Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][OH:2].[Cl:3][C:4]1[C:5]([NH:12][CH2:13][CH2:14][O:15][CH3:16])=[N:6][CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10]>C1COCC1>[Cl:3][C:4]1[CH:11]=[C:8]([C:9](=[N:1][OH:2])[NH2:10])[CH:7]=[N:6][C:5]=1[NH:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCNc1ncc(C#N)cc1Cl
Reactant: NO
Solvent: C1CCOC1
Product: COCCNc1ncc(C(N)=NO)cc1Cl
Temperature: 25 °C
Reaction time: 36 h
Yield: 102.5 %

Procedure:
Hydroxylamine (5.39 g, 164 mmol) was added into a solution of 5-chloro-6-[(2-methoxyethyl)amino]nicotinonitrile (6.9 g, 32.7 mmol) in THF (70 mL) under nitrogen. The reaction mixture was stirred at RT for 36 hours, and then was concentrated under reduced pressure to afford the title compound as a pale yellow solid (8.2 g, quantitative). LC/MS, M+(ESI): 245.1. 1H NMR (DMSO-d6, 400 MHz) δ 9.49 (1H, s), 8.27 (1H, s), 7.78 (1H, s), 6.57 (1H, t), 5.77 (2H, s), 3.53 (2H, m), 3.46 (2H, m), 3.25 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[C:16]1([C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(-c2cnccc2-c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2cnccc2-c2ccccc2)cc1
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of Intermediate 13B in MeOH (3 mL) was added Pd/C (33.2 mg, 0.031 mmol). The resulting mixture was stirred under H2 atmosphere for 2 hours and then filtered through a pad of CELITE®/silica. The filtrate was concentrated to yield the Intermediate 13 (100 mg, 0.406 mmol, 78% yield). MS (ES): m/z=247.0 [M+H]+. Intermediate 13 was used in the synthesis of the compounds of Examples 8 and 9.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:12](Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>[OH-].[Na+]>[CH2:12]([NH:1][CH2:2][C:3]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCCl
Reactant: NCC1(C(=O)O)CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: CCCCC/C=C\C/C=C\CCCCCCCCNCC1(C(=O)O)CCCCC1
Temperature: 25 °C

Procedure:
5 grams of aminomethylcyclohexanecarboxylic acid were dissolved in 50 cm3 of 6% sodium hydroxide. This solution was stirred vigorously and maintained at 10° C while 10 grams of linoleyl chloride were added drop by drop. The stirring was maintained for 1 hour at ambient temperature. The precipitate obtained on centrifuging was washed twice with acetone and allowed to dry.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH3:14])[CH:3]([OH:13])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:6]([O:5][CH2:4][CH:3]1[O:13][C:24](=[O:26])[NH:1][C:2]1([CH3:15])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(N)C(O)COCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)OC1COCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.1 %

Procedure:
To a cold, 0° C., solution of 3-amino-1-(benzyloxy)-3-methylbutan-2-ol (2 g, 9.6 mmol) and triethylamine (3.3 mL, 24 mmol) in 95 mL of anhydrous dichloromethane was added triphosgene (3.1 g, 10.5 mmol). The reaction was stirred at 0° C. for 3.5 hr and at RT for 1.5 hr. A solution of saturated sodium bicarbonate (95 mL) was added and the mixture was stirred for 15 min, then the organic layer was isolated and washed successively with 0.25N HCl, sat. NaHCO3, and brine. The organic layer was dried over sodium sulfate, concentrated to a residue and purified by column chromatography (30 to 75% ethyl acetate in hexanes) to give the title compound (1.8 g, 7.4 mmol, 78%). 1H NMR (CDCl3, 400 MHz) δ 1.27 (s, 3H), 1.40 (s, 2H), 1.90 3.67-3.76 (m, 2H), 4.37-4.41 (t, J=6.4 Hz, 1H), 4.56-4.64 (dd, J=9.6, 12 Hz, 2H), 5.27 (s, H), 7.28-7.40 (m, 5H). LRMS (ESI/APCI) m/z 236 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([F:14])[CH:8]=1.[CH:16](O)=[O:17].O>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]([CH:16]=[O:17])[CH2:6][C:7]1[CH:8]=[C:9]([F:14])[CH:10]=[C:11]([F:13])[CH:12]=1
Reactant: O=CO
Reactant: COC(=O)CNCc1cc(F)cc(F)c1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)CN(C=O)Cc1cc(F)cc(F)c1
Yield: 99.3 %

Procedure:
A solution of N-(3,5-difluorobenzyl)-glycine methyl ester (7.61 g, 0.0352 mole) and formic acid (1.33 ml, 0.0352 mole) was heated at reflux in xylene (60 ml) with azeotroic removal of water for 2.5 hours and the solvent was removed under vacuum to give the product as an oil (8.50 g, 99%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][OH:9])=[CH:3][CH:2]=1.[H][H].[ClH:12]>O.[Pt]=O>[ClH:12].[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: OCCc1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: O
Product: OCCC1CCNCC1

Procedure:
2-(4-pyridyl)ethanol (70. g, 0.57 M) and platinum oxide (2 g) in water (600 ml) and concentrated aqueous HCl (81 ml) was hydrogenated at the pressure of 1000 psig hydrogen to give 4-(2-hydroxyethyl)piperidine hydrochloride in quantitative yield. Treatment of 4-(2-hydroxyethyl)piperidine hydrochloride (20 g 0.12 M) with phosphorus tribromide (7 ml) at 100° C. for 11/2 hr. followed by trituration with diethyl ether (2×50 ml) and filtration gave 4(2-bromoethyl)piperidine hydrogen bromide (20.76 g, 77% yield). The solution of the 4-(2-bromoethyl)piperidine hydrogen bromide (23 g.0.085 M) in tetrahydrofuran (170 ml) and dimethylformamide (170 ml) was prepared. To this solution was added formic acetic anhydride (12.7 ml) at 0° C., followed by the addition of triethylamine (25 ml) with vigorously stirring. The reaction mixture was stirred overnight. After the reaction, it was filtered and the filtrate was stripped in vacuo to dryness and water (100 ml) was then added to the residue and the mixture was extracted with diethyl ether (3×100 ml). Removal of the solvent and purification on silica gel columns, eluted with ethyl acetate-hexane (9:1 parts by volume) gave 4-(2-bromoethyl)-1-piperidinecarboxaldehyde (12.06 g, 66% yield).
Reaction SMILES: [CH3:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[NH:3]1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([CH3:1])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:3][C:4]2=[O:12])=[CH:22][CH:23]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC1(c2ccccc2)NC(=O)Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)NC(C)(c3ccccc3)c3ccccc32)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of 4-Methyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (0.70 g, 2.9 mmol) in DMF (10 mL) is added 1-chloromethyl-4-methoxy-benzene and Cs2CO3 (1.92 g, 5.9 mmol). After the addition the mixture is stirred at −20° C. for 1 h. Then CH3I (2.6 g, 18 mmol) is added dropwise. After the addition the mixture is heated to refluxed overnight. H2O is then added and the mixture extracted with EtOAc which is dried over Na2SO4 and concentrated. The residue is purified by chromatography on silica gel to give product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][NH:13][C:12]3=[O:19])=[N:7][C:6]=12.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:35]=3)=[CH:30][CH:29]=2)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].O1CCOCC1>[CH:16]([C@@H:15]1[N:11]([C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[CH:3][C:2]([C:28]4[CH:29]=[CH:30][C:31]([C:34]5[N:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:35]=5)=[CH:32][CH:33]=4)=[C:6]3[N:7]=2)[C:12](=[O:19])[NH:13][CH2:14]1)([CH3:18])[CH3:17]
Reactant: CC1(C)OB(c2ccc(-c3ncn(COCC[Si](C)(C)C)n3)cc2)OC1(C)C
Reactant: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(Br)c2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 80 °C
Yield: 56.2 %

Procedure:
To a sealed tube was added (S)-1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-5-isopropylimidazolidin-2-one (1.50 g, 4.63 mmol), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (2.51 g, 6.25 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) (0.221 g, 0.463 mmol) and Pd2 dba3 (0.212 g, 0.231 mmol), dioxane (39 mL) and sodium carbonate (2.0 M solution in water) (6.9 mL, 14 mmol) were added. The reaction mixture was heated to 80° C. overnight under nitrogen. After cooling, the reaction mixture was partitioned between EtOAc and water, and the aqueous layer was extracted once with EtOAc. The combined organic layers were washed with saturated aqueous sodium bicarbonate, brine, dried and concentrated in vacuo. The residue was purified by chromatography using EtOAc as eluent to give (S)-5-isopropyl-1-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (1.35 g, 56%) as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].Cl.[CH2:13]([N:15]([CH2:23][CH3:24])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:14].C(=O)([O-])O.[Na+]>ClCCl>[CH2:5]([O:4][C:2]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]([CH2:23][CH3:24])[CH2:13][CH3:14])=[CH:21][CH:20]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 61.2 %

Procedure:
Benzyl chloroformate (15.7 mL, 0.11 mol) was added dropwise to a stirred mixture of N,N-diethyl-p-phenylenediamine hydrochloride (20 g, 0.1 mol) and sodium hydrogen carbonate (42.0 g) in dichloromethane at room temperature under nitrogen. After 16 hours at room temperature, the precipitate which had formed was removed by filtration. The solid residue was washed with dichloromethane and the combined dichloromethane extracts were concentrated to produce a brown oil. This material was purified by preparative high pressure liquid chromatography (hereinafter HPLC) on silica gel eluting with 10% hexanes/dichloromethane followed by dichloromethane alone. The resultant oil was triturated with hexanes to give N-benzyloxycarbonyl-4-diethylaminoaniline (18.25 g, 61% yield) as a crystalline solid. The structure of this compound was confirmed by mass spectroscopy and by 1H NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CO)c(Cl)c1
Reaction time: 0.08 h
Yield: 51 %

Procedure:
The triflate compound (638 mg, 2 mmol) obtained in Step 1-2, palladium acetate (14 mg), 1,3-diphenylphosphinopropane (25 mg), methanol (4 ml) and triethylamine (0.6 ml) were dissolved in dimethylformamide (5 ml), and the obtained solution was stirred at 80° C. in carbon monoxide atmosphere for 16 hours. After leaving the reaction mixture to cool followed by the extraction with ethyl acetate/hexane and the purification by the silica gel column chromatography, methyl 2-chloro-4-t-butylbenzoate was obtained. The ester thus obtained was dissolved in dichloromethane (2 ml). 1 M solution (2.5 ml) of diisobutylaluminum hydride in toluene was added dropwise to the obtained solution at −78° C. in argon atmosphere, and the resulting solution was stirred at that temperature for 5 minutes. 0.5 M hydrochloric acid (20 ml) was added to the reaction mixture, and the temperature was elevated to room temperature. After the extraction with ethyl acetate followed by the purification by the silica gel column chromatography, 2-chloro-4-t-butylbenzyl alcohol (yield: 204 mg, 51%) was obtained.
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]([CH3:19])=[C:8]([CH3:20])[N:7]=1.[OH-].[Na+].O>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[N:10]=[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]1=[O:5]
Reactant: OCCCl
Reactant: Cc1nc(O)c(Cc2ccccc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nc(Cc2ccccc2)c(=O)n(CCO)c1C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
Ethylene chlorohydrin (4.03 g, 50 mM) was added to a solution of 2-hydroxy-3-benzyl-5,6-dimethyl-pyrazine (2.14 g, 10 mM) and 5N NaOH (10 ml) in t-butanol (30 ml), and stirred at 60° C. for 2.5 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted three times with chloroform, the extract dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g) and eluted with chloroform-methanol (100:1) to obtain compound 112 (2.22 g, yield: 86.0%).
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][C:11]2[N:12]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[O:28][CH:27]=[N:26][CH:25]=4)=[CH:20][CH:19]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)=O)(C)(C)C.[C:31]1([CH2:37]O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl>C1COCC1>[CH2:37]([O:16][C:15]1[C:10]2[CH2:9][NH:8][CH2:30][CH2:29][C:11]=2[N:12]=[C:13]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[O:28][CH:27]=[N:26][CH:25]=3)=[CH:22][CH:23]=2)[N:14]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(O)c2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(COc2nc(Nc3ccc(-c4cnco4)cc3)nc3c2CNCC3)cc1
Temperature: 50 °C
Yield: 45.5 %

Procedure:
tert-Butyl-4-hydroxy-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.2 g, 0.49 mmol, Example 3d), phenylmethanol (0.063 ml, 0.61 mmol) and triphenylphosphine (0.160 g, 0.61 mmol) in THF (5 mL) was stirred for 10 min. Diisopropyl azodicarboxylate (0.119 mL, 0.61 mmol) was added and reaction was stirred at 50° C. over night. HCl (2M aq, 2 mL) was added and the solution was heated to 75° C. for 1 h, allowing THF to evaporate. The remaining solvent was evaporated under reduced pressure. The crude product was dissolved in MeOH/DMSO and purified on preparative HPLC to give 4-(benzyloxy)-N-(4-(oxazol-5-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.089 g, 39.7%).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:21][CH:22]1[C:23]([O:56]C(OCC)C)([CH3:55])[CH2:24][CH2:25][CH:26]([O:49]C(OCC)C)[CH2:27][C:28]([O:30][CH:31](/[C:36](/[CH3:48])=[CH:37]/[CH:38]=[CH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:32]([CH3:35])[CH:33]=[CH:34]1)=[O:29])(=[O:20])[CH3:19]>CO.C(OCC)(=O)C>[C:18]([O:21][CH:22]1[C:23]([OH:56])([CH3:55])[CH2:24][CH2:25][CH:26]([OH:49])[CH2:27][C:28]([O:30][CH:31](/[C:36](/[CH3:48])=[CH:37]/[CH:38]=[CH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:32]([CH3:35])[CH:33]=[CH:34]1)=[O:29])(=[O:20])[CH3:19]
Reactant: CCCCCCCCC=C/C=C(\C)C1OC(=O)CC(OC(C)OCC)CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC1C
Agent: CCCCCCCCC=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCCCCCCCC=C/C=C(\C)C1OC(=O)CC(OC(C)OCC)CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCCC=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)C=CC1C
Reaction time: 2.5 h

Procedure:
Pyridinium p-toluenesulfonate (13 mg, 0.051 mmol) was added to a solution of (8E,12E)-7-acetoxy-3,6-bis(1-ethoxyethoxy)-6,10,12-trimethyltricosa-8,12,14-trien-11-olide (3.2 mg, 0.0051 mmol) in methanol (1 mL) at room temperature, followed by stirring at the same temperature for 2.5 hours. The reaction mixture was diluted with 1 mL of ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. The resulting crude product was purified by thin layer chromatography (MERCK Silica gel 60 F254, 0.25 mm, developing solution; hexane:ethyl acetate=1:2) to give the title compound (1.2 mg, 49%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[N:19]([CH3:20])[N:18]=[C:17]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[C:16]=2[C:28]([F:31])([F:30])[F:29])=[O:14])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[N:19]([CH3:20])[N:18]=[C:17]([C:21]([F:27])([F:26])[C:22]([F:25])([F:23])[F:24])[C:16]=2[C:28]([F:29])([F:30])[F:31])=[O:14])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(NC(=O)c2c(C(F)(F)F)c(C(F)(F)C(F)(F)F)nn2C)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.75 g (11.9 mmol) of methyl 2-chloro-5-({[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzoate are dissolved in 30 ml of methanol p.A., and 15.0 ml (30.0 mmol) of 2 N aqueous sodium hydroxide solution are then added. The reaction mixture is stirred at room temperature for 16 hours. The reaction solution is acidified carefully with 6 N hydrochloric acid, and the aqueous phase is then extracted three times with ethyl acetate. The combined organic phases are washed once with saturated sodium chloride solution, dried over sodium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. This gives 5.57 g of 2-chloro-5-({[1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl}amino)benzenecarboxylic acid as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:32])([F:33])[F:19])=[CH:26][CH:25]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)cc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccc(C(F)(F)F)cc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-trifluoromethyl-phenyl)-acrylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:16])([C:10]#[C:11][Si](C)(C)C)[CH3:9])=[N:6][CH:7]=1.[F-].[K+]>CO.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:16])([C:10]#[CH:11])[CH3:9])=[N:6][CH:7]=1
Reactant: CC(O)(C#C[Si](C)(C)C)c1ccc(F)cn1
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#CC(C)(O)c1ccc(F)cn1
Yield: 86.3 %

Procedure:
A solution of 2-(5-fluoropyridin-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol (1 g, 4.21 mmol) and potassium fluoride (987 mg, 16.99 mmol) in methanol (10 mL) was stirred for 2 hr at 50° C. The resulting solution was diluted with ethyl acetate (20 mL) and the solid material was removed by filtration. The filtrate was concentrated in vacuo to give 600 mg (86%) of the title compound as yellow oil: LC-MS: m/z=+166 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[C:12](Cl)(Cl)=[O:13]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:12](=[O:13])[O:8][C:6](=[O:7])[C:5]2=[CH:9][CH:10]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a mixture of 10.0 g (58.0 mmol) of 4-chloroanthranilic acid in 100 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 8.78 g (76.2%) of the 4-chloroisatoic anhydride as a light brown solid. MS (Cl mode) m/z 198 (M+H, 100%), Cl pattern 200, 35%.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:7]=1[NH2:8]>C(Cl)(Cl)Cl.O>[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:7]=1[N:8]=[C:1]=[S:2]
Reactant: Nc1ccc(I)cc1F
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Fc1cc(I)ccc1N=C=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
Thiophosgene (3.55 mL, 46.4 mmol) was added to a rapidly-stirred mixture of 2-fluoro-4-iodoaniline (10.0 g, 42.2 mmol) in CHCl3 (200 mL) and water (100 mL). The mixture was stirred at r.t. for 16 h. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound as an off-white crystalline solid (11.8 g, quant.). δH (DMSO-d6) 7.87 (1H, dd, J 1.8, 9.5 Hz), 7.63 (1H, ddd, J 1.0, 1.8, 8.4 Hz), 7.25 (1H, dd, J 8.2, 8.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([CH:32]=O)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:35][C:36]([NH2:38])=[O:37].C[Si](Cl)(C)C.[BH4-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([CH2:32][NH:35][C:36]([NH2:38])=[O:37])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: O=Cc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)NCc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of the product of example 314 (800 mg) in acetic acid (20 ml) were added urea (2 g) and trimethylsilyl chloride (0.24 ml) at room temperature, and the mixture stirred for 2 hours. Sodium borohydride was added to the reaction mixture at room temperature, and the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, and, chloroform, 2-propanol and water were added. The organic layer was extracted, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with chloroform-methanol-ammonium hydroxide (100:10:1) to give the titled compound (250 mg).