Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.Cl.[NH2:36][OH:37].[OH-].[Na+].O>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](/[C:12](=[N:36]/[OH:37])/[NH2:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:15])=[CH:7]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C#N)n4)ncnc32)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(/C(N)=N/O)n4)ncnc32)cc1
Temperature: 25 °C

Procedure:
A mixture of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl) isoquinoline-1-carbonitrile 29 (600 mg, 1.28 mmol, 1.0 eq), hydroxylamine hydrochloride (269 mg, 3.84 mmol, 3 eq) and NaOH (154 mg, 3.84 mmol, 3 eq) in EtOH (15 mL) was stirred at reflux 4 h. The mixture was cooled to RT, poured into water (100 mL) and then extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product (S,Z)-8-chloro-N′-hydroxy-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboximidamide 30.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:11](OC)(OC)OC.[N-:18]=[N+:19]=[N-:20].[Na+]>C(O)(=O)C>[N:1]1([C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:11]=[N:20][N:19]=[N:18]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(OC)OC
Reactant: Nc1ccccc1C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1-n1cnnn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2-aminobenzoic acid (6.0 g, 0.044 mol), trimethyl orthoformate (14.2 ml, 0.13 mol) and sodium azide (8.4 g, 0.13 mol) in glacial acetic acid (150 ml) was stirred at room temperature for 2 h. Filtration and concentration from toluene gave 2-Tetrazol-1-yl-benzoic acid; 1H NMR (CD3OD, 400 MHz) δ 9.47 (s, 1H), 8.19 (dd, 1H, J=7.7 Hz, J=1.6 Hz), 7.79 (m, 2H), 7.61 (dd, 1H, J=7.7 Hz, J=1.5 Hz).
Reaction SMILES: [F:1][C:2]([P:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])(=O)[OH:9])([F:7])[C:3]([F:6])([F:5])[F:4].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[F:1][C:2]([P:8]([Cl:19])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:9])([F:7])[C:3]([F:6])([F:5])[F:4]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=P(O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Product: O=P(Cl)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
30.0 g (99.3 mmol) of bis(pentafluoroethyl)phosphinic acid and 20.7 g (99.4 mol) of phosphorus pentachloride are mixed with one another and stirred at room temperature for 30 minutes. Bis(pentafluoroethyl)phosphinyl chloride is isolated from the reaction mixture by fractional distillation. The boiling point is 118-119° C. 23.1 g of a colourless liquid are obtained. The yield is 72.6% of the calculated yield of bis(pentafluoroethyl)phosphinyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:51]=[C:52]([CH:56]=[CH:57][CH:58]=1)[CH:53]([OH:55])[CH3:54]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:55][CH:53]([C:52]2[CH:56]=[CH:57][CH:58]=[C:50]([F:49])[CH:51]=2)[CH3:54])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cccc(F)c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4cccc(F)c4)cc3)c2cc1OC
Temperature: 25 °C
Yield: 73.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (97 mg) was added to toluene/triethylamine=10/1 (10 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (150 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-fluoro-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (111 mg, yield 68%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]#[N:17])=[CH:4][CH:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>>[C:16]([C:10]1[CH:11]=[C:12]([NH:15][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([N:22]3[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]3)=[CH:26][CH:27]=2)[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N:22]3[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]3)=[CH:33][CH:32]=2)=[CH:3][CH:4]=1)#[N:17]
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: N#Cc1cc(N)ccc1Nc1ccc(N)cc1
Product: N#Cc1cc(NC(=O)c2ccc(N3CCC(O)CC3)cc2)ccc1Nc1ccc(NC(=O)c2ccc(N3CCC(O)CC3)cc2)cc1

Procedure:
Compound 834 was prepared according to the procedure described in Scheme IV from N1-(4-aminophenyl)-2-cyanobenzene-1,4-diamine and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C37H38N6O4: 631.30; found: 631.11.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([O:29][CH3:30])[CH2:20][NH:21][S:22]([CH2:25][CH2:26][CH2:27][I:28])(=[O:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[S:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>>[I-:28].[CH2:1]([O:17][CH2:18][CH:19]([O:29][CH3:30])[CH2:20][NH:21][S:22]([CH2:25][CH2:26][CH2:27][C:32]1[S:31][CH:35]=[CH:34][NH+:33]=1)(=[O:24])=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: c1cscn1
Reactant: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCOCC(CNS(=O)(=O)CCCc1[nH+]ccs1)OC
Product: [I-]
Yield: 66 %

Procedure:
A solution of 600 mg (1.07 mM) of 1-hexadecyloxy-3-(3-iodopropylsulfonylamino)-2-methoxypropane in 5 ml of thiazole is stirred at 50° C. for 6 hours. After thiazole is evaporated, the residue is purified by the column chromatography on silica gel with a chloroform-methanol (5:1 to 3:1) mixture as an eluent. The product is recrystallized from ether-dichloromethane to give 450 mg (0.70 mM) of 1-hexadecyloxy-2-methoxy-3-(3-thiazoliopropylsulfonylamino)propane iodide Ia11 in 66% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:23][C:24](=[O:34])[C:25]1[C:30]([Cl:31])=[CH:29][C:28]([OH:32])=[CH:27][C:26]=1[Cl:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:8][CH:7]=1.[C:36]([O:40][C:41]([NH:43][CH2:44][CH2:45][CH2:46]Br)=[O:42])([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.CC(C)=O>[CH3:1][O:2][C:3](=[O:35])[C@@H:4]([NH:23][C:24](=[O:34])[C:25]1[C:26]([Cl:33])=[CH:27][C:28]([O:32][CH2:46][CH2:45][CH2:44][NH:43][C:41]([O:40][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:42])=[CH:29][C:30]=1[Cl:31])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:22])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(OCCCNC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a mixture of (S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-(2,6-dichloro-4-hydroxy-benzoylamino)propionic acid methyl ester (5.05 g, 9.07 mmol), 3-tert-butoxycarbonylaminopropyl bromide (2.59 g, 10.89 mmol), and potassium carbonate (3.77 g, 27.29 mmol) were added DMF (66 mL) and acetone (132 mL) at room temperature. Then, the resulting suspension was heated to reflux for 15 h at which time TLC analysis indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with water and the organic compound was extracted into ethyl acetate (2×150 mL). The combined organic layer was washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the crude residue which was purified by ISCO (150 g) column chromatography to obtain 5.75 g (89%) of (S)-2-[4-(3-tert-butoxycarbonylaminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester as a white solid. ES(+)-HRMS m/e calcd. for C32H33Cl4N3O7 (M+Na)+ 734.0965, obsd. 734.0961.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:4]([OH:5])[C:3]=1[OH:11].Br[CH2:13]Br.[F-].[K+].O>CN(C=O)C>[Br:1][C:2]1[C:3]2[O:11][CH2:13][O:5][C:4]=2[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(Br)c(O)c1O
Reactant: BrCBr
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c2c1OCO2
Temperature: 110 °C

Procedure:
3-Bromo-6-methoxycatechol (23.4 g) was dissolved in DMF (150 ml), and dibromomethane (15.4 ml) and potassium fluoride (31.1 g) were added thereto, followed by heating at 110° C. for 6 hours with stirring. After being allowed to stand for cooling, water was added to the mixture followed by extraction with ether. The organic layer was washed with an aqueous solution of sodium hydroxide, with water, and with a saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/1) to give Compound IIbj-a (5.6 g, 40%) as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([OH:16])=O)[CH:10]=2)[C:5]1=[O:17])C=C.Cl.[F:19][C:20]([F:40])([F:39])[C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=2)[NH2:28])=[CH:23][CH:22]=1.CN1C(=O)C2C(=CC=C(C(O)=O)C=2)C1=O>>[CH3:1][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([NH:28][C@@H:27]([C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:40])([F:19])[F:39])=[CH:22][CH:23]=3)[C:29]3[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:32]=[CH:31][N:30]=3)=[O:16])[CH:10]=2)[C:5]1=[O:17]
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Reactant: C=CCN1C(=O)c2ccc(C(=O)O)cc2C1=O
Agent: CN1C(=O)c2ccc(C(=O)O)cc2C1=O
Agent: Cl
Product: CN1C(=O)c2ccc(C(=O)N[C@@H](c3ccc(C(F)(F)F)cc3)c3ncccc3C(F)(F)F)cc2C1=O

Procedure:
2-Allyl-1,3-dioxoisoindoline-5-carboxylic acid was then coupled with Intermediate 1 using the general methods described above for the amide coupling reaction (Table 2) to provide the title compound, (S)-2-methyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.95 (d, J=4.7 Hz, 1H), 8.44 (d, J=7.5 Hz, 1H), 8.31-8.20 (m, 2H), 8.08 (d, J=8.2 Hz, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.65-7.42 (m, 5H), 6.88 (d, J=7.6 Hz, 1H), 3.22 (s, 3H). MS (ESI pos. ion) m/z: 508.1 (M+H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)C.O.[NH2:18][NH2:19]>>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[CH:6]=[CH:5][C:4](=[O:3])[NH:18][N:19]=1
Reactant: NN
Reactant: CCOC(=O)C(O)CC(=O)c1ccccn1
Solvent: O
Product: O=c1ccc(-c2ccccn2)n[nH]1

Procedure:
A solution of 2-hydroxy-4-oxo-4-pyridin-2-ylbutyric acid ethyl ester (2.910 g, 13.000 mmol) in 20 mL of 1-buanol was treated with 0.65 mL (1:1 ratio) of hydrazine hydrate, and the mixture was refluxed overnight. The solvents were evaporated to dryness to give 2.000 g (11.500 mmol) of 6-pyridin-2-yl-2H-pyridazin-3-one as a dark solid, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].[CH:20](OC(=O)C)=[O:21]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH:20]=[O:21])[C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CC(=O)OC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=N[N+](=O)[O-])N(C=O)Cc1ccc(Cl)nc1
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To a mixture of 0.26 g of 1-(6-chloro-3-pyridylmethyl)3,3-dimethyl-2-nitroguanidine (Compound No. 6) and 3 ml of dry THF was added 0.08 g of 60% sodium hydride (in mineral oil) in a water bath of 20° C., followed by stirring for 30 minutes. A solution of 0.26 g of acetic formic anhydride in 0.5 ml of THF was added to the reaction mixture in one minute, and then stirred for 12 hours after the bath was removed. After adding 0.5 ml of acetic acid, the reaction mixture was concentrated. The residue was purified by a column chromatography [developing solvent: dichloromethanemethanol (30:1)] to obtain 0.10 g of 1-(6-chloro-3-pyridylmethyl)-1-formyl-3,3-dimethyl-2-nitroguanidine (Compound No. 22) as a syrup. 1H NMR(CDCl3): 3.03(6H,s), 4.70(2H,s), 7.36(1H,d,J=8.7 Hz), 7.74(1H,dd,J=8.7, 2.7 Hz), 8.40(1H,d,J=2.7 Hz), 8.44(1H,s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([NH2:6])[CH3:5].[CH3:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[C:13]([CH3:16])[C:14]=1[F:15].C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:7])[C@H:4]([NH:6][C:11]1[CH:12]=[C:13]([CH3:16])[C:14]([F:15])=[C:9]([CH3:8])[CH:10]=1)[CH3:5]
Reactant: Cc1cc(B(O)O)cc(C)c1F
Reactant: COC(=O)[C@@H](C)N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 39 h
Yield: 37.5 %

Procedure:
To a suspension of (R)-2-amino-propionic acid methyl ester (0.200 g, 1.940 mmol), 3,5-dimethyl-4-fluorophenylboronic acid (0.652 g, 3.880 mmol), Cu(OAc)2 (0.388 g, 2.134 mmol), and molecular sieves 4 Å (1.456 g) in 15 mL of dichloromethane, was added triethylamine (0.54 mL, 3.880 mmol). After stirring at room temperature under O2 for 39 h, the reaction mixture was filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 0-30% ethyl acetate/hexanes to give the title compound as brown oil (0.164 g, 38% yield). LC-MS: tR=8.1 min; m/z 226 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([OH:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.O[C@H:15]([C@H:17]1[CH2:21][N:20]([C@@H:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:23])[C:19](=[O:32])[CH2:18]1)[CH3:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:13][C@@H:15]([C@@H:17]2[CH2:18][C:19](=[O:32])[N:20]([C@@H:22]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[CH3:23])[CH2:21]2)[CH3:16])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1
Reactant: N#Cc1cnn2cc(Cl)nc(O)c12
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)O)CC2=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cn4ncc(C#N)c34)CC2=O)cc1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
6-chloro-4-hydroxypyrazolo[1,5-a]pyrazine-3-carbonitrile (122 mg, 0.627 mmol) was dissolved in THF (1 mL). (R)-4-((8)-1-hydroxyethyl)-1-4R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.05 (255 mg, 0.97 mmol) and PPh3 (255 mg, 0.97 mmol) were added followed by diethyl azodicarboxylate (0.16 mL, 1.0 mmol). The resulting mixture was heated to 45° C. and was stirred for 45 min. The mixture was then cooled to r.t., let stand overnight, and concentrated onto 2 g silica gel. Purification by silica gel chromatography (25-100% EtOAc in hexanes) provided 6-chloro-4-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)pyrazolo[1,5-a]pyrazine-3-carbonitrile (5.64). LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23ClN5O3: 440.1; found: 439.8.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[O:14])[CH:6]=[C:5]([CH3:28])[N:4]=1>[Pd].CO>[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[O:14])[CH:6]=[C:5]([CH3:28])[N:4]=1
Reactant: Cc1cc(Nc2cccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(Nc2cccc(C(=O)Nc3ccc(N)cc3)c2)nc(N)n1
Reaction time: 0.17 h
Yield: 58.2 %

Procedure:
To a suspension of compound B2 (1.41 g, 3.51 mmol) in (MeOH) 30 (mL) was added 10% Pd/C (20 mg) and hydrogenated under 45 Hg mm for 5 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to dryness. The residue was dissolved in a small volume of MeOH then 1 ml of 1.25M HCl in MeOH was added, stirred 10 min and evaporated to dryness. The residue was recrystallized from MeOH/EtOAc to give B3 (758 mg, 58%); m.p. (MeOH/EtOAc); 1H NMR [(CD3)2SO] δ12.70 (br, 1 H, NH), 10.83 (br s, 1 H, NH), 10.43 (s, 1 H, NH), 9.70 (v br, 2 H, NH2), 8.05-7.84 (br m, 2 H, ArH), 7.85-7.75 (m, 4 H, ArH & NH2), 7.55 (t, J=7.9 Hz, 1 H, ArH), 7.28 (d, J=8.7 Hz, 2 H, ArH), 6.24 (s, 1 H, ArH), 2.30 (s, 3 H, CH3); mass APCI+ 335.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH:32]([CH3:34])[CH3:33])=[C:25]([O:35][CH3:36])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[Cl:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]([C:45]2[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH:54]([CH3:56])[CH3:55])=[C:47]([O:57][CH3:58])[CH:46]=2)[CH:40]=1>>[ClH:37].[ClH:37].[ClH:37].[CH3:30][O:29][C:27]1[CH:28]=[C:23]([C:19]2[CH:18]=[C:17]([CH2:16][N:13]3[CH2:12][CH2:11][CH:10]([N:9]([CH2:38][C:39]4[CH:44]=[CH:43][N:42]=[C:41]([C:45]5[CH:50]=[C:49]([O:51][CH3:52])[C:48]([O:53][CH:54]([CH3:56])[CH3:55])=[C:47]([O:57][CH3:58])[CH:46]=5)[CH:40]=4)[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:15][CH2:14]3)[CH:22]=[CH:21][N:20]=2)[CH:24]=[C:25]([O:35][CH3:36])[C:26]=1[O:31][CH:32]([CH3:33])[CH3:34]
Reactant: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC(C)C)c(OC)c4)c3)CC2)cc1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC(C)C
Product: COc1ccc(N(Cc2ccnc(-c3cc(OC)c(OC(C)C)c(OC)c3)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC(C)C)c(OC)c4)c3)CC2)cc1
Product: Cl

Procedure:
4-(p-anisidino)-1-[[2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridin-4-yl]methyl]piperidine (307 mg) and 4-chloromethyl-2-(3,5-dimethoxy-4-isopropoxyphenyl)pyridine (201 mg) were condensed in the same manner as described in Example 9. A free base obtained was converted to a trihydrochloride giving the title compound as yellow powder.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([CH2:20][CH2:21][CH2:22][N:23](C)[CH3:24])[C:10]=2[CH:26]=1)(=[O:5])=[O:4].N#CN.C(O)(=O)C.Cl>O>[CH3:27][N:2]([CH3:1])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[C:10]=2[CH:26]=1)(=[O:4])=[O:5]
Reactant: CN(C)CCCC1c2ccccc2C=Cc2ccc(S(=O)(=O)N(C)C)cc21
Agent: Cl
Agent: N#CN
Solvent: CC(=O)O
Solvent: O
Product: CNCCCC1c2ccccc2C=Cc2ccc(S(=O)(=O)N(C)C)cc21

Procedure:
3-Dimethylsulfamoyl-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene is converted to the corresponding cyanamide by following the procedure of Example 17, Step B. The cyanamide (0.28 g., 0.00071 mole) together with 2.8 ml. of glacial acetic acid, 2.0 ml. of water and 0.4 ml. of concentrated hydrochloric acid is heated to refluxing for 29 hours. The reaction mixture is evaporated to dryness under reduced pressure and the residue is dissolved in water. The aqueous solution is made alkaline with sodium hydroxide and the oily base that separates is extracted into ether. The washed and dried ether extract is evaporated under reduced pressure, leaving 3-dimethylsulfamoyl-5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene as an oil weighing 170 mg. The base may be converted to the hydrogen oxalate salt by dissolution in absolute ethanol, addition of an equimolar quantity of oxalic acid dissolved in ethanol, and precipitation by the addition of ether. After repeated recrystallizations from absolute ethanol and from isopropyl alcohol, the hydrogen oxalate melts at 133.5°-135.5°C., dec.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:10]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=[O+][O-].C1(P(=C[C:45]([O:47][CH3:48])=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][CH:19]([CH3:21])[CH3:20])[C@H:10]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])/[CH:11]=[CH:12]/[C:45]([O:47][CH3:48])=[O:46])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C[C@@H](OS(C)(=O)=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: O=[O+][O-]
Solvent: ClCCl
Product: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 30.6 %

Procedure:
A solution of 0.22 g (0.69 mmol) of the resultant compound of Example 32 in 15 ml of dichloromethane was cooled to -78° C. and treated with a stream of O3 in air until the blue color persisted. The solution was subsequently purged with air until the blue color was discharged, treated with 0.5 ml of dimethylsulfide, allowed to warm to ambient temperature over 40 min, and treated with 0.29 g (0.87 mmol) of methyl (triphenylphosphoranylidene)acetate. The resulting solution was stirred at ambient temperature for 4 h, concentrated in vacuo, partitioned between dichloromethane and water, dried over MgSO4, and concentrated. Silica gel chromatography using 30% ethyl acetate in hexane provided 0.08 g (31%) of the desired compound (Rf 0.17, 30% ethyl acetate in hexane). 1H NMR (CDCl3) δ 0.89 (d, J=7 Hz, 3 H), 0.93 (d, J=7 Hz, 3 H), 1.22 (m, 2 H), 1.44 (s, 9 H), 1.69 (m, 1 H), 3.06 (s, 3 H), 3.78 (s, 3 H), 3.92 (m, 1 H), 4.58 (br d, 1 H), 5.40 (m, 1 H), 6.16 (dd, J=15, 2 Hz, 1 H), 6.87 (dd, J=15, 6 Hz, 1 H). Mass spectrum: (M+H)+ =380.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].C(N(CC)CC)C>C(OCC)C>[O:15]([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1
Reactant: Oc1ccccc1Cl
Reactant: C#CC(=O)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C=COc1ccccc1

Procedure:
A solution of 5.77 mmol of ethyl propiolate in 20 ml ethyl ether is treated with 5.77 mmol 2-chlorophenol and 0.4 ml triethylamine (added slowly and with stirring). The reaction mixture is stirred overnight at RT, after which the solvent is removed under vacuum to yield ethyl 3-phenoxy-2-propenoate.