Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][C:15]=3[CH:22]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[K+]>C(O)C>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][C:15]=3[CH:22]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1ccc(-c2ccc3oc(C(=O)O)cc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cc(-c3ccc(O)cc3)ccc2o1
Reaction time: 0.5 h

Procedure:
A mixture of 10.4 g of 11 and 7.2 g of potassium hydroxide in 170 ml of ethanol was refluxed for 2 hours. The solvent was evaporated under reduced pressure. The residue was mixed with 200 ml of water, and the mixture was acidified to pH=2 with concentrated hydrochloric acid, stirred for 30 minutes and filtered. The solid was washed with water, dried under reduced pressure and mixed with tetrahydrofuran. The mixture was refluxed and filtered. The filtrate was concentrated, the residue was washed with ether and mixed with tetrahydrofuran. The mixture was filtered, the filtrate was concentrated to about one-fourth its volume and triturated with ether. The resulting solid was collected and dried under reduced pressure to give 16, mp: 297°-300° C.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].OC([N:11]1[C:20]2[C:15](=[C:16]([N+:21]([O-:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH2:12]1)CO.[C:24](OCC)(=[O:26])C>O1CCCC1.O>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][C:12]([CH:24]=[O:26])=[N:11]2)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc2c1C=CCN2C(O)CO
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c([N+](=O)[O-])cccc2n1
Reaction time: 20 h

Procedure:
2.99 g (14.0 mmol) of sodium periodate is added to a solution that consists of 1.64 g (7.0 mmol) of 1-(1,2-dihydroxyethyl)-5-nitroquinoline in 42 ml of tetrahydrofuran and 7.0 ml of water. After 20 hours at room temperature, ethyl acetate is added, and the organic phase is washed with saturated sodium chloride solution. After the organic phase is dried on sodium sulfate, after the solvent is removed, and after purification on silica gel with hexane-ethyl acetate (0-100%), 1.40 g (99% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:19])=[CH:9][C:10]([Cl:18])=[C:11]([CH:17]=1)[C:12]([N:14]=[C:15]=[O:16])=O)=[O:4].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH:30]C(OC(C)(C)C)=O)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:10]1[C:11]([C:12]2[NH:14][C:15](=[O:16])[N:29]([C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[N:30]=2)=[CH:17][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:21])([F:20])[F:1])=[C:8]([F:19])[CH:9]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)cc1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Yield: 45.2 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoyl isocyanate (Intermediate-69, 0.400 g), tert-butyl 2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.400 g), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.250 g of the desired product.
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[N:9]([CH3:13])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16](=[O:31])[C:17](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[C:18]([CH3:20])=O>>[CH3:14][O:15][C:16]([C:17]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:11]2[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][N:9]([CH3:13])[C:10]=2[NH:12][C:18]=1[CH3:20])=[O:31]
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: Cn1nc(C2CCCCC2)cc1N
Product: COC(=O)C1=C(C)Nc2c(c(C3CCCCC3)nn2C)C1c1cccc([N+](=O)[O-])c1

Procedure:
Starting from 3-cyclohexyl-1-methyl-5-pyrazolamine and methyl-2-(3-nitrobenzyliden)acetoacetate in equimolar proportions.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[F:26][C:2]([F:27])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:31]#[C:30][CH2:29][CH2:28][OH:32])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCCO
Product: OCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 3-butyn-1-ol were converted to yield 4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol as orange semisolid, MS: 347 (M).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](C)=[CH:5][CH:4]=1)[CH3:2].[CH2:10]=C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[CH3:10])[CH3:2]
Reactant: C=C
Reactant: CCc1ccc(C)cc1
Solvent: Cc1ccccc1
Product: CCc1ccccc1C

Procedure:
Data from these analyses are combined by computer program to give an overall material-balanced run result. Especially noted is the proportion of para-ethyltoluene in ethyltoluenes, PET/ET, and the ratio of toluene converted to theoretical toluene conversion if all ethylene fed reacted stoichiometrically with toluene to give ethyltoluene.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([Cl:23])=[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]2[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4].B(Br)(Br)Br>C(Cl)Cl>[Cl:23][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[N:8]2[C:7]=1[CH:12]=[CH:11][N:10]=[CH:9]2
Reactant: COC(=O)c1c(Cl)c2ccncn2c1Nc1ccc(I)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1c(Cl)c2ccncn2c1Nc1ccc(I)cc1F
Temperature: 0 °C
Yield: 115.9 %

Procedure:
To a solution of 5-chloro-7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid methyl ester (300 mg, 0.67 mmol) in DCM (6 mL) was added boron tribromide (0.65 mL, 6.7 mmol). The reaction was heated at reflux for 1 hour. The reaction mixture was cooled to 0° C. and carefully quenched by the addition of water (5 mL). The reaction mixture was diluted with aqueous hydrochloric acid (2 mL, 1M) and extracted with ethyl acetate (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo to give the product as a dark brown solid (335 mg, 115%). LCMS (Method B): RT=3.58 min, M+H+=432.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:28]=[C:27]([C:35](O)=O)[N:26]=2)[CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[CH3:13]>>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:25]2[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[N:28]=[C:27]([C:35]3[O:9][N:8]=[C:6]([C:5]4[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=4)[N:7]=3)[N:26]=2)[CH:18]=[CH:19][C:20]=1[C:21]([F:22])([F:23])[F:24])[CH3:13]
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(C(=O)O)n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3nc(-c4ccc(N)nc4)no3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.15 g, 1.0 mmol) and 4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.4) (0.19 g, 0.5 mmol) according to the general procedure V. Obtained as a light yellow solid (0.076 g, 31%). MS (ISP) 497.3 [(M+H)+]; mp 216° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[N:15]1.I[CH3:35].[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:35])[C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[N:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]2[N:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:26]=[CH:25][CH:24]=2)=[N:15]1
Reactant: CI
Reactant: COc1cn(-c2ccc(N3CCNC3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cn(-c2ccc(N3CCN(C)C3=O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of 1-[2-fluoro-4-(2-oxoimidazolidin-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (40 mg, 0.09 mmol), iodomethane (0.02 mL, 0.36 mmol), and sodium hydride (60% in oil) (7.0 mg, 0.18 mmol) in DMF (4.0 mL) was stirred at 0° C. for 2 h. The reaction mixture was quenched with H2O, and extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from iPr2O/AcOEt to give the title compound (24 mg, 59% yield) as a white solid: mp 208-209° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 2.79 (3H, s), 3.42-3.58 (2H, m), 3.77 (3H, s), 3.78-3.86 (2H, m), 6.95 (1H, d, J=1.9 Hz), 7.01 (1H, t, J=9.0 Hz), 7.22-7.51 (6H, m), 7.73 (1H, dd, J=14.1, 2.4 Hz), 7.78 (1H, d, J=1.9 Hz), 8.44 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 461 [M+H]+. Anal. Calcd for C24H21FN6O3.0.75H2O: C, 60.06; H, 4.49; N, 18.27. Found: C, 60.05; H, 4.26; N, 18.16.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])/[CH:4]=[CH:5]/I.C([Li:18])(C)(C)C>CCOCC.CCCCC>[Li:18]/[CH:5]=[CH:4]/[CH:3]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH3:12])[CH:2]([CH3:13])[CH3:1]
Reactant: CCOCCOC(/C=C/I)C(C)C
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: [Li]/C=C/C(OCCOCC)C(C)C
Temperature: -78 °C

Procedure:
2.50 g (8.40 mmol) of trans-4-methyl-3α-ethoxyethoxy-1 -iodopentene was dissolved in 57 ml of anhydrous ether and cooled to -78° C. with stirring under argon atmosphere. To this solution 13.7 ml of 1.23 N t-butyllithium in pentane was injected. The resulting solution was stirred for 2.75 hours at -78° C. under argon atmosphere, yielding the lithio-anion, 1-lithio-trans-4-methyl-3α-ethoxyethoxy-1-pentene. The lithio-anion was added to a solution of 0.44 g hexamethylenephosphorous triamide copper iodide in 50 ml of anhydrous ether at -78° C. under argon. This yellow mixture was stirred for 15 minutes at -78° C. Then 1.97 g (4.22 mmol) of 15α-ethoxyethoxy-PGA2 -methyl ester in 11.5 ml ether was added dropwise and the reaction mixture was stirred at -70° C. for 15 min. The mixture was then slowly warmed to 0° C. over a period of 1.5 hr. by use of an ice water and salt bath, and stirred for 0.5 hr. The mixture was then brought to 25° C. and stirred for an additional 0.5 hr. The mixture was then processed with a 20% aqueous NH4Cl/NH4OH solution and 3.35 g of an orange oil was obtained. NMR(CDCl3) analysis revealed: δ 3.65, singlet, CO2CH3 ; δ Ξ5.45, multiplet, olefinic-H; and no absorption due to olefinic protons on the cyclopen-tenone in the PGA2 starting material. The ethoxyethoxy groups were hydrolyzed by reacting with 70 ml of 65/35 acetic acid/water and 7.0 ml THF for 17 hours at 25° C. After processing, 3.30 g of an orange oil were obtained. NMR (CDCl3) analysis showed no absorption in the δ 4.80 region. The methyl ester was hydrolyzed by reaction with 22 ml of 1N NaOH and 22 ml of THF for 19 hours at 25° C. under argon atmosphere. After processing 3.28 g of a red oil was obtained chromatographed in Silicic Acid and Celite (15%). 1.227 g (65.6%) of (-)-11α-(trans-4'-methyl-3'-β -hydroxy-1-pentenyl-11 -desoxy-PGE2 was obtained. NMR(CDCl3) analysis: δ 3.95, multiplet, 2H, CHOH; δ 5.45, multiplet, 6H, CO2H, -OH. IR analysis: λmaxCHCl3 2.68μ5.75μ, 5.85μ. Optical rotation: [α]D 25° = 36.4 ± 02° (c = 1.0, CH3OH). Mass spectoscopy: 416 (P+ - 18).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:16](=O)[NH:15][C:14]([NH2:21])=[N:13][C:12]2=3)[CH:8]=[CH:7]1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:24])=O.C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([NH2:21])=[N:15][C:16]=3[Cl:24])[CH:8]=[CH:7]1)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@@H]1C=C[C@H](n2cnc3c(=O)[nH]c(N)nc32)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CC(=O)OC[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(N)nc32)C1

Procedure:
(1S,4R)-[4-(2-Amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate (50 mg, 0.17 mmole), phosphoryl chloride (2 mL), and N,N-diethyl aniline (38μL) were refluxed for 3 minutes. Volatiles were evaporated, and ice-water (5 mL) was added to the residual oil. The solution was neutralized and extracted with methylene chloride (3×20 mL). The methylene chloride layers were dried (MgSO4) and evaporated to give crude product. Chromatography on silica gel (5% methanol-chloroform) gave (1S,4R)-[4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate as pale yellow crystals from ethyl acetate, m.p. 124°-127°; 1H-NMR (DMSO-d6) 8.01 (s, 1, purine H-8), 6.90 (s, 2, NH2), 6.11 and 5.99 (both m, 2, CH=CH), 5.46 (m, 1, CH--N), 4.06 (d, J=6.2, 2, CH2O), 3.1 (m, 1, CH--N), 2.7 and 1.65 (both m, 2, CH2), 1.98 (s, 3, CH3CO).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]2[C:6]3[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[O:18]([CH3:20])[K]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:18][CH3:20])[C:5]2[C:6]3[NH:14][C:13](=[O:15])[NH:12][C:11](=[O:16])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CO[K]
Reactant: O=c1[nH]c(=O)c2[nH]c3cc(Br)cc(F)c3c2[nH]1
Solvent: C1COCCO1
Product: COc1cc(Br)cc2[nH]c3c(=O)[nH]c(=O)[nH]c3c12
Temperature: 25 °C
Yield: 36.8 %

Procedure:
1.7 g (5.7 mmol) 7-bromo-9-fluoro-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione, 4.5 g (17.0 mmol) 18-Krone-6 and 12 ml (162.5 mmol) 30% KOMe solution (MeOH) were refluxed in 600 ml dioxan for 20 h. Having cooled down to room temperature, the solvent was concentrated, water was added and acidified using 1 N HCl. The resulting precipitate was sucked off and washed with water. 650 mg (37%) 7-bromo-9-methoxy-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 308, 310 [M−H]−
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2>>[OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11](/[CH:14]=[C:29]3\[C:30](=[O:35])[NH:31][C:32]4[C:28]\3=[CH:27][C:26]([O:25][CH3:24])=[CH:34][CH:33]=4)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: COc1ccc2c(c1)/C(=C/c1[nH]c3c(c1C)C(=O)N(C[C@@H](O)CN1CCOCC1)CC3)C(=O)N2
Yield: 76.6 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 5-methoxy-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-2-(5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 19 (40 mg, yield 76.6%) as a red solid.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][CH2:37][C:38]([F:41])([F:40])[F:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[F:41][C:38]([F:39])([F:40])[CH2:37][NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34]
Reactant: Nc1cccc(S(=O)(=O)NCC(F)(F)F)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=C(Nc1cccc(S(=O)(=O)NCC(F)(F)F)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2,2,2-trifluoroethyl)-benzenesulfonamide [synthesis: see part aniline derivatives] according to general procedure II. Yellow solid. MS (ISP) 592.0 [(M−H)−]; mp 257° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@@H:21]2[CH3:20])[C:5]2[CH2:11][S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCSC2
Reactant: C[C@H]1COCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CSCC2
Yield: 58.3 %

Procedure:
To a solution of 2,4-dichloro-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (200 mg, 0.9 mmol), and Et3N (182 mg, 1.8 mmol) in DMF (3 mL) at 0° C. was added 3-(S)-methylmorpholine (100 mg, 0.99 mmol). The resultant mixture was stirred at rt overnight. The solvent was removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was washed with brine dried and concentrated to give the product which was purified by preparative TLC (petroleum ether/ethyl acetate=2/1) to produce (S)-2-chloro-4-(3-methylmorpholino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (150 mg, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:11]/[CH:12]=[CH:13]/[C:14](Cl)=[O:15])[CH3:10].O>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])/[CH:13]=[CH:12]/[O:11][CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCO/C=C/C(=O)Cl
Reactant: Nc1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCO/C=C/C(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
26.63 g (0.155 mol) of 4-bromoaniline are dissolved in 120 ml of pyridine and 23.14 g (0.172 mol) (E)-3-ethoxy-acrylic acid chloride are added dropwise at a temperature between 0° C. and 5° C. and the mixture is stirred for one hour at 0° C. Then the reaction mixture is allowed to warm up to RT and stirred for 14 h. The reaction mixture is combined with water, the precipitate formed is filtered off and washed with water. The solid is dried at 65° C. in the drying cupboard.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([CH:16]([CH3:18])[CH3:17])[C:3]=1[C:19]([NH2:21])=[O:20].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=O)[CH:27]=[CH:28][CH:29]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:31]([CH2:30][C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=3)=[N:21][C:19](=[O:20])[C:3]2=[C:4]([CH:16]([CH3:18])[CH3:17])[NH:5]1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CC(C)c1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.2 %

Procedure:
Part C: To a stirred solution of 167 mg (0.5 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 170 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 204-205° C., Mass Spec: 477 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:34][C:12]([C:9]2[C:8](=[O:15])[N:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]3=[N:11][CH:10]=2)=[O:14])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCCC1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC3CCCCC3)c(=O)n12
Reaction time: 0.08 h
Yield: 73.2 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, 8.73 g (0.088 mol) of cyclohexylamine dissolved in 80 ml of chloroform are dropped to the above solution at -15° C. during 30 minutes. The reaction mixture is stirred for 1 hour below -10° C. and then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.7 g (73.2%) of the named product as yellow crystals after recrystallization from ethanol, m.p.: 174°-176° C.
Reaction SMILES: C(O[C:4]([CH2:6][C:7]([O:9][CH3:10])=[S:8])=[O:5])C.[C:11](#[N:13])[CH3:12].C[O-].[Na+]>CO>[C:11]([C:12]1[S:8][C:7]([O:9][CH3:10])=[CH:6][C:4]=1[OH:5])#[N:13]
Reactant: CCOC(=O)CC(=S)OC
Reactant: CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(O)c(C#N)s1
Temperature: 20 °C
Yield: 54.2 %

Procedure:
81 g of O-methyl 2-ethoxycarbonyl-thioacetate and then 38 g of acetonitrile were added to a solution of 27 g of sodium methylate in 250 ml of methanol and the mixture was refluxed for one hour. A solution of 27 g of sodium methylate in 100 ml of methanol were added to the reaction which was cooled to 20° C. and concentrated to dryness. The residue was dissolved in water and the solution was washed with ether, acidified with concentrated hydrochloric acid and was vacuum filtered. The recovered crystals were dried to obtain 42 g of 2-cyano-3-hydroxy-5-methoxy-thiophene with a melting point of 138°-140° C. A microanalytically pure sample obtained by crystallization from isopropyl ether melted at 140° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: CS(=O)(=O)OCCCc1ccccc1Cl
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3ccccc3Cl)n2)ccc1F
Yield: 76.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as a yellow crystalline powder (yield: 76.8%).