Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4](=[CH2:8])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CCOCC.CN(C)C1C=CN=CC=1>[CH:1]([C:4](=[CH2:8])[C:5]([O:7][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: OCc1ccccc1
Reactant: C=C(C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C=C(C(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 44 h

Procedure:
α-Isopropylacrylic acid (13 mmol) in dry ether (40 ml) was treated with dicyclohexylcarbodiimide (12 mmol), benzyl alcohol (12 mmol) and 4-dimethylaminopyridine (2.5 mmol). After stirring at ambient temperature for 44 h, the mixture was filtered and evaporated. Silica gel chromatography provided the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5](=[O:14])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1cc(Br)cn(-c2ccccc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Br)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
Methyl 5-bromo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (0.554 g, 1.80 mmol) was dissolved in dioxane (10.5 mL) then diluted with water (3.5 mL). 2N aqueous sodium hydroxide solution (0.944 ml, 1.89 mmol) was slowly added to the mixture. The reaction mixture was stirred at room temperature overnight, then concentrated under vacuum to remove the dioxane followed by dilution with water. This aqueous layer was acidified with 1N aqueous hydrochloric acid (1.89 mL, 1.89 mmol). A precipitate formed was collected on a glass frit, and washed with minimal water. The solid was dissolved in dichloromethane and then dried over sodium sulfate. This mixture was filtered, and the filtrate was concentrated under vacuum. The remaining residue was dried under high vacuum to afford 5-bromo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid as a yellow solid (0.458 g, 1.56 mmol, 86.6% yield). MS (ESI pos. ion) m/z: 295 (MH+). Calc'd exact mass for C12H8BrNO3: 294.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:4]([OH:6])=[O:5].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:14]([O:1][N:2]=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:4]([OH:6])=[O:5])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)C(=NO)c1cccc(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: O=C(O)C(=NOC(=O)c1ccccc1)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.9 %

Procedure:
A mixture of 2-hydroxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (9.06 g.), benzoyl chloride (32.25 g.) and tetrahydrofuran (50 ml.) was stirred for 6 hours at ambient temperature. To the reaction mixture was added petroleum ether under 5° C. Precipitates were collected by filtration, washed with petroleum ether and dried to give 2-benzoyloxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (11.12 g.), mp 140° to 142° C. (dec.).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[H-].[Na+]>>[CH2:1]([C:8]1[N:9]([CH2:17][CH2:18][O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: Cc1cc(=O)[nH]c(Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(=O)n(CCOc2ccc(C=O)cc2)c(Cc2ccccc2)n1
Yield: 20.5 %

Procedure:
The title compound (2.0 g, 20.6%) was prepared from 2-benzyl-4-methyl-1,6-dihydro-6-pyrimidone (5.6 g, 28.0 mmol), 4-[2-bromoethoxy]benzaldehyde (17.05 g, 30.1 mmol) in the presence of 95% NaH (873 mg, 35.0 mmol) as base by a similar procedure to that described in preparation 1.
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[C:17]([O:21][CH3:22])(=[O:20])[C:18]#[CH:19].C([SnH](CCCC)CCCC)CCC.[Cl:36][C:37]1[CH:38]=[CH:39][C:40]2[C:46](=[O:47])[C:45](I)=[C:44]([O:49][CH3:50])[C:43](=[O:51])[NH:42][C:41]=2[CH:52]=1>C1(C)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:36][C:37]1[CH:38]=[CH:39][C:40]2[C:46](=[O:47])[C:45](/[CH:19]=[CH:18]/[C:17]([O:21][CH3:22])=[O:20])=[C:44]([O:49][CH3:50])[C:43](=[O:51])[NH:42][C:41]=2[CH:52]=1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: C#CC(=O)OC
Agent: [Pd]
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: 103 °C
Reaction time: 0.25 h
Yield: 16.6 %

Procedure:
Tris(dibenzylideneacetone)dipalladium (O) (0.12 g) in toluene (45 mL) was treated with tri-2-furyl phosphine (0.12 g) under argon. The solution was stirred for 15 minutes at low temperature and treated with methyl propiolate (1.15 mL, 1.09 g) followed by tri-n-butyltin hydride (3.50 mL, 3.78 g). The solution was stirred for 19 hours and then treated with more tris (dibenzylacetone) dipalladium (O) (0.10 g) and tri-2-furylphosphine (0.10 g). The mixture was stirred for 15 minutes and then treated with 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (3.63 g) followed by toluene (35 mL). The mixture was heated to 103° C. and it was stirred for 19 hours. The mixture was cooled and concentrated to a dark solid. It was dissolved in chloroform and chromatographed on a silica gel column (8 cm diameter by 17 cm long) using 17% ethyl acetate in hexane to give a pale yellow solid (0.533 g). The solid was recrystallized twice from ethyl acetate (30 mL). The solution was concentrated to 10 mL volume and the crystals were filtered off, washed with cold ethyl acetate, washed with hexane to give a white solid (0.083 g); mp 260.1°-260.5° C. (dec); 1H NMR (CDCl3) 7.73 (d,1, J=16.1), 6.71 (d,1, J=16.1) for trans olefin protons; MS: m/z=322 (M+1). Analysis for C15H12ClNO5 : Calculated: C, 56.00; H, 3.76; N, 4.35; Found: C, 55.45; H, 3.85; N, 4.13.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([CH3:32])[CH:21]([C:23]1OC2C=CC=CC=2N=1)[OH:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[K+].[Br-]>CCOC(C)=O>[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([CH3:32])[CH:21]([C:23]1[O:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2)[OH:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ccccc2o1
Reactant: Nc1ncccc1O
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ncccc2o1
Yield: 12 %

Procedure:
This material was prepared as a 1:1 mixture of isomers in 12% yield from the above cyanohydrin (978 mg, 4.18 mmol) and 2-amino-3-hydroxypyridine (505 mg, 4.60 mmol) using the procedure described above for compound 16. An analytical sample was obtained by recrystallization from EtOAc in hexanes (one isomer). mp: 159-161° C.; IR (KBr) υ 1719, 1699 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J=4.8, 1.2 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 7.44 (dd, J=8.1, 5.1 Hz, 1H), 7.39-7.08 (m, 6H), 6.33 (d, J=6.0 Hz, 1H), 5.00-4.82 (m, 2H), 4.74 (m, 1H), 4.10-4.00 (m, 1H), 1.21 (d, J=6.7 Hz, 3H); 13C-NMR (100.6 MHz, DMSO-d6) δ 169.34, 155.32, 154.73, 146.08, 142.32, 136.99, 128.21, 127.59, 127.37, 120.57, 119.04, 69.99, 64.99, 49.91, 16.31; FAB MS m/z: 328 (MH+); HRMS calcd for C17Hl8N304 (MH+) 328.1297, found: 328.1286; Anal (C17H17N3O4) C, H, N.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([Cl:23])[N:17]=1.[OH-].[Na+]>CN(C=O)C>[Cl:23][C:18]1[N:17]=[C:16]([NH:15][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:21]=[C:20]([Cl:22])[N:19]=1
Reactant: Nc1cc(Cl)nc(Cl)n1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc(Nc2ncnc3[se]c4c(c23)CCCC4)nc(Cl)n1
Yield: 68.5 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (500 mg, 1.83 mmol, from step b of example 1) in DMF (10 mL) was added sequentially 4-amino-2,6-dichloropyrimidine (450 mg, 2.75 mmol) and powdered NaOH (220 mg, 5.50 mmol) at rt. Work-up of the mixture as described in example 2, gave the product as an off-white color solid (500 mg, 68%), mp 268-270° C. 1H NMR (400 MHz, CDCl3): δ 8.67 (1H, s), 8.64 (1H, s), 8.23 (1H, s, exchangeable with D2O), 3.11 (2H, t, J=6.1 Hz), 2.97 (2H, t, J=6.1 Hz), 2.01-2.06 (2H, m), 1.92-1.98 (2H, m); 13C NMR (100 MHz, CDCl3): δ 172.9, 162.7, 160.0, 159.2, 152.4, 151.0, 142.7, 126.3, 121.3, 107.8, 28.3, 28.2, 22.7, 22.4; LC-MS (negative ion mode): m/z 396, 398, 400, 402 (M−H)−.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].C(C(O)=[O:22])(F)(F)F>O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:22])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCCl

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodolbenzene (15.6 g, 36.2 mmol), H2O (18 ml), CF3CO2H (2.8 ml) and CH3 CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99°-101° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[C:5]([C:7](O)=[O:8])[CH:6]=1.[NH2:21][NH:22][C:23]([NH2:25])=[S:24]>O1CCCC1.N1C=CC=CC=1>[NH2:25][C:23](=[S:24])[NH:22][NH:21][C:7](=[O:8])[C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NC(=S)NNC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
N,N'-Carbonyldiimidazole (4.56 g, 27.6 mmol) is added to a room temperature solution of flufenamic acid (5.07 g, 18.0 mmol) in 70 ml of tetrahydrofuran. The clear yellow solution is stirred at room temperature for three hours. The solution is then added via cannula to a suspension of thiosemicarbazide (3.41 g, 37.5 mmol) in 55 ml of pyridine. The suspension is heated at reflux overnight. The clear orange solution is concentrated in vacuo and the residue is partitioned between ethyl acetate and water. The organic layer is washed with water, dried over magnesium sulfate and concentrated. The resulting solid is slurried with a 1:3 mixture of ethyl acetate and hexane. The off-white solid is collected by filtration providing 2.80 g (44%) of 2-[(3-trifluoromethylphenyl)amino]-benzoic acid, 2-(aminothioxomethyl)hydrazide.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[C:4]([CH3:27])[CH:3]=1>C1COCC1.CO.[Pt](=O)=O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:13]3[C:18]4=[N:19][S:20](=[O:24])(=[O:23])[CH2:21][CH2:22][N:17]4[CH2:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=2)=[C:4]([CH3:27])[CH:3]=1
Reactant: Cc1cc(F)ccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(4-fluoro-2-methylphenoxy)phenyl]-3,4-dihydropyrid o[2,1-c][1,2,4]thiadiazine 2,2-dioxide (303 mg) in THF (dry) (30 mL) and MeOH (30 mL) and the mixture was stirred at 50° C. under hydrogen for 4 hr. The starting material was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and recovered. Platinum(IV) oxide (30 mg) was added to a solution of the purified starting material in THF (dry) (30 mL) and MeOH (30 mL) and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from MeCN/IPE to give the title compound (115 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([NH:13][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccnc2c(N)cccc12
Product: COc1ccnc2c(NS(=O)(=O)c3ccccc3)cccc12
Yield: 17.1 %

Procedure:
In a similar fashion using route 14 general procedure 26, 4-methoxy-quinolin-8-ylamine (Intermediate 71) (71 mg, 0.41 mmol), benzenesulfonyl chloride (79 mg, 0.44 mmol) gave the title compound (22 mg, 17%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].Cl.Cl.[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:18]([C:20]3[CH:21]=[C:22]([Cl:33])[C:23]([C:31]#[N:32])=[C:24]4[C:30]=3[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)[CH3:19])[N:15]=[C:16]([CH3:17])[C:9]=12.C(N(CC)CC)C>CN(C)C=O>[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:18]([C:20]3[CH:21]=[C:22]([Cl:33])[C:23]([C:31]#[N:32])=[C:24]4[C:30]=3[O:29][CH2:28][CH2:27][N:26]([CH2:2][CH2:3][OH:4])[CH2:25]4)[CH3:19])[N:15]=[C:16]([CH3:17])[C:9]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCNC3)c2ncnc(N)c12
Reactant: OCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(CCO)C3)c2ncnc(N)c12
Temperature: 80 °C
Yield: 479.4 %

Procedure:
2-Bromoethanol (4.7 μL, 0.066 mmol) was added to a mixture of 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (15 mg, 0.039 mmol) (from Example 46, step 13) and triethylamine (10 μL, 0.09 mmol) in N,N-dimethylformamide (2 mL). The reaction was heated at 80° C. for 3 h and then allowed to cool. The product was purified without workup by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the desired compound as white amorphous solid (0.08 g, 50%). LCMS calculated for C20H23ClN7O2 (M+H)+: m/z=428.1; found: 428.2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[C:14]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:15][C:16]([CH3:20])=[C:17]([CH3:19])[CH:18]=1>>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:14]3[C:13]([CH3:12])=[CH:18][C:17]([CH3:19])=[C:16]([CH3:20])[N:15]=3)[CH2:22][CH2:23]2)=[O:8])=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: Cc1cc(F)ncc1C(=O)O
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2nc(C)c(C)cc2C)CC1
Yield: 83.8 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (119 mg) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (170 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (220 mg) was obtained.
Reaction SMILES: [C:1](Cl)(=[O:17])[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].C1C=CN=CC=1.[FH:25]>>[C:1]([F:25])(=[O:17])[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: F
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)F
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
Palmitoyl chloride (651 mg, 2.2 mole) was added to pyridinium poly(hydrogen fluoride) (1 ml) in a teflon reaction vial and the mixture stirred at 20° C. for 20 min. After cooling to 0° C., it was quenched with ice-water (5 ml), extracted with ethyl acetate, and the organic layer washed (water, brine), dried over anhydrous magnesium sulfate, concentrated and evaporatively distilled (120° C./0.025 torr) to give palmitoyl fluoride (76%) (contaminated with 5% of the corresponding acid). Since this concentration of contaminant is not harmful to the biological activity of the compound, no further purification is required.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][N:17]([CH3:34])[S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24]([OH:26])=O)(=[O:20])=[O:19]>>[CH3:34][N:17]([CH3:16])[S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:26])(=[O:19])=[O:20]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-[(dimethylamino)sulfonyl]-5-(trifluoromethyl)benzoic acid (Butt Park Ltd.). The product was purified a second time using preparative HPLC (Phenomenex Gemini® column) and a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2). Light brown foam (20%). MS (ESI): m/z=478.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:9]([C:12](=[O:19])[CH:13]([O:17]C)[CH:14]([CH3:16])[CH3:15])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH:14]([CH:13]1[C:12](=[O:19])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=2)=[C:10]([NH2:11])[O:17]1)([CH3:16])[CH3:15]
Reactant: COC(C(=O)C(C#N)c1cccc(C(F)(F)F)c1)C(C)C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)C1OC(N)=C(c2cccc(C(F)(F)F)c2)C1=O
Reaction time: 8 h

Procedure:
In this example, a mixture containing 11.4 g of (3-trifluoromethylphenyl)-(2-methoxyisovaleryl)acetonitrile and 7.8 g of concentrated sulfuric acid in 50 ml of acetic acid was warmed to reflux for 30 minutes and then concentrated by evaporation under vacuum. The concentrate was mixed with diethylether, washed three times with 1N aqueous sodium hydroxide, dried over magnesium sulfate and concentrated by evaporation affording an oil. The oil was triturated in 20% (vol.) ethyl acetate:80% petroleum ether and allowed to stand overnight (14-16 hours). The solids were collected by filtration and washed three times with 20% (vol.) ethyl acetate:80% petroleum ethyl affording 2.9 g of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([O:17][C:18](=[O:20])[CH3:19])[C@@H:10]([CH2:21][N:22]=[N+:23]=[N-:24])[O:9][C@@H:6]1OC)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[C:30]([OH:33])(=[O:32])[CH3:31]>C(OC(=O)C)(=O)C>[C:30]([O:33][C@H:6]1[O:9][C@H:10]([CH2:21][N:22]=[N+:23]=[N-:24])[C@@H:11]([O:17][C:18](=[O:20])[CH3:19])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:5]1[O:4][C:1](=[O:3])[CH3:2])(=[O:32])[CH3:31]
Reactant: CO[C@H]1O[C@H](CN=[N+]=[N-])[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1O[C@H](CN=[N+]=[N-])[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 82 %

Procedure:
To a solution of methyl 2,3,4-tri-O-acetyl-6-azido-6-deoxy-α-D-glucopyranoside (III, 1.0 g, 2.9 mmol) in acetic acid (20 mL) and acetic anhydride (20 mL) at 0° C. was added sulfuric acid (97%, 1 mL) and the mixture was stirred at rt for 20 hr and then poured into ice (100 g). Extraction with dichloromethane (3×50 mL) and washed with water, saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with 1:1 hexane-ethyl acetate, to give IV (886 mg, 82%) as a white foam. 1H NMR (500.1 MHz) (CD3Cl) δ: 6.28 (d, J=4.0 Hz, 1H), 5.41 (t, J=9.5 Hz, 1H), 5.03 (m, 2H), 4.03 (m, 1H), 3.24-3.37 (m, 2H), 2.13 (s, 3H), 2.04 (s, 3H), 1.99 (s, 3H), 1.95 (s, 3H). 13C NMR (125.8 MHz) (CDCl3) δ: 170.11, 169.53, 169.33, 168.62, 88.78, 70.83, 69.58, 69.08, 68.94, 50.61, 20.75, 20.55, 20.46, 20.34.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[N:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[C:15]=[O:16]>CN(C)C=O.ClCCl>[F:24][C:23]([F:25])([F:26])[C:19]1[CH:18]=[C:17]([NH:14][C:15]([N:2]2[CH2:3][CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A solution of 2,3,4,9-tetrahydro-1H-β-carboline (172 mg) in dimethylformamide (5 mL) was added by a solution of 1-isocyanato-3-(trifluoromethyl)benzene (173 mg) in dichloromethane (5 mL) and stirred overnight at the room temperature. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=6:1) to give the title compound (205 mg) having the following physical data.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21](O)[CH2:22][CH2:23][OH:24]>>[C:1]([O:20][CH2:3][CH2:2][CH2:1][O:19][C:23](=[O:24])[CH2:22][CH2:21][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: OCCCO
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
(Diester of GLA and Oleic Acid with 1,3-Propane Diol).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@H:11]([O:17][CH3:18])[C@@H:10]1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](I)[CH3:21]>>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[CH2:15][O:16][C@H:12]([O:13]2)[C@H:11]([O:17][CH3:18])[C@@H:10]1[O:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CO[C@H]1[C@@H]2OC[C@@H](O2)[C@@H](OCc2ccccc2)[C@H]1O
Product: CCO[C@H]1[C@@H](OC)[C@@H]2OC[C@@H](O2)[C@H]1OCc1ccccc1

Procedure:
The title compound was prepared from 1,6-anhydro-4-O-benzyl-2-O-methyl-β-D-allopyranose (0.135 g) (see Example 29) in the same way as described for the 3-O-methyl analogue (see Example 30) but employing ethyl iodide (0.624 g) instead of methyl iodide. It was obtained as a colourless oil (0.089 g); 1H-nmr data: 7.2-7.5 (m, Ph), 5.6 (d, H-1), 4.8 (m, PhCH2O), 4.55 (m, H-5), 1.25 (t, CH2CH3), and 3.4-3.7 (m, remaining protons).