Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:15])[C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>CCCCCC.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][C:11]2([CH3:12])[CH3:13]
Reactant: CC(C)=CC(=O)N(C)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)CC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
N-(4-bromophenyl)-N-methyl-3-methyl-2-butenamide (Intermediate 54, 6.42 g, 24 mmol) was heated to 130° C. and aluminum chloride (5 g, 37.4 mmol) was added in portions over 0.5 h. The reaction mixture was stirred for 1 hour at the same temperature and then cooled to room temperature. Ice was added cautiously to the solid, followed by˜200 mL of iced water. The reaction mixture was then extracted with ether (×2) and dichloromethane (×1) and the combined organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo to yield a brown solid. The solid was treated with hexane-dichloromethane and filtered to afford 1.7 g of product. The mother liquor was evaporated and purified by flash column chromatography on silica gel (230-400 mesh) to afford 2.9 g of the title compound as a solid (total 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15]C)=[O:14])[CH2:10][CH2:9][N:8]2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.[Li+].[OH-].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][CH2:9][N:8]2[C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(Cl)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Dimethyl 2-(4-chlorobenzyl)piperidine-1,4-dicarboxylate (4.74 g, 14.55 mmol) was dissolved in tetrahydrofuran (15 mL) followed by addition of LiOH (0.430 g, 17.97 mmol), MeOH (10 mL) and water (10 mL). The reaction mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was taken up in water. The pH was adjusted to <2 by addition of 2 M HCl. The product was poorly soluble and attempts to extract the aqueous phase with DCM and ethyl acetate failed. Instead the mixture was concentrated and then filtered, washed with water and dried to give a yellow solid material. The water phase did contain some product and was extracted with DCM (×3) and dried with a phase separator to give about 500 mg. Crude 2-(4-chlorobenzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.27 g, quant.) was isolated. MS m/z 312, 314 (M+H)+
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].I[CH3:14].[H-].[Na+].[H][H]>O1CCCC1.O>[CH3:14][O:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH2:12])=[CH:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: C=Cc1ccc(C(C)(C)O)cc1
Reactant: [H][H]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)(C)OC)cc1
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A solution of 4.10 g of 1-(1-hydroxy-1-methylethyl)-4ethenyl-benzene in 25 ml of dry tetrahydrofuran containing 7 g of iodomethane was heated to 40°-50° C. and treated portionwise in a dry atmosphere with 1 g of a sodium hydride dispersion (60% NaH in mineral oil) under rapid stirring. Reaction was accompanied by evolution of hydrogen. Once the addition was complete stirring was continued for another 30 minutes. The cooled mixture was then poured into water and extracted with ether. The organic phase was then washed with brine, dried over magnesium sulfate and evaporated to yield a crude product which was purified by preparative HPLC using ethyl acetate-hexane as the eluent to afford 2.25 g (51%) of the desired methyl ether.
Reaction SMILES: [Li+].[OH-].[F:3][C:4]([F:33])([F:32])[C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]([C:27]([O:29]C)=[O:28])[CH2:15]2)=[CH:7][CH:6]=1.Cl>C1COCC1.CO.O>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:12]([NH:11][C:8]2[CH:9]=[N:10][C:5]([C:4]([F:32])([F:33])[F:3])=[CH:6][CH:7]=2)=[O:31])[CH2:15][C@@H:16]1[C:27]([OH:29])=[O:28])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)Nc2ccc(C(F)(F)F)nc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(F)(F)F)nc2)C[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
LiOH (118 mg, 4.93 mmol) was added to a solution of (2R,4R)-1-tert-butyl 2-methyl 4-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidine-1,2-dicarboxylate (550 mg, 1.23 mmol) in THF/MeOH/water (3:2:1) (24 mL) and the resulting solution was stirred at room temperature for 18 hours. 1M HCl solution was added to reaction solution to adjust the pH to about 3, extracted with ethyl acetate (2×50 mL). The organic layers were dried over MgSO4 and concentrated to give the acid as a white solid 500 mg (94%). LC-MS: 433.2, 431.3; (t=2.1 min.)
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[S-2:15].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH:21]1[CH2:27][N:26]([CH3:28])[C:25](=O)[C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=2[O:22]1>C1(C)C=CC=CC=1>[Cl:18][CH2:19][CH2:20][CH:21]1[CH2:27][N:26]([CH3:28])[C:25](=[S:15])[C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=2[O:22]1
Reactant: CN1CC(CCCl)Oc2ccccc2C1=O
Reactant: [S-2]
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccccc2C1=S

Procedure:
A mixture of 18.5 g (0.0834 mole) of phosphorus pentasulfide and 18.5 g potassium sulfide was ground together and added to a solution of 100 g (0.417 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in dry toluene, the mixture refluxed 24 hr. and filtered. The filtrate was concentrated and partitioned between chloroform and diluted sodium hydroxide. The chloroform layer was concentrated and the residue was crystallized several times from ethanol. Yield of product was 55 g (52%), m.p. 105°-108° C.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[OH:9][CH2:10][C:11]([CH3:15])([CH2:13]O)[CH3:12].S(=O)(=O)(O)O>ClCCl>[CH3:12][C:11]1([CH3:15])[CH2:10][O:9][C:4]2([CH2:5][CH2:6][C:1](=[O:8])[CH2:2][CH2:3]2)[O:7][CH2:13]1
Reactant: O=C1CCC(=O)CC1
Reactant: CC(C)(CO)CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(C)COC2(CCC(=O)CC2)OC1

Procedure:
1,4 cyclohexane dione (25.0 grams) and neopentyl glycol (23.5 grams) were dissolved in dichloromethane (200 ml). Then sulfuric acid (4.0 grams) was added to the reaction solution at an ambient temperature and stirred till the reaction substantially completes, accompanied by cooling the reaction mixture to 10–20° C. The resulting reaction mixture was washed with saturated aqueous sodium bicarbonate solution (100 ml) and separated the organic layer from the resulting biphasic mixture. The solvent was distilled off from organic layer till substantial completion under reduced pressure. n-Heptane (250 ml) was added to the resulting residual mass and followed by cooling the reaction mass to a temperature of 0–5° C. to filter the by-products. Then the solvent from the filtrate was distilled off till the substantial completion under vacuum to yield the desired 1,4 cyclohexanedione mono-2,2-dimethyl trimethylene ketal.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)=[CH:4][CH:3]=1.C=O.[C:20](=O)([O-])[O-:21].[K+].[K+].C(O)(C)C>O.CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9]([CH2:20][OH:21])=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc(-c2nc(-c3cccnc3)c[nH]2)s1
Agent: C=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)O
Product: OCc1[nH]c(-c2ccc(Cl)s2)nc1-c1cccnc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A mixture of 2-(5-chlorothiophen-2-yl)-4-(3-pyridyl) imidazole (1.07 g), 35% formalin aqueous solution (35 ml), potassium carbonate (1.70 g), isopropanol (30 ml) and N,N-dimethyl-formamide (10 ml) was stirred at 90° C. for 2 hours. After cooling, water was added to the mixture and precipitated solid was collected by filtration. The solid was dissolved in methanol and, after removing insolubles by filtration, the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate to obtain 2-(5-chlorothiophen-2-yl)-5-hydroxymethyl-4-(3-pyridyl)imidazole (519 mg) as colorless powder.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12]2[N:16]=[C:15]([NH:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:14][N:13]=2)[C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.CO.[OH-].[Na+]>O1CCCC1>[CH:1]1([O:4][N:5]=[C:6]([C:12]2[N:16]=[C:15]([NH:17][C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:14][N:13]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(=NOC1CC1)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=NOC1CC1)c1nsc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A solution of ethyl 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetate (syn isomer)(11 g) in a mixture of tetrahydrofuran (72 ml), methanol (72 ml) and 2N sodium hydroxide (72 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water and adjusted to pH 2 with 3N hydrochloric acid. The organic layer was separated, washed with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo, and triturated with petroleum ether to give 2-cyclopropyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (7.75 g) as a solid.
Reaction SMILES: [C:1]([CH2:3][N:4]1C(=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:5]1(=[O:7])=[O:6])#[N:2].[CH3:16][O-:17].[Na+].Cl.[CH3:20][OH:21]>>[C:16]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH2:3][C:1]#[N:2])(=[O:7])=[O:6])([O:21][CH3:20])=[O:17]
Reactant: CO
Reactant: N#CCN1C(=O)c2ccccc2S1(=O)=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1ccccc1S(=O)(=O)NCC#N
Reaction time: 1 h

Procedure:
To a suspension of N-cyanomethylsaccharin (276 g) in methanol (1000 ml) was added dropwise 28% sodium methoxide (145 ml) over 30 minutes at 5°-10° C. After stirring at 5°-10° C. for 1 hour, 6N HCl (ca. 230 ml) was added dropwise maintaining the temperature at 10°-15° C. The resulting crystals were collected by filtration, washed with water and dried in vacuo at 50° C. for 16 hours to give o-carbomethoxy-N-cyanomethylbenzenesulfonamide, 264 g (78.7%).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[Cl:23][SiH:24]([Cl:26])[Cl:25]>>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Si:24]([Cl:26])([Cl:25])[Cl:23])=[CH:17][CH:16]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCCP(CCCC)CCCC
Product: Fc1ccc(C[Si](Cl)(Cl)Cl)cc1
Yield: 87.6 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 1.08 g (7.5 mmol) of 4-fluorobenzyl chloride, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.6 g of (4-fluorobenzyl)trichlorosilane (bp; 56° C./13 mmHg, yield; 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:13]([C:14]#[N:15])=[C:12]([N:16]=[CH:17][N:18](C)C)[NH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]1([C@H:27](N)[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:13]3[C:12](=[N:16][CH:17]=[N:18][C:14]=3[NH:15][C@@H:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:28])[NH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=Nc1[nH]nc(Nc2cccc(Cl)c2)c1C#N
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](Nc1ncnc2[nH]nc(Nc3cccc(Cl)c3)c12)c1ccccc1
Product: Cl
Temperature: 120 °C
Reaction time: 40 h

Procedure:
Under a nitrogen atmosphere, a mixture of 1.5 g (5.19 mmol) of 3-(3-chloro-phenylamino)-4-cyano-5-(dimethylamino-methyleneamino)-pyrazole (Step 49.2) and 10 ml of (R)-1-phenylethylamine is stirred at 120° C. for 40 hours and then concentrated by evaporation under a HV. The oily residue is purified by flash chromatography on silica gel having a particle size of 0.04-0.06 mm using ethyl acetate/hexane (7:3). The product-containing fractions are concentrated by evaporation and the resinous residue is dissolved in a mixture of 5 ml of ethanol and 1.4 ml of 4N hydrochloric acid. Concentration by evaporation again and recrystallization of the residue from ethanol/diethyl ether and from ethanol yield the title compound; m.p. 150-152° C.; EI-MS: (M)+ =364; [a]D20 =-233.7±2.1° (c=0.486% methanol).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Br:26][C:27]1[CH:28]=[N:29][C:30](I)=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:30]3[N:31]=[CH:32][C:27]([Br:26])=[CH:28][N:29]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Brc1cnc(I)nc1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1ncc(Br)cn1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 187 mg (0.66 mmol) of 5-bromo-2-iodo-pyrimidine in 2 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 31 mg of a white powder. LC-MSD, m/z for C20H12Br2N4O2 [M+H]+=498.9, 500.9, 502.9; HPLC retention time: 2.2 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1.IC.[C:29]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:29][O:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1
Reactant: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(O)cnc23)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCC1CC(=O)N(Cc2c(-c3ccccc3)nn3cc(OC)cnc23)C1
Yield: 30.5 %

Procedure:
To a solution of 1-[(6-hydroxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one x149 (1.71 mmol, 1 eq, 0.6 g) in acetone (100 ml) is added iodomethane (17.1 mmol, 10 eq, 1.065 ml) and K2CO3 (17.1 mmol, 10 eq, 2.36 g). The mixture is refluxed for 5 minutes. Solvent is evaporated under reduced pressure. The crude product is purified by chromatography on silicagel (AcOEt/hexane:1/1) and recrystallized in AcOEt to afford 0.19 g of 1-[(6-methoxy-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 204.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:26])[CH:17]=[C:18]([N:20]2[CH2:24][CH2:23][CH2:22][C@@H:21]2[CH3:25])[CH:19]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][C:16]2[CH:17]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][C@@H:21]3[CH3:25])[CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: COc1cc(N)cc(N2CCC[C@@H]2C)c1
Reactant: Clc1nc(Cl)c2ncsc2n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(Nc2nc(Cl)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Temperature: 30 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
The mixture of 5,7-dichlorothiazolo[5,4-d]pyrimidine (200 mg, 0.97 mmol), (S)-3-methoxy-5-(2-methylpyrrolidin-1-yl)benzenamine (220 mg, 1.07 mmol) and DIPEA (150 mg, 1.17 mmol) in DMSO (50 mL) was heated to 30° C. with stirring for 16 h. The mixture was diluted with water, extracted with ethyl acetate (50 mL), combined organics washed with water (10 mL×4) then brine (10 mL×2), dried over Na2SO4 and concentrated to give the residue which was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to afford (S)-5-chloro-N-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenyl)thiazolo[5,4-d]pyrimidin-7-amine (280 mg, 77%) as yellow oil. LC-MS: 376 [M+H]+, tR=1.825 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:23][CH:22]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:29](=[O:31])[CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([OH:20])=[CH:26][CH:25]=1
Reactant: CCCCCCCNCc1cccc(OC)c1OC
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
N-(2,3-Dimethoxybenzyl)-N-heptylamine (0.70 g, 2.65 mmol) was dissolved in DM (10 ml), 3-(4-hydroxyphenyl)propanoic acid (0.4 g, 2.41 mmol), was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.85 g, 2.65 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). EtOAc was removed by evaporation and the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation and gave 0.98 gram N-(2,3-dimethoxybenzyl)-N-heptyl-3-(4-hydroxyphenyl)propanamide (yield 70%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.C(C1C=C2C([C:20](=[O:26])CCO2)=CC=1)(C)(C)C.[NH3:27]>>[CH3:20][O:26][N:27]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2][CH2:3]1
Reactant: O=C1CCOc2ccccc21
Reactant: N
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2=O
Product: CON=C1CCOc2ccccc21

Procedure:
The title compound was prepared using the procedure as described in Example 1B, substituting chroman-4-one for the product of Example 1A. 1H NMR (300 MHz, d6-DMSO) δ 7.79 (dd, J=1.0 and 7.5 Hz, 1H), 7.28 (m, 1H), 6.90 (m, 2H), 4.18 (t, J 6.0 Hz, 2H), 3.90 (s, 3H, minor), 3.88 (s, 3H, major), 2.82 (t, J 6.0 Hz, 2H). MS (DCI/NH3) m/e 178 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1.[CH3:20][N:21]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:22](Cl)=[O:23].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:22](=[O:23])[N:21]([CH3:20])[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1
Reactant: C=CCCN1CCC(O)N(c2nnc(OC)s2)C1=O
Reactant: CN(C(=O)Cl)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCCN1CCC(OC(=O)N(C)C2CCCCC2)N(c2nnc(OC)s2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), N-methyl-N-cyclohexylcarbamoyl chloride (0.06 mole), pyridine (0.06 mole) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 3 hours. After this time the reaction mixture is cooled to room temperature and is filtered to remove pyridine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvent leaving a residue. The residue is recrytallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-(N-methyl-N-cyclohexylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:36]([CH2:38][NH2:39])[OH:37]>O1CCCC1.O>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:39][CH2:38][CH2:36][OH:37])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: NCCO
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)NCCO
Yield: 94 %

Procedure:
6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid was dissolved in 50 ml of tetrahydrofuran and 3.1 ml of triethylamine was added thereto. While cooling the mixture in ice with stirring, 2.1 ml of ethyl chlorocarbonate was added dropwise. Then the mixture was stirred for 15 minutes and 1.8 ml of ethanolamine was added thereto. After the mixture was stirred for 30 minutes at room temperature, water was added thereto and the resulting aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was separated from the aqueous layer, washed with 5% aqueous hydrochloric acid solution and then water, and dried over magnesium sulfate. The solvent was distilled off. The resulting reaction mixture was subjected to chromatography on silica gel column to afford 6.5 g (yield 94%) of the title compound as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].IC1C=CC(C(O)=O)=CC=1[N+]([O-])=O.S(Cl)(Cl)=O.[Cl:31][C:32]1[CH:38]=[C:37]([C:39]([F:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])[CH:36]=[C:35]([C:49]([F:52])([F:51])[F:50])[C:33]=1[NH2:34]>>[Cl:31][C:32]1[CH:38]=[C:37]([C:39]([F:48])([C:40]([F:42])([F:43])[F:41])[C:44]([F:45])([F:47])[F:46])[CH:36]=[C:35]([C:49]([F:50])([F:51])[F:52])[C:33]=1[NH:34][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Agent: O=C(O)c1ccc(I)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1ccc(I)c([N+](=O)[O-])c1

Procedure:
According to the method of 1-3 of Example 1, a target compound was prepared from 4-iodo-3-nitrobenzoyl chloride prepared from 4-iodo-3-nitrobenzoic acid and thionyl chloride, and 2-chloro-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)aniline.