Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[F:15][C:16]([F:29])([F:28])[C:17](=[O:27])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].C(O)(=O)C.N1CCCCC1>ClCCl>[F:15][C:16]([F:28])([F:29])[C:17](=[O:27])[C:18](=[CH:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[O:3][C:2]([CH3:1])=[CH:11][C:10]2=[O:12])[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cc1cc(=O)c2cccc(C=C(C(=O)c3ccccc3)C(=O)C(F)(F)F)c2o1

Procedure:
A solution of 200 mg (1.06 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 20 ml of dichloromethane is mixed with 229.73 mg (1.06 mmol) of 4,4,4-trifluoro-1-phenyl-1,3-butanedione, 0.08 ml (1.33 mmol) of acetic acid and 0.01 ml (0.11 mmol) of piperidine and stirred under reflux with a water trap overnight. After cooling, the mixture is diluted with dichloromethane and washed with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated. 474 mg (>100% of theory) of the desired product are obtained as a yellow oil which is reacted further without purification.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1.[OH-].[Na+]>C(Cl)Cl>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23]([NH:10][C@H:11]([CH2:15][OH:16])[CH:12]([CH3:14])[CH3:13])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)C(N)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)N[C@H](CO)C(C)C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
Diisopropylethyl amine (17.4 ml, 134 mmol) was added a solution of (DL)-valinol (9.85 g, 95 mmol) in methylene chloride (100 ml). The reaction mixture was cooled to 0° C., treated with a solution of p-toluoyl chloride (12.8 ml, 91 mmol ) in methylene chloride (50 ml) and then allowed to warm to room temperature. After stirring for 3 hours, excess aqueous sodium hydroxide solution was added and the reaction was transferred to a separatory funnel. The organic layer was separated and the aqueous layer washed with one portion of methylene chloride. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. Chromatography eluting with 25% ethyl acetate in hexanes, followed by 50% ethyl acetate in hexanes gave N-p-toluoyl valinol (18.04 g).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:9]2=[O:26])=CC=1>C(O)(C(F)(F)F)=O>[F:25][C:22]([F:23])([F:24])[O:21][C:18]1[CH:17]=[CH:16][C:15]([S:14][C:10]2[C:9](=[O:26])[NH:8][CH:13]=[CH:12][N:11]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2ccnc(Sc3ccc(OC(F)(F)F)cc3)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccnc1Sc1ccc(OC(F)(F)F)cc1
Reaction time: 168 h
Yield: 78 %

Procedure:
A solution of 1-(4-methoxybenzyl)-3-(4-(trifluoromethoxy)phenylthio)-pyrazin-2(1H)-one (2.76 g, 6.76 mmol) in TFA (25 mL) was stirred at reflux for 2 days. Since LC-MS analysis revealed that 28% SM remained, the reaction was stirred for 7 days. After removal of the TFA under vacuum, the crude product was purified by silica gel chromatography employing a solvent gradient (hexane to 100% EtOAc to elute 3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (1.60 g, 5.27 mmol, 78% yield) as off-white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.61 (2H, d, J=9.03 Hz), 7.29 (2H, d, J=7.78 Hz), 7.24 (1H, d, J=4.02 Hz), 7.07 (1H, d).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C

Procedure:
To a mixture of 60% sodium hydride and THF were added dropwise ethyl diethylphosphonoacetate and further 4-[4-(t-butoxycarbonyl)piperazin-1-yl]benzaldehyde under cooling to 0° C., followed by stirring. Then, post-treatment and purification were carried out in a usual way to obtain ethyl 3-{4-[4-(t-butoxycarbonyl)piperazin-1-yl]phenyl}acrylate. Further, catalytic reduction was carried out using palladium/carbon to obtain an objective compound.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:18]Cl>C(O)(=O)C>[F:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([I:18])[CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: ClI
Reactant: Nc1ccc(-c2nc3c(F)cccc3s2)cc1
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc3c(F)cccc3s2)cc1I
Reaction time: 2 h

Procedure:
A solution of the 4-fluoro-2-(4′-aminophenyl)benzothiazole prepared as described in Example 3 (4.5 mmol) in acetic acid (20 ml) was added dropwise to a solution of iodine monochloride (5.8 mmol) in acetic acid (20 ml) at 25° C. The resulting solution was stirred for 2 hr, then the solvent was removed under vacuum. The residue was dissolved in chloroform (100 ml) and washed with aqueous sodium carbonate (50 ml), aqueous sodium thiosulfate (50 ml) and water (50 ml). Evaporation of the solvent, followed by column chromatography (chloroform) and recrystallization from methanol gave pale cream needles.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH:12]2[CH:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]=12.[C:23]1([C:29]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[C:36]3[C:31](=[CH:32][C:33](B4OC(C)(C)C(C)(C)O4)=[CH:34][CH:35]=3)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH:15]2[CH:12]([C:4]3[N:5]4[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[C:6]4=[C:2]([C:33]4[CH:32]=[C:31]5[C:36]([C:37]([C:39]([F:42])([F:40])[F:41])=[CH:38][C:29]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)=[N:30]5)=[CH:35][CH:34]=4)[N:3]=3)[CH2:13][CH2:14]2)[CH2:17][CH2:18]1
Reactant: CN1CCN(C2CCC2c2nc(I)c3c(N)nccn23)CC1
Reactant: CC1(C)OB(c2ccc3c(C(F)(F)F)cc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN(C2CCC2c2nc(-c3ccc4c(C(F)(F)F)cc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
1-Iodo-3-[4-(4-methyl-piperazin-1-yl)-cyclobutyl]-imidazo[1,5-a]pyrazin-8-ylamine (120 mg, 0.00029 mole), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-quinoline (230 mg, 0.00058 mole), cesium carbonate (330 mg, 0.0010 mole), 1,2-dimethoxyethane (6 mL, 0.06 mole) and water (1 mL) were combined in a 25 ml round bottom flask with a magnetic stir bar. The flask was subjected to three vacuum, argon cycles and charged with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.000030 mole). The flask was subjected to three vacuum, argon cycles again. The reaction was stirred under argon at 75° C. (external temperature) overnight. The product mixture was concentrated in vacuo, then allowed to stand under vacuum for 1 h. The product mixture was then chromatographed on silica gel with methylene chloride, methanol, concentrated ammonium hydroxide (140:10:1). Only the purest fractions were combined and concentration in vacuo, and placement under high vacuum for 30 minutes afforded the title compound as a yellow solid. The solid was re-crystallized from hexanes/ether to afford the title compound as a yellow solid; 1H NMR (CD3OD, 400 MHz) δ 2.14-2.62 (m, 15H), 2.78-2.82(Q, 1H, J=7.9 Hz), 3.62-3.67 (Q, 1H, J=7.9H), 6.32 (bs, 2H), 7.12-7.14 (d, 1H, J=4.8 Hz), 7.58-7.64 (m, 4H), 8.16-8.22 (m, 2H), 8.39-8.42 (m, 3H), 8.48 (s, 1H); 19F NMR (DMSO, 400 MHz) δ-60.15; MS(ES+): 557.98 (10) [MH+]; HPLC TR3.408 min. (100%) (polar—15 min).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]([NH:13][C:14]1[NH:18][N:17]=[CH:16][C:15]=1[C:19]#[N:20])=[O:12].C[O-].[Na+]>O>[NH2:20][C:19]1[C:15]2[CH:16]=[N:17][NH:18][C:14]=2[NH:13][C:11](=[O:12])[C:10]=1[C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: N#Cc1cn[nH]c1NC(=O)Cc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: Nc1c(-c2nc3ccccc3[nH]2)c(=O)[nH]c2[nH]ncc12

Procedure:
2-(1H-Benzimidazol-2-yl)-N-(4-cyano-1H-pyrazol-5-yl)acetamide (1.0 eq) was heated in NaOMe (20 eq, 0.5 M in MeOH) at 100° C. for 2 days. H2O was added, and the mixture was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a solid. The material was purified by reverse phase HPLC. LC/MS m/z 267.1 (MH+), Rt 1.57 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.CC([O:15][C@H:16]1[CH:20]=[CH:19][C@@H:18](O)[CH2:17]1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:19]2[CH2:20][C@H:16]([OH:15])[CH:17]=[CH:18]2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reaction time: 0.08 h

Procedure:
2,6-Dichloropurine (10 g, 52.90 mmol), (1S,4R)-cis 4-acetoxy-2-cyclopenten-1-ol (10 g. 70.40 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.20 g, 3.50 mmol) and polymer supported triphenylphosphine (3 mmol/g, 11.60 g, 35.00 mmol) are placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (80 ml) is added and the reaction mixture is stirred gently for 5 minutes. Triethylamine (20 ml) is added and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 1 hour. The reaction mixture is allowed to cool, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, dichloromethane/methanol 25:1). 1H nmr (CDCl3, 400 MHz); 8.30 (s, 1H), 6.40 (m, 1H), 5.90 (m, 1H), 5.50 (m, 1H), 4.95 (m, 1H), 3.05 (m, 1H), 2.10 (m, 1H), MS (ES+) m/e 271 (MH+).
Reaction SMILES: COC1C=CC(NCC(OCC)=O)=CC=1.ClC1C=CC(C(Cl)=O)=CC=1.[Cl:26][C:27]1[CH:49]=[CH:48][C:30]([C:31]([N:33]([CH2:42][C:43]([O:45]CC)=[O:44])[C:34]2[CH:41]=[CH:40][C:37]([O:38][CH3:39])=[CH:36][CH:35]=2)=[O:32])=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.C1C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([N:33]([CH2:42][C:43]([OH:45])=[O:44])[C:34]2[CH:41]=[CH:40][C:37]([O:38][CH3:39])=[CH:36][CH:35]=2)=[O:32])=[CH:48][CH:49]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1
Agent: CCOC(=O)CNc1ccc(OC)cc1
Agent: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(N(CC(=O)O)C(=O)c2ccc(Cl)cc2)cc1

Procedure:
Ethyl p-anisidinoacetate is dissolved in an inert solvent (benzene) and is mixed with an equivalent quantity of p-chlorobenzoyl chloride in the presence of an equivalent quantity of pyridine. The resultant ethyl N-(p-chlorobenzoyl)-p-anisidinoacetate is saponified with alcoholic potash to produce N-(p-chlorobenzoyl)-p-anisidinoacetic acid, melting point: 195° to 197°.
Reaction SMILES: C[O-].[Na+].C(OC)=O.[CH3:8][C:9]([S:12]([NH:15][C@@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)(=[O:14])=[O:13])([CH3:11])[CH3:10].Cl>C1(C)C=CC=CC=1>[CH3:11][C:9]([S:12]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)(=[O:14])=[O:13])([CH3:8])[CH3:10]
Reactant: COC(=O)[C@H]1CC[C@@H](NS(=O)(=O)C(C)(C)C)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)C(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a suspension of powder sodium methylate (7.06 g, 2.5 eq) in toluene (145 mL) was added methyl formate (1.61 mL, 0.5 eq). After the mixture was stirred for an hour at room temperature, (15) (14.5 g, 52.3 mmol) was added to the mixture. The mixture was heated under reflux for 2 hours 25 minutes, cooled and poured into 0.76 mol/L hydrochloric acid (344 mL). The mixture was extracted with ethyl acetate (300 mL×2), and the obtained organic layer was washed with water and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain 14.42 g of crystalline residue (cis:trans=3:97). The residue was recrystallized from toluene to obtain (12) (10.2 g, 70% from (15)).
Reaction SMILES: C([N:8]1[CH2:20][CH2:19][C:11]2([O:16][C@H:15]([CH3:17])[CH2:14][C@@H:13]([CH3:18])[O:12]2)[C@H:10]([CH3:21])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH3:17][C@@H:15]1[CH2:14][C@@H:13]([CH3:18])[O:12][C:11]2([CH2:19][CH2:20][NH:8][CH2:9][C@H:10]2[CH3:21])[O:16]1
Reactant: [H][H]
Reactant: C[C@@H]1C[C@@H](C)OC2(CCN(Cc3ccccc3)C[C@H]2C)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1C[C@@H](C)OC2(CCNC[C@H]2C)O1
Reaction time: 5 h
Yield: 93.6 %

Procedure:
To a solution of (2R,4R,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane (880 mg, 3.04 mmol) from Example 2B in methanol (25 mL) was added palladium hydroxide (82 mg) and the mixture stirred under 1 atmosphere pressure of hydrogen. After 5 h, the mixture was filtered and concentrated to provide 567 mg (94%) of the title compound as an oil. 1H NMR (300 MHz, CDCl3) δ 4.11-3.97 (m, 2H), 2.93-2.71 (m, 3H), 2.61 (dd, 1H, J=12.3, 8.7 Hz), 1.97 (ddd, 1H, J=13.9, 5.6, 3.6 Hz), 1.79-1.70 (m, 1H), 1.65-1.47 (m, 4H), 1.21 (d, 3H, J=6.4 Hz), 1.19 (d, 3H, J=6.4 Hz), 0.95 (d, 3H, J=6.7 Hz); MS (DCI/NH3) m/e 200 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH3:2].[CH3:23][C:24]([OH:26])=[O:25]>[Pt]=O>[C:24]([OH:26])(=[O:25])[CH3:23].[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH:16][C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH3:2]
Reactant: CCOc1cc(-c2ccncc2)ccc1NC(=O)C(F)(F)F
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOc1cc(C2CCNCC2)ccc1NC(=O)C(F)(F)F
Reaction time: 24 h
Yield: 98 %

Procedure:
N-[2-(Ethyloxy)-4-(4-pyridinyl)phenyl]-2,2,2-trifluoroacetamide (4.6 g, 14.82 mmol) was place in a 250 mL high pressure vessel and dissolved in 70 mL of HOAc. Platinum oxide (0.373 g, 1.48 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (60 psi). The solution stirred for 24 h. The vessel was evacuated and filled with N2 six times to remove any N H2. The solution was filtered through celite and evaporated to give the title compound of step E (4.8 g, 7.46 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.27 (d, J=8.07 Hz, 1H), 6.94 (d, J=1.47 Hz, 1H), 6.81 (dd, J=8.07, 1.83 Hz, 1H), 4.05 (q, J=6.97 Hz, 2H), 3.20 (d, J=12.10 Hz, 2H), 2.79 (td, J=12.56, 2.38 Hz, 2H), 2.68-2.74 (m, 1H), 1.84 (s, 3H), 1.78-1.83 (m, 2H), 1.70 (td, J=12.56, 3.48 Hz, 2H), 1.28 (t, J=6.97 Hz, 3H).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[I:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1>CCOC(C)=O>[I:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]=[C:4]=[O:3])=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: O=C=Nc1ccc(I)cc1[N+](=O)[O-]

Procedure:
To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0° C. was added a solution of the 4-iodo-2-nitroaniline (45.5 mmol) in EtOAc (200–500 mL), and the mixture was heated to reflux for 18 h. The solvent was removed in vacuum to leave a brown solid, which was triturated with hot hexane (200 mL). The solid material was filtered off and the filtrate was concentrated under reduced pressure to leave the pure 4-iodo-2-nitrophenylisocyanate as a yellow solid. This material was refluxed in a mixture of excess tert.-BuOH in CH2Cl2 for 2.5 h. Removal of the solvent left an orange solid which was purified by silica gel column chromatography with hexane/EtOAc to give the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[OH-:14].[Na+]>S([O-])([O-])(=O)=O.[Cu+2]>[OH:14][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(C(=O)O)c(Br)cn1
Reactant: [OH-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cc(C(=O)O)c(O)cn1
Temperature: 165 °C
Reaction time: 20 h

Procedure:
A mixture of 500 mg of 5-bromo-2,4-pyridinedicarboxylic acid from Example 2, 20 ml of 10 N aqueous sodium hydroxide solution and 250 mg of copper sulfate is heated at 165° C. in an autoclave for 4 hours. After cooling, the copper salt is filtered off with suction, the pH is brought to 1 with concentrated hydrochloric acid and the solution is evaporated. The solid is heated in a little methanol, the salts are filtered off and the solution is left to stand at 0° C. for 20 hours. The solid which has precipitated out is separated off and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([CH:18]=O)[N:15]=[N:14]1.[NH2:20]/[C:21](/[C:26]#[N:27])=[C:22](\[NH2:25])/[C:23]#[N:24]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([CH:18]=[N:20][C:21]([C:26]#[N:27])=[C:22]([NH2:25])[C:23]#[N:24])[N:15]=[N:14]1
Reactant: O=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1
Reactant: N#C/C(N)=C(/N)C#N
Solvent: CO
Product: N#CC(N)=C(C#N)N=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1
Reaction time: 60 h

Procedure:
A mixture of this alcohol (1.7 g) and manganese dioxide (6.9 g) in chloroform (40 ml) was stirred at room temperature for 24 hours. This mixture was then filtered through Kieselguhr and the solvent evaporated to give crude material, which was purified by flash column chromatography (silica) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazole-4-carboxaldehyde, m.p 143°-144.5°. The aldehyde (2.32 g) and diaminomaleonitrile (0.85 g) were heated under reflux in methanol (40 ml) for 6 hours and then left to stand for 60 hours at room temperature. The solvent was evaporated and the residue was purified by column chromatography and recrystallisation from ethyl acetate/light petroleum (bp. 60°-80°) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(2-amino-1,2-dicyanoethenylimino)methyl]-1H-1,2,3-triazole, m.p.184°-186° (dec.).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH:24]([CH:27]1[NH:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]1=[O:34])([CH3:26])[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:31]4[CH:27]([CH:24]([CH3:25])[CH3:26])[C:28](=[O:34])[N:29]([CH3:33])[C:30]4=[O:32])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC(C)C1NC(=O)N(C)C1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C(C)C)nc3)CC2)c(C)c1
Yield: 55 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 5-isopropyl-3-methylimidazolidine-2,4-dione (69 mg) described in Preparation Example 216 and by the reaction and treatment in the same manner as in Example 536, the title compound (99 mg) was obtained.
Reaction SMILES: [CH:1]1[C:7](=[O:8])[CH:6]=[C:5]([OH:9])[C:4]([OH:10])=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].BrBr.[OH-:16].[K+]>>[CH:1]1[C:7](=[O:8])[C:6]([OH:16])=[C:5]([OH:9])[C:4]([OH:10])=[CH:3][C:2]=1[C:11]([OH:13])=[O:12]
Reactant: [OH-]
Reactant: O=C(O)c1cc(O)c(O)cc(=O)c1
Agent: BrBr
Agent: [K+]
Product: O=C(O)c1cc(O)c(O)c(O)c(=O)c1

Procedure:
Puberulic acid is also obtainable by direct chemical synthesis, as disclosed by Johns et al., Jour. Chem. Soc. 1954, 198. According to this method, a solution of 3,4,6-trimethoxycycloheptatriene-caboxylic acid (an intermediate obtained by reacting diazoacetic ester and 1,2,4-trimethoxybenzene) in chloroform is reacted with a solution of bromine in carbon tetrachloride; the obtained precipitate is then heated in ethyl acetate, cooled in ice and then hydrolyzed with hydrobromic acid, obtaining stipitatic acid. Said stipitatic acid is then reacted with bromine, in order to obtain monobromostipitatic acid which is in turn reacted with potassium hydroxide to obtain the desired puberulic acid.
Reaction SMILES: C(C(CCCC)COC(=O)[CH2:7][CH2:8][S:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]1[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:21][N:22]=[C:15]1[CH:14]=[CH:13]2)C.CC(C)([O-])C.[K+].[CH3:40][O:41][C:42]([C:44]1([C:50]2C=C[CH:53]=[C:52](Br)[CH:51]=2)[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)=[O:43].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:40][O:41][C:42]([C:44]1([C:50]2[CH:51]=[CH:52][CH:53]=[C:8]([S:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]3[C:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[N:21][N:22]=[C:15]3[CH:14]=[CH:13]4)[CH:7]=2)[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1)=[O:43]
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Reactant: COC(=O)C1(c2cccc(Br)c2)CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(c2cccc(Sc3ccc4c(ccc5nnc(-c6ccccn6)n54)c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5m (216 mg, 0.47 mmol) was dissolved in 1,4-dioxane (5 mL) and degassed with N2 for 20 minutes. Potassium tert-butoxide (55 mg, 0.49 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was degassed with N2 for an additional 20 minutes, and then 4-(3-Bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (5o, 141 mg, 0.47 mmol) in 1,4-dioxane (1 mL) was added, followed by iPr2NEt (0.18 mL, 1.03 mmol), Pd2dba3 (11 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15 mg, 0.02 mmol). The reaction was sealed and heated to 110° C. for 1.5 hours. The mixture was cooled to room temperature and concentrated, and the residue was purified by silica gel chromatography (20-100% EtOAc in hexanes, followed by 0-10% MeOH in EtOAc) to give the desired product, 5p.