Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:3]=1[C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:9][CH:8]=1)=[O:5].[CH2:23]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:29][CH:30]=2)[CH:19]=[CH:18][C:3]=1[C:4]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:11][CH:12]=1)=[O:5]
Reactant: CCCCCc1ccc(OC(=O)c2ccc(O)cc2Cl)cc1
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCc1ccc(OC(=O)c2ccc(OC(=O)c3ccc(CCCCC)cc3)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
A mixture of 4-pentylphenyl 2-chloro-4-hydroxybenzoate (0.0075 mole) prepared as in Example 1 and p-pentylbenzoyl chloride (0.0075 mole) in pyridine (35 ml.) is stirred at room temperature for 5 hours. The reaction mixture is then poured into ice-water. The product is filtered and washed with water to give 4-n-pentylphenyl 2-chloro-4-(4-pentylbenzoyloxy)benzoate (3.1 g., 84%), m.p. 38°-122°C. The analytical sample, m.p. 39°-122°C is obtained by chromatography on Florisil and crystallization from ethanol. The theoretical values calculated for C30H33ClO4 and the values actually found are as follows:
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Br:13][C:14]1[CH:22]=[C:18]([C:19]([OH:21])=O)[C:17]([OH:23])=[CH:16][CH:15]=1.[NH2:24][CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:35])[CH:31]=2)[CH2:26]1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([CH:22]=1)[C:19]([NH:24][CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:34]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[O:35])[CH:31]=2)[CH2:26]1)=[O:21]
Reactant: NC1Cc2ccc(C(=O)N3CCOCC3)cc2C1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NC1Cc2ccc(C(=O)N3CCOCC3)cc2C1)c1cc(Br)ccc1O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 11.7 %

Procedure:
WSC•HCl (96 mg, 0.5 mmol) was added to a solution of 5-bromosalicylic acid (109 mg, 0.5 mmol), 2-amino-5-(morpholino)carbonylindan (refer to Chem. Pharm. Bull., 2000, 48, 131; 141 mg, 0.5 mmol) and triethylamine (70 μL, 0.5 mmol) in dichloromethane (5 mL), and the mixture was stirred at 40° C. for 1.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with 2 N hydrochloric acid, water and brine one after another, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=19:1) to give the title compound (26 mg, 11.9%) as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=O)=[CH:4][CH:3]=1.NN.FC1C=CC(NO)=CC=1.[CH3:22][N:23]=[C:24]=[O:25]>O1CCCC1.[Pd]>[CH3:22][NH:23][C:24]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[OH:10])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN=C=O
Agent: [Pd]
Agent: NN
Agent: ONc1ccc(F)cc1
Solvent: C1CCOC1
Product: CNC(=O)N(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
p-Fluoronitrobenzene (14.1 g; 0.1 mole) was dissolved in tetrahydrofuran (100 ml.). Ten percent palladium on charcoal catalyst (0.1 g.) was added to the solution followed by hydrazine (6.0 ml; 0.105 mole), and the resulting mixture stirred at room temperature for about 48 hours with cooling as necessary. The reaction mixture containing N-(4-fluorophenyl) hydroxylamine was dried over anhydrous magnesium sulfate and filtered. To this solution was added methyl isocyanate (6.2 ml; 0.1 mole) and the mixture stirred for about 15 minutes. The reaction mixture was concentrated by distilling and then washed with hexane and filtered to yield 1-methyl-3-(4'-fluorophenyl)-3-hydroxyurea as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:20][CH:21]=2)[CH3:15])=[CH:9][C:8]=1[CH3:33])C.ClC(C1C(C)=NC(C2C=CC=C(C(F)(F)F)C=2)=CC=1)C.ClC(C1C(C)=NC(C2C=CC(C(F)(F)F)=CC=2)=CC=1)CCC>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][CH:14]([C:16]2[C:17]([CH3:32])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)=[CH:20][CH:21]=2)[CH3:15])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)COc1ccc(OC(C)c2ccc(-c3cccc(C(F)(F)F)c3)nc2C)cc1C
Agent: CCCC(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C(C)Cl
Product: Cc1cc(OC(C)c2ccc(-c3cccc(C(F)(F)F)c3)nc2C)ccc1OCC(=O)O

Procedure:
A] The title compound was prepared in analogy to example 46, via [rac]-(2-methyl-4-{1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenoxy)-acetic acid ethyl ester, but using in step A] [rac]-3-(1-chloro-ethyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine (example 3C]) instead of [rac]-3-(1-chloro-butyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine as colorless solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([F:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:30])[CH3:29]>C(#N)C>[F:23][C:22]1[C:16]2[O:15][CH2:14][CH:13]([CH2:12][NH:30][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CCNCC1COc2c(F)cc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.3 g, 0.8 mmol), ethanamine (1 ml, 70% in water) and ACN (2 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and on flash column chromatography (Isooctane/EtOAc/MeOH). Yield: 0.1 g, 61%. The amine was converted to the hydrochloric acid salt and crystallized from EtOH. M.p. 256° C. MS m/z (rel. intensity, 70 eV) 289 (M+, 12), 70 (17), 59 (20), 58 (bp), 56 (19).
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[CH:6]=1)C.[OH-].[Na+].Cl>C(O)C.O>[C:14]([C:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:16])=[O:3])([CH3:13])[CH3:12])#[N:15]
Reactant: CCOC(=O)c1cccc(C(C)(C)C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C#N)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 300 mg 3-(1-Cyano-1-methyl-ethyl)-benzoic acid ethyl ester and 165 mg sodium hydroxide in 1 ml ethanol and 0.5 ml water were stirred 2 hrs at RT. 20 ml water were added and the pH was adjusted to 1-2 by addition of conc. hydrochloric acid. The title product precipitated and was isolated by filtration, washed with water and dried, yielding 184 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[CH:12](=O)/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N)cn1
Reactant: O=C/C=C/c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=CC=Cc2ccccc2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 7.61 g of 5-amino-pyridine-2-carboxylic acid methyl ester, 7.61 g of trans-cinnamaldehyde and 130 ml of benzene is stirred and refluxed on a water trap for 41/2 hours. It is evaporated and the residue recrystallized from ethyl acetate, to yield the 5-cinnamylideneaminopyridine-2-carboxylic acid methyl ester melting at 128°-131°.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:12](=[O:13])[C:7]2=[C:6]([OH:22])[C:5]=1[C:23]([O:25]CC)=O)(=O)[CH3:2].[CH3:28][NH:29][NH2:30].C(O)(=O)C>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]3[C:7](=[C:6]([OH:22])[C:5]4[C:23](=[O:25])[N:29]([CH3:28])[N:30]=[C:1]([CH3:2])[C:4]=43)[C:12]2=[O:13])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(O)c2n(c1C(C)=O)CCN(Cc1ccc(F)cc1)C2=O
Reactant: CNN
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nn(C)c(=O)c2c(O)c3n(c12)CCN(Cc1ccc(F)cc1)C3=O

Procedure:
A mixture of ethyl 6-acetyl-2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (75 mg, 0.2 mmol), methylhydrazine (46 mg, 1 mmol), and a drop of acetic acid in ethanol (4 mL) was heated in a sealed tube at 105° C. overnight. The product mixture was concentrated under vacuum. The residue was recrystallized from methanol to provide the titled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([CH3:40])[C:32]3[NH:37][C:36](=[O:38])[CH2:35][O:34][C:33]=3[CH:39]=2)[CH:23]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([CH3:40])[C:32]6[NH:37][C:36](=[O:38])[CH2:35][O:34][C:33]=6[CH:39]=5)[CH:23]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2c1NC(=O)CO2
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5c(c4)OCC(=O)N5)ncn3)CC1)C(=O)N2

Procedure:
70 mg (0.25 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 65 mg (0.20 mmol) 7-(6-chloropyrimidin-4-yloxy)-5-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one and 50 μL (0.27 mmol) DIPEA in 2.0 mL DMF were stirred overnight at RT and for 3 h at 40° C. The reaction mixture was combined with water and methanol. The precipitate formed was suction filtered, washed and dried. The filtrate was again suction filtered, washed and dried.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([OH:8])=[CH:6][CH:5]=[N:4]1.C(N(CC)CC)C.[CH3:16][N:17]1[C:22](=[O:23])[N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:30])[C:19]([C:31](Cl)=[O:32])=[N:18]1.CC(C)(O)C#N>C(#N)C.ClCCl>[OH:8][C:7]1[N:3]([CH3:2])[N:4]=[CH:5][C:6]=1[C:31]([C:19]1[C:20](=[O:30])[N:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:22](=[O:23])[N:17]([CH3:16])[N:18]=1)=[O:32]
Reactant: Cn1nc(C(=O)Cl)c(=O)n(-c2ccccc2)c1=O
Reactant: Cn1nccc1O
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncc(C(=O)c2nn(C)c(=O)n(-c3ccccc3)c2=O)c1O
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Next, 1.22 g (9.10 mmol) of 1-methyl-5-hydroxypyrazole hydrochloride and 1.53 g (15.17 mmol) of triethylamine were added to dichloromethane (30 ml) under ice cooling. To the mixture, the dichloromethane solution (15 ml) of 2-methyl-3,5-dioxo-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonyl chloride was slowly added dropwise, and stirred for 30 minutes. The reaction mixture was extracted with chloroform, and the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residues obtained were dissolved in acetonitrile (30 ml), added with 0.92 g (9.10 mmol) of triethylamine and 0.05 g (0.61 mmol) of acetone cyanohydrin, and refluxed for 30 minutes under heating. The reaction mixture was concentrated under reduced pressure, and then the residues were dissolved in water and washed with ethyl acetate. The aqueous layer was acidified by using citric acid, extracted with chloroform, dried over magnesium sulfate, and concentrated under reduced pressure. The crystals obtained were washed with methanol to obtain 0.40 g of the target compound (yield 20%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:22])[CH3:21])[CH:12]=2)=[O:7])CCC.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28]>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH:28][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]([CH3:21])[CH3:22])[CH:12]=2)=[O:7]
Reactant: CN(C)CCN
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(OC(C)C)ccc2c1O
Product: CC(C)Oc1ccc2c(O)c(C(=O)NCCN(C)C)nc(Cl)c2c1

Procedure:
Synthesized from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and N,N-dimethyl-ethane-1,2-diamine in analogy to example B-4, followed by deprotection in analogy to example B-1 f); MS-(+)-ion: M+1=352.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]1>O>[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:22][CH2:21]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Solvent: O
Product: Nc1ccc(Nc2cc(N[C@H]3CC[C@H](N)CC3)nn3ccnc23)cc1
Reaction time: 72 h

Procedure:
To N1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)benzene-1,4-diamine (0.2 g, 0.77 mmol) from 1a was added trans-1,4-diaminocyclohexane (1.7 g, 15.0 mmol). The mixture was allowed to melt at 160° C. for 3 days. The melt was then cooled, diluted with water and extracted with dichloromethane. The organic layer was then concentrated in vacuo to give 0.4 g of crude N6-(trans-4-aminocyclohexyl)-N8-(4-aminophenyl)imidazo[1,2-b]pyridazine-6,8-diamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH2:11])[CH3:2].Cl.[Cl:14]OC(C)(C)C>CO>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[C:9]([Cl:14])[CH:8]=[N:7][C:6]=1[NH2:11])[CH3:2]
Reactant: CCOC(=O)c1cccnc1N
Reactant: CC(C)(C)OCl
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A solution of 2-amino-nicotinic acid ethyl ester (3.60 g, 21.7 mMol) in methanol (100 mL) was treated with HCl gas via sparge tube for 5 minutes, causing the colorless solution to turn yellow. The solution was concentrated in-vacuo, then stripped from methanol (2×50 mL) to remove excess HCl. The residue was dissolved in methanol (100 mL), treated with tert-butyl hypochlorite (2.6 g, 23.8 mMol), and the mixture was allowed to stir overnight at room temperature. Analysis by TLC showed that some starting material remained, so additional tert-butyl hypochlorite (0.47 g, 4.3 mMol) was added, and stirring was continued overnight. Analysis by TLC showed that all starting material had been consumed. The solution was concentrated in-vacuo, the residue was taken up in methylene chloride (150 mL), washed with saturated sodium bicarbonate (3×50 mL), 5% aqueous sodium thiosulfate (3×50 mL), water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 20%-30% ethyl acetate/heptane, to yield 1.50 g of colorless solids as product. MS (AP+)=201 (M+H)+. Yield=35%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].C[Si](C)(C)[O:15][C:16]([CH3:21])=[CH:17][C:18](=[O:20])[CH3:19]>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([CH:17]([C:18](=[O:20])[CH3:19])[C:16](=[O:15])[CH3:21])=[O:7])([O-:3])=[O:2]
Reactant: CC(=O)C=C(C)O[Si](C)(C)C
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: CC(=O)C(C(C)=O)C(=O)c1ccccc1[N+](=O)[O-]
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 21.3 %

Procedure:
A mixture of 2-nitrobenzoyl chloride (500 mg) with 4-trimethylsilanyloxy-pent-3-en-2-one (540 mg) was stirred at 140° C. for 5 min. The reaction solution was cooled to room temperature and was then purified by column chromatography using acetone-hexane to give 3-(2-nitro-benzoyl)-pentane-2,4-dione (143 mg, yield 20%).
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>CO>[OH:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:3]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-hydroxy-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionate (10.0 g, 28.4 mmol) in methanol (40 ml) was added 2N aqueous sodium hydroxide solution (28.4 ml, 56.8 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give (2RS,3RS)-3-hydroxy-3-phenyl-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (7.87 g, 86%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][C:24]([O:26]CC)=[O:25])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:29][CH3:30])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].O>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][C:24]([OH:26])=[O:25])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:29][CH3:30])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)COc1ccccc1-c1nc2n(C3CCCC3)[nH]c(CC)c-2c(=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccccc3OCC(=O)O)nc(=O)c1-2
Yield: 74.9 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-[2-(ethoxycarbonylmethoxy)pheny]pyrazolo[3,4-d]pyrimidin-4-one (3.0 g, 7.3 mmol), K2CO3 (3.04 g), water (20 ml) and ethanol (50 ml) was refluxed for 1.5 hours. The reaction mixture was cooled, the solvent was removed in vacuo and the residue was slurried with water and acidified. A precipitate formed which was collected by filtration, recrystallized from isopropanol and dried at 90° C. The solid was dissolved in 10% K2CO3 (100 ml), treated with DARCO®, filtered and the filtrate was acidified with acetic acid. A precipitate formed which was collected by filtration and dried at 110° C. The solid product was combined with the solid product obtained from a similar experimental run, stirred with 6N HCL (100 ml), filtered and dried with P2O5 at 100° C. under vacuum to afford 2.09 g of 1-cyclopentyl-3-ethyl-6-[2-(carboxymethoxy)phenyl]pyrazolo[3,4-d]pyrimidin-4-one 1/2 hydrate, m.p. 208-209° C.
Reaction SMILES: C[N:2](C)[CH:3]=[N:4][C:5]([C:7]1[CH:8]=[C:9]2[N:15]([N:16]=1)[C:14]1[CH:17]=[C:18]([Br:21])[CH:19]=[CH:20][C:13]=1[O:12][CH2:11][CH2:10]2)=O.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>C(O)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:13]2[O:12][CH2:11][CH2:10][C:9]3[N:15]([N:16]=[C:7]([C:5]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:2]=[CH:3][N:4]=4)[CH:8]=3)[C:14]=2[CH:17]=1
Reactant: CN(C)C=NC(=O)c1cc2n(n1)-c1cc(Br)ccc1OCC2
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(Br)ccc1OCC2
Temperature: 110 °C
Yield: 75.6 %

Procedure:
A mixture of 9-bromo-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-2-carboxylic acid 1-dimethylaminomethylideneamide (1.27 g, 3.5 mmol), isopropylhydrazine hydrochloride (0.48 g, 4.37 mmol) and glacial acetic acid (6 mL) was heated at 110° C. for 6.5 h, then cooled and concentrated in vacuo. The resultant residue was dissolved in aqueous sodium bicarbonate and DCM and the phases were separated. The aqueous phase was extracted several times with DCM, the combined organic extracts dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 30 to 70% ethyl acetate in cyclohexane) to give 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (0.99 g, 76%). LCMS: RT=5.07 min, M+H+=374/376. 1H NMR δ (ppm) (CDCl3): 8.07 (1H, d, J=2.41 Hz), 7.96 (1H, s), 7.39 (1H, dd, J=8.63, 2.43 Hz), 7.08 (1H, d, J=8.63 Hz), 6.91 (1H, s), 5.73-5.65 (1H, m), 4.53 (2H, t, J=5.91 Hz), 3.18 (2H, t, J=5.91 Hz), 1.60 (6H, d, J=6.62 Hz)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][CH:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16]>ClCCl>[CH3:14][CH:15]([S:17]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:19])=[O:18])[CH3:16]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of piperazine (1 g) and triethylamine (1.78 mL) in dichloromethane (20 mL) at 0° C. was added dropwise 2-propanesulfonyl chloride (1.30 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (20 mL) and extracted into dichloromethane (2×40 mL). The combined organic layers were washed with saturated aqueous brine solution (2×40 mL), dried (MgSO4) and concentrated to afford 1-(propane-2-sulfonyl)-piperazine as a white solid (1.87 g, 84%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:7][CH:6]=1.[H-].[Na+]>>[N:10]1[C:9]2[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]=2[CH:7]=[CH:6][C:5]=1[CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: NCCCCc1ccc(CCCN)nc1
Agent: [H-]
Agent: [Na+]
Product: NCCCc1ccc2c(n1)NCCCC2
Yield: 26.9 %

Procedure:
A mixture of 3-5 (3.0 g, 14.5 mmol) and NaH (1.7 g of a 60% weight dispersion in mineral oil, 47 mmol) in xylenes (100 mL) was purged with argon for 30 min, and then heated at reflux for 72 hours. The mixture was cooled, quenched with ethanol, diluted with 10% aqueous potassium carbonate and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated to an oil. The residue was chromatographed on silica gel (15:10:1:1 EtOAc/EtOH/NH4OH/H2O) to give 800 mg of 3-6 as a yellow oil.
Reaction SMILES: [C:1]([N:5]([CH3:29])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=1)=[CH:19][C:18]([NH2:21])=[C:17]([O:22][CH3:23])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[C:1]([N:5]([CH3:29])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH:9]=1)=[CH:19][C:18]([NH:21][C:40](=[O:41])[CH2:39][O:38][CH3:37])=[C:17]([O:22][CH3:23])[CH:16]=3)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)cc(C(=O)N(C)C(C)(C)C)n1CC2
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1cc2c(cc1OC)CCn1c(C(=O)N(C)C(C)(C)C)cc(-c3cccs3)c1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product of example 95 (30 mg), triethylamine (10.2 μl) and methoxyacetyl chloride (6.7 μl) was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (0→90% acetonitrile; system 1).