Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH2:23])[CH2:18]1.C(N(CC)CC)C.[C@@H:31]12[C:38](=[O:39])[O:37][C:35](=[O:36])[C@@H:32]1[CH2:33][CH2:34]2>CN(C=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([NH:23][C:38]([CH:31]2[CH2:34][CH2:33][CH:32]2[C:35]([OH:37])=[O:36])=[O:39])[CH2:18]1
Reactant: O=C1OC(=O)[C@@H]2CC[C@H]12
Reactant: Cc1cccc(-c2nc(COCC3CCCC(N)C3)c(C)o2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nc(COCC3CCCC(NC(=O)C4CCC4C(=O)O)C3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
50 mg of 3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexylamine were dissolved in 0.97 ml of DMF, and 32 mg of triethylamine were added. 22 mg of cis-cyclobutane-1,2-dicarboxylic anhydride were then added, and the solution was stirred at RT overnight. The solution was purified directly by HPLC, which gave 36 mg of 2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxymethyl)cyclohexylcarbamoyl]cyclobutanecarboxylic acid. C25H32N2O5 (440.54), MS (ESI): 441 (MH+).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[C:6]1=[O:15]>CN(C)C=O.O>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[C:6]1=[O:15])#[N:2]
Reactant: O=C1c2ccc(Cl)cc2CC1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1Cc2cc(Cl)ccc2C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
10.4 g of sodium cyanide were dissolved in a mixture of 100 ml of dimethylformamide and 6 ml of water and initially charged. This solution was heated with stirring to 50° C., and 20.4 g of 2,5-dichloroindan-1-one, dissolved in 100 ml of dimethylformamide, were then added dropwise over a period of 60 minutes. After the addition had ended, stirring was continued at 50° C. for 1 hour. The mixture was then allowed to cool to room temperature and the solvent was stripped off using a rotary evaporator. The resulting crystal slurry was mixed with 200 ml of water and acidified to pH 4.5 using 10% by weight strength aqueous hydrochloric acid. The precipitated solid was filtered off with suction, washed with water, recrystallized from toluene and dried in a vacuum drying cabinet. This gave 18.5 g of 2-cyano-5-chloroindan-1-one (yield: 97% of theory).
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=3[CH3:35])[CH:20]=[C:21]([C:25](=[O:27])[CH:26]=2)[C:22]([OH:24])=[O:23])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1>O1CCOCC1.O.[C].[Pd]>[NH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=3[CH3:35])[CH:20]=[C:21]([C:25](=[O:27])[CH:26]=2)[C:22]([OH:24])=[O:23])[CH2:14][CH2:13]1
Reactant: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1CCC(N)CC1
Reaction time: 3 h
Yield: 88.1 %

Procedure:
In a mixture of 10 ml of dioxane and 5 ml of water was dissolved 0.15 g of 6-(4-benzyloxycarbonylaminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid, and 0.03 g of 5% by weight palladium carbon was added. The above acid was hydrogenated under atmospheric pressure for 3 hours. The catalyst was removed by filtration and the solvent was then removed by distillation under reduced pressure. To the residue was added 3 ml of diethyl ether, and the precipitated crystals were collected by filtration and washed with 3 ml of diethyl ether to obtain 0.095 g of 6-(4-aminocyclohexyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 237°-250° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Br:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([Br:17])=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 10 h
Yield: 44.3 %

Procedure:
To a mixture of 1.7 g of 2-amino-5-chlorobenzoic acid and 100 ml of N,N-dimethylformamide was added 1.8 g of N-bromosuccinimide at room temperature, and the mixture was stirred at room temperature for 10 hours. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 1.1 g of 2-amino-3-bromo-5-chlorobenzoic acid of the formula:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Fc1ccc(Sc2ccc(Br)cc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3ccc(F)cc3F)cc2)c1C
Yield: 32.9 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,4-difluorobenzene (0.184 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,4-difluoro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.082 g, 33%) as a solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:8][C:7](=[O:9])[C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: OCc1ccccc1
Product: CC(C)C[C@@H](N)C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
D-leucine (10 g, 76.23 mmol) is suspended in benzyl alcohol (157 mL) and warmed to 55° C. HCl gas is bubbled through the mixture and the reaction becomes quite viscous. 150 mL of benzene is then added with vigorous stirring. After 30 minutes of bubbling gas through with heating the mixture begins to thin and stirring is achieved more easily. The reaction stirs further at 55° C. for one hour until the solution becomes homogeneous. Flow of HCl is ceased and the reaction is closed off and allowed to stir further at 55° C. for 30 minutes. The reaction is allowed to cool to room temperature and is diluted with ethyl acetate. The product is extracted into 1M HCl (3×) and the organics are discarded. The aqueous washings are combined taken to pH 8 with 50% aqueous NaOH. The amine is extracted several times with ethyl acetate. The organics are dried over sodium sulfate and evaporated. Ether is added to the oil and HCl is bubbled through to precipitate D-leucine benzyl ester as the hydrochloride salt.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([O:23]C(C)(C)C)=[O:22])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)O)C2CCCC2)cc1

Procedure:
2.3 g (5 mmol) of the compound from Example IV are stirred for 5 h at 25° C. in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid. After concentration, the crude product is chromatographed on silica gel 60 using dichloromethane/methanol (100:5). Yield: 1.8 g (87.6% of theory) Solidification point: 95°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[C:23]2[CH:27]=O>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][CH:24]=[C:23]2/[CH:27]=[CH:14]/[C:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: COc1cccc2c(C=O)c[nH]c12
Product: COc1cc(C(=O)/C=C/c2c[nH]c3c(OC)cccc23)cc(OC)c1OC
Yield: 48.3 %

Procedure:
Substantially the same procedure as in Example 39 was repeated using 3',4',5'-trimethoxyacetophenone (1.74 g) and 7-methoxyindole-3-carboxaldehyde (1.45 g) to give Compound 46 (1.47 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C>[CH3:3][C:4]1([CH3:10])[CH2:8][CH2:7][C:6](=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[C:5]1=[O:9]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C)CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(=Cc2ccc(Cl)cc2)C1=O
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
10% strength sodium hydroxide solution (100 cc) is added to a mixture of 2,2-dimethylcyclopentanone (10 g) and 4-chlorobenzaldehyde (13.8 g) in ethanol (100 cc) at 0° C. After 10 minutes, the thick slurry is filtered and the solid washed and then dried. 2,2-Dimethyl-5-(4-chlorobenzylidene)-1-cyclopentanone (12.5 g), m.p. 120° C., is obtained.
Reaction SMILES: C(O[C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)C.[CH3:35][S:36][Si](C)(C)C.C(NC(C)C)(C)C>C(Cl)Cl>[C:9]([O:8][C@H:7]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]([S:36][CH3:35])[C@@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=[O:11])[CH3:10]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CS[Si](C)(C)C
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CS[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
A mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-galactose (680 mg, 1.425 mmol), methylthiotrimethylsilane (0.8 ml, 5.64 mmol), and trimethyl silyl triflate (0.32 ml, 1.66 mmol) in CH2Cl2 was stirred at room temperature for 2 days. Diisopropylamine (~1 ml) was added, diluted with CH2Cl2 (~50 ml) and washed with saturated NaHCO3 solution and water, respectively. The organic layer was dried (Na2SO4) and evaporated to dryness. Column chromatography (heptane-EtOAc) gave pure 20 (630 mg, 95%) as an amorphous powder, having [α]D24 +25° (c1, CHCl3).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:9]([O:11][CH2:12][CH3:13])=[O:10].[OH-].[Na+]>Cl>[N:1]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNC1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)N1CCCNCC1

Procedure:
To a solution of homopiperazine (50.0 g, 0.5 mol) in aqueous HCl adjusted to pH 4 using approximately 400 mL of 2N HCl was added ethyl chloroformate (50 mL, 0.53 mol) dropwise maintaining the pH at 4 by the addition of 25% aqueous NaOH. The reaction mixture was brought to pH 14 with 25% aqueous NaOH and extracted with 3×250 mL of Et2O. These extracts were discarded and the aqueous was brought to pH 10 with 2N HCl and Na2CO3. After extracting the aqueous with 3×150 mL of Et2O, these combined extracts were dried over Na2SO4, and stripped of all solvent under reduced pressure. The residue was vacuum distilled at 0.1 mm of Hg and the title compound was obtained as the fraction (25.0 g) distilling at 103° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42]/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@H:21]([O:23][CH2:42]/[CH:43]=[CH:44]\[C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(/C=C\CBr)(CC)O[Si](CC)(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(/C=C\CO[C@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 98.9 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5(10 μl) and (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene (103 mg, 0.321 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (84.6 mg, 99%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13](B4OC(C)(C)C(C)(C)O4)[CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=2)[CH:4]=[N:3]1.C(O)(=[O:35])C.OO>O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([OH:35])[CH:14]=3)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)cn1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)cn1
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of 25 (1.00 g, 2.20 mmol), glacial acetic acid (5.0 mL), H2O (5.0 mL) and 30% aq. H2O2 (370 μL, 3.30 mmol) were stirred for 8 h and partitioned between AcOEt/brine. The layers were separated, the aqueous phase extracted with more AcOEt and the combined organic extracts dried (MgSO4) and concentrated to give 27 as a creamy white solid (731 mg, 96%); 1H NMR (400 MHz, CDCl3) δ-0.058 (s, 9H), 0.92 (t, J=8.3 Hz, 2H), 3.58 (t, J=8.3 Hz, 2H), 4.01 (s, 3H), 2.01 (s, 2H), 7.37 (s, 1H), 7.56 (s, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.95 (s, 1H), 8.17 (d, J=2.2 Hz, 1H), 9.00-9.60 (bs, OH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([CH2:24][N:25]([CH3:36])[CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)=[CH:15][N:16](C3CCCCO3)C=2)[CH:5]=[C:6]([CH3:12])[C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.C(O)(C(F)(F)F)=O.CC#[N:47]>Cl>[CH:9]([O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:13]2[C:14]([CH2:24][N:25]([CH3:36])[CH2:26][CH2:27][NH2:28])=[CH:15][NH:16][N:47]=2)=[CH:5][C:6]=1[CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1cc(-c2cn(C3CCCCO3)cc2CN(C)CCNC(=O)OC(C)(C)C)cc(C)c1OC(C)C
Reactant: CC#N
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]cc2CN(C)CCN)cc(C)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
A solution of tert-butyl N-[2-[([4-[3,5-dimethyl-4-(propan-2-yloxy)phenyl]-1-(oxan-2-yl)-1H-pyrrol-3-yl]methyl)(methyl)amino]ethyl]carbamate (650 mg, 1.30 mmol, 1.00 equiv) in 3N hydrochloric acid (20 mL) was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2(HPLC-08)): Column, Xbridge Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 50 mmol CF3COOH and CH3CN (10.0% CH3CN up to 28.0% in 2 min, up to 46.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm to give 269 mg (38%) of N1-((3-(4-isopropoxy-3,5-dimethylphenyl)-1H-pyrazol-4-yl)methyl)-N1-methylethane-1,2-diamine as a light yellow oil. 1H-NMR (300 MHz, D2O): δ 7.88 (s, 1H), 7.17 (s, 2H), 4.42 (s, 2H), 4.35-4.26 (m, 1H), 3.30-3.10 (m, 4H), 2.57 (s, 3H), 2.23 (s, 6H), 1.23 (d, J=6.3 Hz, 6H) ppm. LCMS (method J, ESI): RT=1.57 min, m/z=317.1 [M+H]+.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)C.[O:17]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][C:4]2[C:5](=[O:16])[C:6](=[O:15])[C:7]=2[NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Reactant: CCOc1c(Nc2ccncc2)c(=O)c1=O
Product: O=c1c(NCCc2ccc(Oc3ccccc3)cc2)c(Nc2ccncc2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridin-4-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 7A and 2-(4-phenoxyphenyl)-ethylamine. The reaction mixture was heated to reflux for 2 hours instead of stirring 18 h at r.t.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:7]=[C:8]([CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1)[C:9]([O:11]N1C(=O)CCC1=O)=O)[CH:2]=[CH2:3].Cl.[CH3:27][NH:28][O:29][CH3:30].C(N(CC)CC)C>ClCCl>[CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:8]([C:9](=[O:11])[N:28]([O:29][CH3:30])[CH3:27])[CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(C(=O)ON2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(C(=O)N(C)OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (7(b)) (2.00 g), N,O-dimethylhydroxylamine hydrochloride (0.62 g), triethylamine (0.86 ml) and dichloromethane (60 ml) was stirred at 5° for 30 min and then allowed to warm to ambient temperature and stirred for a further 16 h. The mixture was poured onto a flash column and eluted with ethyl acetate/hexane (40:60)to give 3-(N-methyl-methoxycarbamoyl)-5-nitro benzoic acid allyl ester (7(c)) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([O:18]CC)=[O:17])=[N:15][N:6]3[C:5](=[O:21])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[C:29]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:6]3[C:5](=[O:21])[C:4]=2[CH:3]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc2n(C)c3ccc(N)cc3c(=O)n2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c2ccc(NC(=O)c3ccccc3)cc2c(=O)n2nc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7-amino-4,9-dihydro-4-methyl-9-oxopyrazolo[5,1-b]quinazoline-2-carboxylic acid, ethyl ester (0.75 g, 2.62 mmol, Example 2) and triethylamine (0.46 mL, 3.30 mmol) in 500 mL of methylene chloride was added dropwise a solution of benzoyl chloride (0.34 mL, 2.93 mmol) in 50 mL of methylene chloride at room temperature. A yellow solid slowly formed. The mixture was stirred at room temperature for 12 hours and filtered. The yellow solid was washed with methylene chloride and diethyl ether and vacuum-dried, affording the title compound as its ethyl ester, mp 275°-278° C., dec.
Reaction SMILES: [CH3:1][O-].[Na+].[N+:4]([C:7]1[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:10][CH:11]=1)([O-:6])=[O:5].CI>CO>[CH3:1][N:10]1[CH:11]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=[C:9]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1C
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
A solution of 2.5 g. of sodium methoxide in 25 ml. of methanol is cooled to 10° C. and a mixture of 7.0 g. of ethyl 4-nitro-2-pyrrolecarboxylate in 15 ml. of methanol is added. After 10 minutes, 18.6 g. of methyl iodide is added. The dark-colored solution is warmed to 35° C. for 0.5 hours, then cooled and allowed to stir at room temperature for 16 hours. Chilling and filtration affords a solid which is collected by filtration and recrystallized from ethanol to yield the product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1.CCOC(C)=O>CS(C)=O>[Cl:21][C:22]1[N:27]=[C:26]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 25 °C

Procedure:
To a solution of 6-hydroxy-1-naphthoic acid (10.0 g, 53.1 mmol) in DMSO (60 mL) was added Cs2CO3 (51.9 g, 159.4 mmol). Bubbling was evident. The mixture was stirred at RT for 5 min, at which time 2,4-dichloropyrimidine (15.8 g, 16.3 mmol) was added. The reaction was stirred at RT and monitored by LCMS for the disappearance of starting material. EtOAc (1.0 L) was added, and the reaction was filtered to remove solid Cs2CO3. The mixture was extracted with 2N aqueous NaOH. The aqueous layer was washed with EtOAc, then acidified with 6N aqueous HCl to provide a white suspension. Filtration yielded a white solid.