GC/MS m/z 308/310 (M+ and M+2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(F)c1

Procedure:
The title compound was synthesized from methyl 4-(3,4-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.10 g, 0.34 mmol) and lithium hydroxide (0.143 g, 3.4 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 46 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.99-2.16 (m, 1H), 2.45-2.68 (m, 3H), 2.68-2.86 (m, 2H), 3.17-3.29 (m, 1H), 6.30 (s, 1H), 6.97 (ddd, J=6.36, 4.19, 2.05 Hz, 1H), 7.02-7.21 (m, 2H). 19F NMR δ ppm −141.99 (m), −145.62 (m); LCMS-MS (ESI−) 276.0 (M−H); HPLC (UV=98.41%), (ELSD=100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[I:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[C:18](=O)([O-])O.[Na+]>CO>[CH3:18][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([OH:12])[C:10]([I:11])=[C:2]([NH2:1])[CH:3]=1
Reactant: O=C([O-])O
Reactant: Nc1cc(C(=O)O)cc(O)c1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(N)c(I)c(O)c1
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 3-amino-5-hydroxy-4-iodo-benzoic acid (0.20 g, 0.72 mmol, 1.0 equiv) in methanol (5 mL) was added conc. sulfuric acid (0.20 mL, 0.035 g, 0.36 mmol, 0.5 equiv) and the reaction mixture heated to reflux. After 2 h, the reaction mixture was poured on ice, the pH adjusted to 9 by addition of a sat. solution of sodium hydrogencarbonate and extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (1:1) providing 0.07 g (33%) of the title compound. 1H NMR (250 MHz, DMSO): δ 3.78 (s, 3H), 5.45 (br s, 2H), 6.68 (s, 1H), 6.85 (s, 1H), 10.32 (br s, 1H). MS (EI): 293.0 [M]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[SH:7].[Cl-].[Zn+2:9].[Cl-]>[OH-].[Na+].O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][Zn:9][S:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: [Zn+2]
Reactant: Sc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(S[Zn]Sc2ccccn2)nc1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
In a mixture of 525 ml of 1N aqueous sodium hydroxide solution and 400 ml of water was dissolved 61.00 g of 2-pyridinethiol. To this solution was added dropwise 300 ml of water containing 39.36 g of zinc chloride, and the resulting mixture was stirred at 20°C for 3 hours. The reaction mixture was then filtered off, washed with one liter of water and dried. There was obtained 74.25 g of bis(2-pyridylthio)zinc as slightly yellowish colorless crystals. The crystals gradually decomposed at about 240°C.
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=1.[C:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH3:35])[C:23](O)=O)(=[O:18])[CH3:17]>CO>[C:16]([NH:19][C:20]1[CH:21]=[C:22]([C:23]2[O:15][N:14]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:13])[CH:4]=3)[N:1]=2)[CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH3:35])(=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1N1CCCCC1C
Solvent: CO
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(NC(C)=O)c3)n2)cc1F

Procedure:
The title compound was obtained following procedure described for example 4, step 1, but starting from Intermediate 1 (70 mg; 0.33 mmol) and Intermediate 32 (91.17 mg; 0.33 mmol). Title compound was isolated after trituration with MeOH as an off-white powder. 1H NMR (DMSO-d6, 300 MHz) δ 9.10 (bs, 1H), 8.88, (bs, 1H), 8.11 (t, J=7.6 Hz, 1H), 8.03 (dd, J=8.1, 1.5 Hz, 1H), 7.97-7.87 (m, 2H), 7.45 (d, 8.4 Hz, 1H), 3.90 (s, 3H), 3.19-3.12 (m, 1H), 2.96-2.89 (m, 1H), 2.65-2.57 (m, 1H), 2.19 (s, 3H), 1.87-1.66 (m, 4H), 1.53-1.44 (m, 2H), 0.84 (d, J=6 Hz, 3H). LC/MS (Method B): 453.3 (M+H)+. HPLC (Method A) Rt 5.16 min (purity: 97.5%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[O:22][CH2:21]2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[H][H]>O1CCOCC1.[Pd]>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[C:25](=[O:26])[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[O:22][CH2:21]2)=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(=Cc1ccc(OCCN2COc3ccccc3C2=O)cc1)OCC
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1ccc(OCCN2COc3ccccc3C2=O)cc1)OCC
Yield: 80.6 %

Procedure:
A solution of ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-2-propenoate (4.5 g, 10.5 mmol) obtained in Example 1, in 1,4-dioxane (50 ml) was reduced with hydrogen in the presence of 10% palladium charcoal (450 mg) at 50-60 psi for 12 h. The reaction mixture was filtered through a bed of celite and the celite bed was washed with 1,4-dioxane. The filtrate was evaporated to dryness under reduced pressure to yield the title compound (3.5 g, 78%): mp 78-80° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([OH:25])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:26]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:19]1[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O[C@H]1CCC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCC[C@@H](N(Cc2ccccc2)Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 87.8 %

Procedure:
Oxalyl chloride (3.81 mL, 43.6 mmol) was dissolved in dry DCM (150 mL) and cooled to −78° C. DMSO (6.75 mL, 95.0 mmol) in dry DCM (20 mL) was added dropwise to the reaction mixture and the reaction was stirred for 15 minutes at −78° C. Next, (1S,3R)-3-(dibenzylamino)-cyclohexanol (11.7 g, 39.6 mmol) in dry DCM (100 mL) was added dropwise using an addition funnel and the reaction was stirred at −78° C. for 15 minutes. TEA (27.6 mL, 198 mmol) was then added and the reaction was stirred at −78° C. for 1 h. The dry-ice bath was removed and the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction mixture was washed with brine (5×500 mL), the organic layer was separated, dried over magnesium sulfate and concentrated to yield (R)-3-(dibenzylamino)cyclohexanone (10.2 g, 88%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.26-7.39 (m, 8H), 7.17-7.25 (m, 2H), 3.56-3.70 (m, 4H), 2.71-2.81 (m, 1H), 2.60-2.69 (m, 1H), 2.25-2.42 (m, 2H), 2.04-2.11 (m, 1H), 1.88-1.99 (m, 2H), 1.69-1.82 (m, 1H), 1.18-1.33 (m, 1H); MS (ESI) m/z 294.4 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6].[CH2:21](I)[CH2:22][CH2:23][CH3:24].O>C(O)CCC>[CH2:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH2:3][CH2:2][CH2:10][CH3:9])=[O:6])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCI
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1
Solvent: CCCCO
Solvent: O
Product: CCCCNc1cc(C(=O)OCCCC)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
A solution of 3-amino-4-phenyl-5-sulfamylbenzoic acid (1.46 g) and n-butyl iodide (1.5 ml) in n-butanol (20 ml) is refluxed for 3-4 days under such conditions, that the water formed during the reaction is separated. After 12, 24, 36 and 48 hours, additional amounts of n-butyl iodide (each time 0.75 ml) are added. The resulting solution is evaporated in vacuo, and the obtained crude n-butyl 3-n-butylamino-4-phenyl-5-sulfamylbenzoate is saponified by heating with 2 N sodium hydroxide (20 ml) for 30 minutes. After cooling, the resulting solution is acidified with 4 N hydrochloric acid (12 ml) to precipitate 3-n-butylamino-4-phenyl-5-sulfamylbenzoic acid, which is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, the acid is obtained with a melting point of 134°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=O)[NH:7][C:6]=2[CH:12]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1
Reactant: O=C1COc2ccc(Cl)cc2N1
Agent: B
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)NCCO2
Yield: 28.6 %

Procedure:
Using 6-chloro-4H-benzo[1,4]oxazin-3-one (0.6 g, 3.3 mmol) and borane-THF (16.4 mL of a 1M solution in THF, 16.4 mmol) in THF (15 mL) to yield the title compound as a clear oil (0.16 g, 55%). δH (CDCl3) 3.35-3.47 (2H, m), 3.81 (1H, br s), 4.17-4.29 (2H, m), 6.54-6.62 (2H, m), 6.64-6.72 (1H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([N:8]=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[NH2:25].[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[Na+]>C(O)(=O)C.O>[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[NH2:24][C:21]1/[C:22](=[N:8]/[C:5]2[C:4](=[O:10])[N:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:2]([CH3:1])[C:6]=2[CH3:7])/[CH:23]=[C:18]([CH3:17])[C:19](=[NH2+:25])[CH:20]=1
Reactant: Cc1c(N=O)c(=O)n(-c2ccccc2)n1C
Reactant: Cc1ccc(N)cc1N
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC1=C/C(=N\c2c(C)n(C)n(-c3ccccc3)c2=O)C(N)=CC1=[NH2+]
Reaction time: 0.5 h

Procedure:
50 mmol of 1,5-dimethyl-4-nitroso-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in a solution of 850 ml of acetic acid and 1250 ml of water. This solution was admixed with 50 mmol of 4-methylbenzene-1,3-diamine and stirring was continued for 2 h 30 min. Sodium perchlorate was added to saturation, and the mixture was left to stand for 30 minutes at zero degrees.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][C:21](=[O:24])[CH2:22]Br)[CH3:19].C(O)C>CC(C)=O>[CH:2]([C:3]1[CH:11]=[CH:10][C:8]([O:9][CH2:22][C:21]([O:20][CH2:18][CH3:19])=[O:24])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:1]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1ccc(C=O)cc1OC
Yield: 77.6 %

Procedure:
The compound was prepared according to general procedure E with vanillin (5.3 mmol) in dry acetone (20 ml), anhydrous K2CO3 (6.8 mmol), and ethylbromoacetate (6.3 mmol) at reflux for 1 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 980 mg of pure compound were obtained (78% yield). 1H NMR (250 MHz, CDCl3): δ 1.23 (m, 3H), 3.88 (s, 3H), 4.21 (m, 2H), 4.78 (s, 2H), 6.90 (m, 1H), 7.38 (m 2H), 9.80 (s, 1H) 13C NMR (63 MHz, CDCl3): δ 13.9, 55.7, 61.2, 65.6, 109.8, 112.3, 125.7, 130.8, 149.7, 152.4, 167.9, 190.6 MS (ESI): m/z 253.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>ClCCl>[CH3:21][N:22]([CH:24]=[N:18][C:16]([C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=[N:10][C:11]=12)=[O:17])[CH3:23]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cnn2c(-c3ccccc3)ccnc12
Solvent: ClCCl
Product: CN(C)C=NC(=O)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 600 mg of 7-phenylpyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 7), 5.0 ml of N,N-dimethylformamide dimethyl acetal and 25.0 ml of dichloromethane are heated on a steam bath for 2 hours with complete solution taking place. The solution is evaporated in vacuo to give a solid. The solid is then recrystallized from acetone to give 58 mg of the desired product as yellow needles, mp 198°-201.5° C.