Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[CH:6][CH:7]=1.[N:29]#[C:30]Br.[OH-].[Na+]>ClCCl.CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[C:30]([NH2:29])=[N:28][C:4]=2[CH:3]=1
Reactant: N#CBr
Reactant: COc1ccc(COc2ccc(CNc3ccc(I)cc3N)cc2OC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
To a stirred suspension of 4-iodo-N1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)benzene-1,2-diamine (3.82 g, 7.77 mmol) in dichloromethane (40 mL) and methanol (20 mL) was added cyanogen bromide solution (5.0 M in acetonitrile, 7.8 mL, 38.87 mmol). The resulting brown reaction mixture was allowed to stir at room temperature. After 18 h, the mixture was treated with 1N sodium hydroxide solution (50 mL) and allowed to stir. After 30 min, the phases were separated, and the aqueous phase was extracted with chloroform. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 5.26 g of a brown semi solid. Chromatographic purification (Combi-Flash, 80 g SiO2 column, 5-10% methanol/dichloromethane elute) afforded 2.78 g (69%) of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-2-amine as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:14](Br)=[C:13]([N+:16]([O-:18])=[O:17])[C:12]([Br:19])=[N:11]1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:14]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:13]([N+:16]([O-:18])=[O:17])[C:12]([Br:19])=[N:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCn1nc(Br)c([N+](=O)[O-])c1Br
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Yield: 67.2 %

Procedure:
A mixture of [2-(3,5-dibromo-4-nitropyrazol-1-yl)ethyl]carbamic acid tert-butyl ester (3.5 g; 8.45 mmol), EtOH (100 ml) and benzylamine (12.9 g, 117 mmol) was heated at reflux for 1.5 h. The reaction medium was concentrated as much as possible under reduced pressure. The residue was taken up in DCM (100 ml) and the organic phase was washed with water (5×50 ml) until all excess benzylamine had been removed and was then dried over Na2SO4. The organic solvent was evaporated under reduced pressure to give the [2-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)ethyl]carbamic acid tert-butyl ester (2.5 g, 67%) in the form of a pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH3:34])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]1[C@@H:9]([NH:16][C:17]([C:19]2[S:20][C:21]([CH3:34])=[C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[C:31]([Cl:33])[CH:30]=[N:29][C:28]=34)[CH:23]=2)=[O:18])[C:10]([F:15])([F:14])[CH2:11][CH2:12][CH2:13]1
Reactant: Cc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(Cl)cnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1sc(C(=O)N[C@@H]2[C@H](N)CCCC2(F)F)cc1-c1cnn2cc(Cl)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.3 %

Procedure:
To tert-butyl-[(1R,2R)-2-({[4-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-5-methylthiophen-2-yl]carbonyl}amino)-3,3-difluorocyclohexyl]carbamate (3.36 g, 6.39 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL, 130 mmol) and stirred for 16 h at ambient temperature. The reaction was evaporated to dryness, partitioned dichloromethane and saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane 3×. The organic layers were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (2.46 g, 5.77 mmol). LRMS (APCI) calc'd for (C18H18ClF2N5OS) [M+H]+, 426.1; found 426.0. 1H NMR (CDCl3, 500 MHz) δ 8.74 (s, 1H), 8.48 (s, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 6.98 (d, J=9.3, 1H), 4.46 (d, J=25.3, 1H), 3.34 (m, 1H), 2.57 (s, 3H), 2.18 (m, 1H), 1.67-1.90 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[C:6]=2[N:22]=1.[CH3:23][NH:24][C:25]1[N:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[N:26]=1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:30]3[CH:31]=[C:32]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([NH:24][CH3:23])[N:34]=[CH:33]4)=[N:22][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Product: CNc1ncc2cc(-c3cnc4c(n3)N(Cc3c(F)ccc(F)c3Cl)CCCN4)ccc2n1

Procedure:
The entitled compound can be prepared from 2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine and N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-quinazolin-2-amine as described in example 1 or 30.
Reaction SMILES: [C:1]([NH:20][C@H:21]([C:25]([O:27][CH3:28])=[O:26])[C@@H:22]([CH3:24])[OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>CCOCC.C(OCC)(=O)C.C1COCC1>[C:29]([O:23][C@@H:22]([CH3:24])[C@@H:21]([C:25]([O:27][CH3:28])=[O:26])[NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](C)OC(=O)c1ccccc1
Temperature: 0 °C
Yield: 25.9 %

Procedure:
A 500-mL, round-bottomed flask was charged with methyl N-trityl-L-threoninate (3.75 g, 10.0 mmol), benzoic acid (2.44 g, 20.0 mmol) and triphenylphosphine (5.24 g, 20.0 mmol). Anhydrous THF (50 mL) was added and the solution was cooled to 0° C. under N2 with stirring. A 40% solution of diethylazodicarboxylate in toluene (9.06 mL, 20.0 mmol) was added dropwise and the reaction mixture was allowed to warm to ambient temperature overnight. The reaction mixture was treated with 50 mL of ethyl acetate and 50 mL of saturated aqueous NaHCO3 solution. The layers were separated and the organic portion was washed successively with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow syrup. The yellow syrup was dissolved in 25 mL of Et2O and then treated with hexanes until a white precipitate formed. The solid was removed by filtration and the filtrate was concentrated to give a yellow oil. Chromatography (SiO2, 33-100% CH2Cl2/hexanes) gave 1.24 g of methyl O-benzoyl-N-trityl-L-allothreoninate as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:24][CH2:25]2)=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
1-(N-t-Butoxycarbonylamino)-2-aminobenzene (Method 17, 3.1 g, 14.7 mmol) was added to a stirred solution of 4-(1-t-butoxycarbonylpiperidin-4-yl)benzoic acid (4.1 g, 13.4 mmol) in DMF (50 ml) and the mixture stirred at ambient temperature for 10 minutes. 4-(4,6-dimethoxy-1,3,5-triazinyl-2-yl)-4-methylmorpholinium chloride (Method 18, 4.45 g, 16.1 mmol) was added and the mixture stirred at ambient temperature for 24 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (100 ml) and washed with water. The organics were dried over magnesium sulfate, filtered and evaporated. The resultant gum was purified by flash chromatography using 1% methanol/dichloromethane to give the title compound as a foam (5.44 g, 82%); NMR Spectrum: (DMSO-d6) 1.41 (s, 9H), 1.43 (s, 9H), 1.54 (m, 2H), 1.77 (m, 2H), 2.79 (m, 3H), 4.08 (m, 2H), 7.15 (m, 2H), 7.40 (d, 2H), 7.52 (m, 2H), 7.87 (d, 2H), 8.60 (br, 1H), 9.74 (br, 1H), Mass Spectrum: (M+H+-Boc) 396.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]([CH3:15])([CH3:14])[C:8]([F:13])([F:12])[CH2:9][CH2:10][OH:11])[CH3:5])[CH3:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:11][CH2:10][CH2:9][C:8]([F:12])([F:13])[C:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])([CH3:15])[CH3:14])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)OC(C)(C)C(F)(F)CCO
Solvent: c1ccncc1
Product: CCOC(C)OC(C)(C)C(F)(F)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 1.00 g (0.0044 mol) of 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol, 4 mL of pyridine and 1.27 g (0.0066 mol) of p-toluenesulfonyl chloride was stirred at 0° C. for 18 hr. The mixture was quenched with ice chips. The mixture was then poured into water and extracted with methylene chloride. The organic phase was sequentially washed with 10% aqueous sulfuric acid and saturated aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield oily 4-(1-ethoxyethoxy)-3,3-difluoro-4-methyl-1-pentanol 1-(4-methylbenzenesulfonate).
Reaction SMILES: P(=[S:5])([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[OH:10][N:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17](=[NH:20])[CH2:18][Cl:19])[CH2:13]1.Cl>O>[ClH:19].[OH:10][N:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17](=[NH:20])[CH2:18][SH:5])[CH2:13]1
Reactant: N=C(CCl)N1CCC(=NO)C1
Reactant: [O-]P([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(CS)N1CCC(=NO)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
945 mg of trisodium phosphorothioate were added to a solution of 1.05 g of 2-(3-hydroxyiminopyrrolidin-1-yl)-2-iminoethylchloride hydrochloride in 6.4 ml of water, cooled with ice-water, and the mixture was stirred at room temperature for about one hour. 5.2 ml of 1N hydrochloric acid were added, and the mixture was heated at 65° C. for 30 minutes and then concentrated under reduced pressure. The concentrate was mixed with 5.2 ml of methanol, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. Anhydrous ether was added to the concentrate, and the precipitated crystals were collected by filtration and washed with ether, giving 670 mg of 2-(3-hydroxyiminopyrrolidin-1-yl)-2-iminoethylmercaptan hydrochloride.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([OH:9])[CH2:2]2.C[O:11][C:12]([C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O>C1(C)C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:12]([C:14]1([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:11])[CH2:2]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)C1(c2ccccc2)CCCCCC1
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A solution of (R)-(3)-quinuclidinol (10.13 g) and 1-phenyl-cycloheptanecarboxylic acid methyl ester (Example 14d) (9.25 g) in toluene (90 mL) was heated to reflux with a Dean-Stark trap for 30 min. The reaction mixture was allowed to cool to room temperature and the trap was removed. Sodium hydride (60% dispersion in mineral oil) (3.19 g) was added portionwise under nitrogen and the reaction mixture was heated to reflux overnight under nitrogen. The reaction mixture was cooled in an ice bath and diluted with ethyl acetate (200 mL) and water (200 mL). The mixture was filtered and the layers separated. The aqueous layer was extracted with ethyl acetate (2×250 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to give the crude product which was purified by silica gel chromatography eluting with EtOAc containing 1% triethylamine to give the sub-titled compound as a colourless oil (7.63 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:9]([NH:15][C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[N-:55]=[N+:56]=[N-:57].[Na+]>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[C:9]([N:15]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:57][N:56]=[N:55]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(NC(=O)c1ccccc1)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Reaction time: 0.75 h
Yield: 69.4 %

Procedure:
To a suspension of 5.8 g (14 mmoles) of ethyl 3,3-bis-(4-fluorophenyl)-2-(benzoylamino)-2-propenoate and 11.2 g of triphenylphosphine in 150 mL of dry acetonitrile at room temperature was added dropwise 8.3 mL of carbon tetrachloride. The pale suspension was stirred for 45 minutes. To this clear orange solution was added 2.8 g of sodium azide and 1 g of tetra n-butyl ammonium bromide and stirring was continued. The orange suspension soon became pale with the formation of a white precipitate. After three hours, the mixture was filtered and the solution was concentrated under reduced pressure. More triphenylphosphine oxide was removed and the desired product was purified by crystallizations from ethyl acetate-hexanes to give 4.2 g (69%) of the title compound; m.p.=148.6-150.1° C.
Reaction SMILES: [CH:1]1([CH:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C@H:7]([CH3:19])[CH2:6]2)[CH2:3][CH2:2]1.[ClH:30]>>[ClH:30].[ClH:30].[CH:1]1([CH:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=2)[N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=[O:13])[C@H:7]([CH3:19])[CH2:6]2)[CH2:3][CH2:2]1
Reactant: C[C@@H]1CN(C(c2cccc(C(F)(F)F)c2)C2CC2)CCN1CC(=O)OC(C)(C)C
Agent: Cl
Product: C[C@@H]1CN(C(c2cccc(C(F)(F)F)c2)C2CC2)CCN1CC(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
To tert-butyl 2-((R)-4-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetate (350 mg, 0.849 mmol) in 150 mL flask was added 3 mL of 37% HCl and the resulting solution was stirred at 50° C. for 3 h. After HPLC-MS showed complete conversion, the solvent was evaporated to dryness under high vacuum to give 2-((R)-4-(cyclopropyl(3-(trifluoromethyl)phenyl)methyl)-2-methylpiperazin-1-yl)acetic acid dihydrochloride (290 mg, 79.6% yield) as a white solid. MS (ESI, pos. ion) m/z: 357 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:10].CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[C:11]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:10]
Reactant: COC(OC)N(C)C
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Solvent: CN(C)C=O
Product: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Yield: 100 %

Procedure:
A solution of 4-chlorobenzyl 2,4-dichlorophenyl ketone (4.5 g, 14.4 mmol) and dimethylformamide dimethylacetal (7.7 mL, 58 mmol) in DMF (60 mL) was heated at 75° C. for 20 h. The volatiles were removed in vacuo to provide the crude 3-dimethylamino-1-(2,4-dichlorophenyl)-2-(4-chlorophenyl)prop-2-en-1-one (14.4 mmol assumed) which was used directly in the next step. HPLC/MS: 354 (M+1), 356 (M+3); Rt=3.47 min
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C(OCC)(=O)C>[N:31]1([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:9]3[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:1])=[C:3]([CH:8]=3)[C:4]([O:6][CH3:7])=[O:5])=[CH:26][CH:27]=2)[CH:35]=[CH:34][CH:33]=[N:32]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Reactant: BrCc1ccc(-n2cccn2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.60 g) in DME (12.0 mL) were added 1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.51 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.08 g) and 2 mol/L aqueous sodium carbonate solution (1.96 mL), and the mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.54 g).
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:19][C:20](=[O:21])[C:15]3=[C:14]([CH3:28])[NH:13]2)[CH:8]=[CH:9][CH:10]=1)#[N:4].OO.C(O)(=[O:33])C>O>[C:3]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]2[C:16]3=[N:17][C:18]([C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)=[N:19][C:20](=[O:21])[C:15]3=[C:14]([CH3:28])[NH:13]2)[CH:8]=[CH:9][CH:10]=1)(=[O:33])[NH2:4]
Reactant: CC(=O)O
Reactant: Cc1[nH]n(Cc2cccc(C#N)c2)c2nc(-c3ccncc3)nc(=O)c1-2
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1[nH]n(Cc2cccc(C(N)=O)c2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A mixture of potassium hydroxide (0.7 g, 9.9 mmol) in water (75 ml) was stirred in an ice-bath for 30 minutes and 1-(3-cyanophenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one (1.1 g, 3.3 mmol), followed by 30% hydrogen peroxide (1.7 ml, 16.5 mmol) were added. The mixture was slowly warmed to room temperature and stirred for 24 hours. The mixture was chilled in an ice-bath and neutralized with acetic acid. The product was collected by filtration and washed with water, ethanol and ether. The product was recrystallized from DMF to afford 0.87 g (73%) of 1-(3-carbamoylphenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as an off-white powder, m.p. >300° C. when dried at 120° C. for 24 hours in high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8](C1C=CC=CC=1)=[C:7]2[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>>[CH2:7]([C:8]1[N:9]=[N:10][C:11]2[C:6]([C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[Cl:25])[CH:19]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[C:6]1[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: Oc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: Clc1ccccc1CBr
Product: Clc1ccccc1COc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenol and 2-chlorobenzyl bromide according the procedure of Example 14. MS (ES) m/z 470.8.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][C@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)=[CH:9][C:8]=1[C:22]([F:25])([F:24])[F:23].CN([CH:29]=[O:30])C>C1COCC1>[CH3:18][C:15]1([CH3:19])[O:14][C@@H:13]([CH2:12][O:11][C:10]2[CH:20]=[CH:21][C:7]([CH:29]=[O:30])=[C:8]([C:22]([F:25])([F:24])[F:23])[CH:9]=2)[CH2:17][O:16]1
Reactant: CN(C)C=O
Reactant: CC1(C)OC[C@H](COc2ccc(Br)c(C(F)(F)F)c2)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OC[C@H](COc2ccc(C=O)c(C(F)(F)F)c2)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A solution of nBuLi in hexanes (6.76 mL, 1.6 M in hexanes) was added dropwise to a solution of (S)-4-((4-bromo-3-(trifluoromethyl)phenoxy)methyl)-2,2-dimethyl-1,3-dioxolane (127; 3.20 g, 9 mmol) in THF (50 mL) at −78° C. over a period of 30 min. After stirring for additional 10 min, DMF (1.4 mL) was added dropwise over a period of 10 min. The resulting reaction mixture was warmed to room temperature and stirred for 30 min. It was then quenched with water and extracted by EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:EtOAc=50:1) to afford (S)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-(trifluoromethyl)benzaldehyde 128 (2.3 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1nc(-c2ccc(Cl)cc2)co1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-oxazoleproprionic acid (0.5 g), benzyl bromide (0.25 ml), potassium carbonate (0.33 g) and dimethylformamide (DMF)(10 ml) was stirred for 3 hours at room temperature. The reaction mixture was poured into water to obtain crystals of benzyl 4-(4-chlorophenyl)-2-oxazolepropionate (0.664 g, 98%). Recrystallization from ether-hexane gave colorless prism crystals of mp 66°-67° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])([O-])=O.[Na+].[Na+].[CH3:10][S:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>O.CO>[OH:3][NH:2][C:16](=[NH:17])[C:15]1[CH:18]=[CH:19][C:12]([S:11][CH3:10])=[CH:13][CH:14]=1
Reactant: NO
Reactant: CSc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CSc1ccc(C(=N)NO)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
Hydroxylamine hydrochloride (104 mg, 1.5 mmol) and Na2CO3 (80 mg, 0.75 mmol) were dissolved in 0.5 mL of water. A solution of 4-methylsulfanyl-benzonitrile (223 mg, 1.5 mmol) in 4 mL of methanol was added and the combined solution was stirred at RT for about 48 h. After removal of the solvent, the precipitate was washed with water, filtered and dried to give N-hydroxy-4-methylsulfanyl-benzamidine (203 mg, 75%) which was used without further purification.