Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].Br[CH2:4][CH:5]1[CH2:7][C:6]1([F:9])[F:8].[SH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>CO>[F:8][C:6]1([F:9])[CH2:7][CH:5]1[CH2:4][S:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: FC1(F)CC1CBr
Reactant: O=C(O)CCS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCSCC1CC1(F)F
Temperature: 65 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
Powdered potassium hydroxide (423 mg, 7.54 mmol) and 2-(bromomethyl)-1,1-difluorocyclopropane (657 mg, 3.84 mmol) were sequentially added to a stirred solution of 3-mercaptopropanoic acid (400 mg, 3.77 mmol) in methanol (2 mL) at room temperature. The resulting white suspension was stirred at 65° C. for 3 hours and quenched with 1N aqueous hydrochloric acid and diluted with ethyl acetate. The organic phase was separated and the aqueous phase extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title molecule as a colorless oil (652 mg, 84%): IR (thin film) 3025, 2927, 2665, 2569, 1696 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.85 (t, J=7.0 Hz, 2H), 2.82-2.56 (m, 4H), 1.88-1.72 (m, 1H), 1.53 (dddd, J=12.3, 11.2, 7.8, 4.5 Hz, 1H), 1.09 (dtd, J=13.1, 7.6, 3.7 Hz, 1H); ESIMS m/z 195.1 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[C:7](C(O)=O)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH3:16])[CH:9]=3.O>N1C2C(=CC=CC=2)C=CC=1.C1(C)C=CC=CC=1.C(Cl)Cl.C([O-])([O-])=O.O.O.[Cu].[Cu+2]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[C:10]([CH3:16])[CH:9]=3
Reactant: Cc1ccc2c(c1)c(C(=O)O)cc1ccc(Br)cc12
Agent: [Cu+2]
Agent: [Cu]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(ccc3ccc(Br)cc32)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.1 %

Procedure:
A stirred mixture of 3-Bromo-7-methyl-phenanthrene-9-carboxylic acid (5.50 g, 17.5 mmol) and CuCo3.Cu(OH)2.H2O (1.5 g) in 50 ml of quinoline was rapidly heated to 210° C. Gas evolution was observed and the mixture became extremely dark. After 10 min the mixture was allowed to cool to room temperature and was diluted with PhCH3 --CH2Cl2 (9:1) and filtered. The filtrate was washed with 1N HCl (2x) and brine. Drying (Na2SO4) and evaporation gave 4.89 g of a brown oil which was flash chromatographed through 450 g of silica gel (10% CH2Cl2 /hexane) to yield 2.63 g (56%) of the title compound as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH:21]1(O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:13]([O:15][CH:4]2[CH2:5][CH2:6][CH2:7][CH2:11][CH2:12]2)=[O:14])[C:7](=[CH:11][CH:12]=1)[C:8]([O:10][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:9])([O-:3])=[O:2]
Reactant: OC1CCCCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(=O)O
Agent: O=S(=O)(O)O
Product: O=C(OC1CCCCC1)c1ccc([N+](=O)[O-])cc1C(=O)OC1CCCCC1
Temperature: 120 °C
Yield: 65.5 %

Procedure:
4-nitrophthalic acid (2.0 g, 9.5 mmol) was dissolved in 30 ml of cyclohexanol, and then 0.3 ml of conc. sulfuric acid was added. The mixture was heated at 120° C. for 24 hours and the solvent was evaporated under reduced pressure. The oily residue was dissolved in diethyl ether and washed three times with water and once with 10% Na2CO3 solution. The ether solution was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (n-hexane: acetic acid =10:1) to give 2.3 g (65.5%) of dicyclohexyl 4-nitrophthalate (compound 405).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:29][CH:6]2[CH:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][CH:20]=3)[O:8][C:9]3[CH:10]=[CH:11][C:12]([O:15]COC)=[CH:13][C:14]=3[CH:5]2[CH2:4]1.Cl.CCOC(C)=O.CCOC(C)=O.CCCCCC>C1COCC1>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([C@@H:7]2[C@@H:6]3[CH2:29][C@H:3]([O:2][CH3:1])[CH2:4][C@@H:5]3[C:14]3[CH:13]=[C:12]([OH:15])[CH:11]=[CH:10][C:9]=3[O:8]2)=[CH:24][CH:23]=1
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(OC)CC32)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CO[C@H]1C[C@@H]2[C@H](C1)c1cc(O)ccc1O[C@@H]2c1ccc(O)cc1
Yield: 78.4 %

Procedure:
Dissolve methyl ether 40 (205 mg, 0.51 mmol) in THF (8 mL) and add 3M HCl (2 mL). Stir the reaction at room temperature overnight. Dilute the reaction with EtOAc and wash with saturated aqueous sodium bicarbonate and brine. Extract the aqueous solutions with EtOAc (1×). Combine the organic solutions, dry (Na2SO4), filter and concentrate them in vacuo. Purify the product by flash chromatography (10 g SiO2, dry loading on 700 mg silica, 40 ml/min, 0-50% EtOAc/Hexane over 20 minutes and then 50% EtOAc/hexane for 13 minutes) to afford methyl ether 41 (125 mg, 0.4 mmol,78%) as a white solid. HRMS(ES+) calcd for C19H23NO4: 330.1705; found: 330.1695 (M+NH4); HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 8.95 min). The enantiomers wre separated by preparative chiral chromatography, chiralpol AD, IPA/Heptane.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)=[CH:22][C:17]=2[CH:16]=[C:15]([C:36]([OH:38])=O)[CH2:14][CH2:13]1.S(Cl)(Cl)=O>O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:39]=[CH:40][CH:41]=1)[CH2:11][N:12]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)=[CH:22][C:17]=2[CH:16]=[C:15]([C:36]([NH:12][C:18]2[CH:19]=[CH:20][C:21]([CH2:4][N:2]([CH3:1])[CH:3]3[CH2:31][CH2:30][O:29][CH2:26][CH2:25]3)=[CH:22][CH:17]=2)=[O:38])[CH2:14][CH2:13]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cccc(OC)c2)cc1
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cccc(OC)c2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 1-(3-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (110 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (80 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (60 mg) and triethylamine (273 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 1-(3-methoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 53) (62 mg) as yellow crystals.
Reaction SMILES: [C:1]1([O:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:19]CC2C=CC=CC=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O1CCCC1>[C:1]1([O:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[OH:19])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Oc1ccccc1)c1cc2cccc(OCc3ccccc3)c2[nH]1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)c1cc2cccc(O)c2[nH]1
Yield: 87.9 %

Procedure:
Under the conditions of Example 14(C), a solution of 5.4 g of 7-benzyloxyindole-2-carboxylic acid phenyl ester in a mixture of 50 ml of methanol and 30 ml of tetrahydrofuran is hydrogenated and worked up, yielding 3.5 g of 7-hydroxyindole-2-carboxylic acid phenyl ester, mp 156°-157° C.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:13][OH:14])([CH3:3])[CH3:2]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH:13]=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)c1c(CO)[nH]c2ccccc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CC(C)c1c(C=O)[nH]c2ccccc12
Yield: 84.3 %

Procedure:
The mixture of 3-isopropyl-2-hydroxymethylindole (29 g) and manganese dioxide (66.7 g) in ethyl acetate (435 ml) was reflux for 2 hours. After filtration of the insoluble materials, the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography (10% ethyl acetate-toluene) to give 3-isopropyl-2-indolecarbaldehyde (24.2 g) as crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][CH2:35][CH2:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([NH:34][CH2:35][CH2:36][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NCCC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NCCC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(2-cyclohexyl-ethylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.I[CH2:15][CH2:16][CH2:17][CH3:18].[H-].[Na+]>O1CCCC1>[CH2:15]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH2:16][CH2:17][CH3:18]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
A mixture of 6-methoxy-3,4-dihydro-1(2H)-naphthalenone (400 mg, 2.27 mmol), iodobutane (0.284 mL, 2.5 mmol), NaH (98 mg of a 61.1% dispersion in mineral oil, 2.5 mmol), and anhydrous tetrahydrofuran (THF, 1 mL) was placed under a N2 atmosphere and stirred at room temperature for 15.5 hours. The mixture was partitioned between EtOAc (20 mL) and water (30 mL) containing 2N HCl (3 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford an oil. The crude product was purified by preparative layer chromatography on five 0.1×20×20 cm silica gel GF plates (Analtech, Newark, Del.), developing with CH2Cl2. The UV visible product band was eluted with EtOAc and the eluant evaporated under vacuum to provide 2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.[C:21](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:21])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reaction time: 0.02 h
Yield: 39.5 %

Procedure:
To a solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile (1 eq, 71 mg, 0.27 mmol) in dimethylformamide (0.5 mL) was added potassium carbonate (5 eq, 0.18 g, 0.1.35 mmol). After 1 min, iodomethane (3 eq, 0.05 mL, 0.81 mmol) was added and the suspension was stirred for 2 hours, poured into water (5 mL) and the product was extracted with ethyl acetate (3×5 mL). The layers were then separated, the aqueous layer extracted with ethyl acetate (3×10 mL) and the combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexane to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (30 mg, 41%) as a white solid; MS (ES) m/z 280 (M−H)−; Anal. Calcd. For C16H15N3O2: C, 68.3; H, 5.37; N, 14.9. Found, C, 68.4; H, 5.51; N, 14.6.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([C@:7]2([CH3:22])[O:11][C:10](=[O:12])[C:9]([O:13]CC3C=CC=CC=3)=[C:8]2[OH:21])=[CH:3][CH:2]=1>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:6]=[CH:5][C:4]([C@:7]2([CH3:22])[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:21])=[CH:3][CH:2]=1
Reactant: C[C@@]1(c2ccc(-c3ccccc3)cc2)OC(=O)C(OCc2ccccc2)=C1O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: C[C@@]1(c2ccc(-c3ccccc3)cc2)OC(=O)C(O)=C1O
Yield: 20 %

Procedure:
The (S)-(+)-5-[(1,1'-biphenyl)-4-yl]-4-hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone was subjected to hydrogenation over 100 mg of 5% Pd/BaSO4 in 100 mL of MeOH at room temperature under 30 psi of H2. The reaction was monitored periodically by TLC analysis. Upon reaction completion, the suspension was filtered through two #1 filter papers, concentrated and recrystallized from CHCl3 and hexanes to provide 300 mg (20% overall yield from methyl (S)-(+)-2-[(1,1'-biphenyl)-4-yl]-2-hydroxypropionate) of (S)-(+)-5-[(1,1'-biphenyl)-4-yl]-3,4-dihydroxy-5-methyl-2(5H)-furanone as a light weight white crystalline material: mp 204-206° C. dec.; [α]25D +121° (c=0.66; MeOH); 1H NMR (acetone-d6) δ 7.72-7.41 (m, 9H), 1.89 (s, 3H). Anal Calcd for C17H14O4 +0.75 H2O: C, 69.03; H, 5.28. Found: C, 68.69; H, 4.95.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([NH2:11])=O)=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[C:13]1=[O:22]>S(Cl)(Cl)=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:11])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=2[C:13]1=[O:22]
Reactant: NC(=O)c1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Solvent: O=S(Cl)Cl
Product: N#Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reaction time: 16 h
Yield: 59 %

Procedure:
To 30 ml of thionyl chloride, 1.13 g of N-(2-fluoro-4-chloro-5-aminocarbonylphenyl)-3,4,5,6-tetrahydrophthalimide was added and the mixture was heated to reflux under stirring for 16 hours. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel, benzene/ethyl acetate=10/1 (v/v)) to obtain 0.63 g of the desired product.m.p.: 160°-162° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:41][CH3:42])[C:4](=[O:40])[CH2:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[CH2:12][N:13]1[C:17](=[O:18])[C:16]2([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[N:15]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:14]1)=[O:8])[CH3:2].Cl>O1CCOCC1>[O:18]=[C:17]1[C:16]2([CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[N:15]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:14][N:13]1[CH2:12][C:11]1[CH:10]=[C:9]([CH:39]=[CH:38][CH:37]=1)[C:7]([O:6][CH2:5][C:4]([N:3]([CH2:41][CH3:42])[CH2:1][CH3:2])=[O:40])=[O:8]
Reactant: CCN(CC)C(=O)COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)C(=O)COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl 3-(3-((2-(diethylamino)-2-oxoethoxy)carbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.22 g, 0.38 mmol) was added 4M solution of HCl in dioxane (3 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated in vacuo to obtain 2-(diethylamino)-2-oxoethyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate as a hydrochloride salt.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].N[C:9]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=1[C:11](O)=[O:12]>COC(O)C>[CH3:19][O:18][C:15]1[CH:14]=[C:10]2[C:9](=[CH:17][CH:16]=1)[N:7]=[CH:5][NH:6][C:11]2=[O:12]
Reactant: N=CN
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: COC(C)O
Solvent: CC(=O)O
Product: COc1ccc2nc[nH]c(=O)c2c1
Temperature: 140 °C
Reaction time: 17 h

Procedure:
Formamidine acetate (12.5 g, 119.6 mmol) was added to a stirred solution of 2-amino-5-methoxybenzoic acid (2.0 g, 119.6 mmol) in methoxy ethanol (40 mL) at RT. The reaction mixture was stirred at 140° C. (T oil bath) for ˜17 h. LC/MS showed completion of the reaction. The reaction cooled to RT and concentrated in vacuo. Aq. NaHCO3 solution was added to the concentrate and the precipitated solids were filtered (rinsing with water) to afford 6-methoxyquinazolin-4(3H)-one as off-white solid. MS [M+H]=177.1; Calc'd for C9H8N2O2: 176.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:31])(=[O:30])[NH:28][CH3:29])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([NH:28][CH3:29])(=[O:31])=[O:30])[CH:25]=[CH:26][C:18]=3[Cl:17])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCN(c3ccc(C(C)=O)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-methylsulfamoyl-benzoic acid (CAS: 68901-09-7; BE 620741) (69%, light yellow foam, MS (m/e): 452.1 (M−H, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].Br[CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:19][CH3:20])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:15])([F:17])[F:16]
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Reactant: CCBr
Product: CCN1CCN(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(4-Chloro-3-trifluoromethyl-phenyl)-piperazine and bromo-ethane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 293 (M+, 6), 292 (30), 277 (29), 57 (bp), 56 (41).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([CH3:14])=[CH:4][C:3]=1[N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1.[OH:24][C:25]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28].C[O-].[Na+].C1(C)C=CC=CC=1>CO>[N:16]1[N:15]([C:3]2[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]([CH2:8][C:38]3[C:37]([O:39][CH3:40])=[CH:36][CH:35]=[C:26]([C:27](=[O:28])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]=3[OH:24])[C:2]=2[OH:1])[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=12
Reactant: CCN(CC)Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 130 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
2-(2-Hydroxy-3-diethylaminomethyl-5-methylphenyl)-2H-benzotriazole (20.0 g, 0.064 tool), 2-hydroxy-4-methoxybenzophenone (14.7 g, 0,064 mol), and sodium methoxide (1.0 g, 25% in methanol) are charged to a reaction flask. The mixture is heated to 130° C. and held at this temperature for 20 hours with agitation under a nitrogen flow. At that time, the product is identified using thin layer chromatography, with toluene as the mobile phase. To the brown-yellow solid is added hot methanol. The yellow solids are vacuum filtered and triturated twice using methanol, yielding 20.6 g product. To remove the yellow color, the solids are dissolved in hot toluene, and silica gel is introduced. The silica gel is gravity filtered hot. The toluene is removed by vacuum distillation, yielding 12.1 g of the title compound as a pale yellow solid, m.p. 206°-209° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]1([CH:14]([CH3:18])[C:15](O)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:16])[CH:14]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH3:18])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C(=O)O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)Nc1ccc(Br)cc1)N1CCCC1
Reaction time: 8 h

Procedure:
4-Bromo aniline (0.25 g, 1.45 mmol), 2-pyrrolidin-1-ylpropanoic acid (0.25 g, 1.74 mmol) and diisopropylethylamine (0.3 ml, 1.74 mmol) were dissolved in dimethylacetamide (5 ml). HBTU (0.66 g, 1.74 mmol) was subsequently added and the mixture was stirred overnight. The reaction mixture was added to water and extracted twice with ethyl acetate. The combined organics were washed several times with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield: 0.43 g, 100%. LCMS method: 2, RT: 2.73 min; MI: 297-299 [M+1].
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH2:9][NH2:10]>C(O)C>[CH:2]([C:3]1[CH:4]=[C:5]([NH2:6])[NH:10][N:9]=1)([CH3:8])[CH3:1]
Reactant: CC(C)C(=O)CC#N
Reactant: NN
Solvent: CCO
Product: CC(C)c1cc(N)[nH]n1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
To a mixture of 4-methyl-3-oxopentanenitrile (0.9 g, 0.008 mole) in ethyl alcohol (5 mL) was added hydrazine (0.25 mL, 0.008 mole). The reaction mixture was refluxed for 1 hour and then cooled to room temperature. The reaction mixture was concentrated and the residue was dissolved in MeOH (2 mL). The crude product was loaded on a sulfuric acid bound resin (AG 50W-X2, hydrogen form, 100-200 mesh, BioRad), washed with MeOH (50 mL), then washed with 2N NH3 in methanol (10 mL). The ammonia washes were combined and concentrated to afford the desired product (700 mg, 68%). 1HNMR (400 MHz, MeOD) δ 5.44 (s, 1H), 2.84-2.90 (m, 1H), 1.24 (d, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[C:19]1([N:25]2[C:29]([NH2:30])=[C:28]([NH2:31])[CH:27]=[N:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:31]=[C:28]3[CH:27]=[N:26][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:29]3=[N:30][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1cnn(-c2ccccc2)c1N
Reactant: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(-c2nc3cnn(-c4ccccc4)c3nc2-c2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of 1,2-bis-(4-chloro-phenyl)-ethane-1,2-dione from Step A (˜20 mg), 2-phenyl-2H-pyrazole-3,4-diamine from Step B (25 mg) and p-TSA in MeOH (1 mL) is heated to 80° C. for 2 h. After cooling down to room temperature, the mixture is treated with saturated aqueous NaHCO3 solution (3 mL) and extracted with EtOAc (3×2 mL). The organic layers are combined and concentrated. The residue is purified by Preparative LC/MS to provide the title compound 5,6-bis-(4-chloro-phenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyrazine. 1H NMR (CDCl3) δ(ppm) 8.51(s, 1H), 8.34 (d, 2H), 7.56(t, 2H), 7.46(d, 2H), 7.32˜7.43 (m, 7H); HPLC-MS calculated for C23H14Cl2N4 (M+H+): 417.1. Found: 417.1.