Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[CH:6]2.P(Cl)(Cl)([Cl:16])=O.C([O-])(O)=O.[Na+]>>[Cl:16][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc2c(Cl)nccc2c1
Temperature: 90 °C
Yield: 86.4 %

Procedure:
A slurry of 6-methoxyisoquinolone (116 g, 662 mmol) in phosphorous oxychloride (200 mL, 2.14 mol) was charged to a rotavap flask. The resulting thick paste was heated on the rotovap to 90° C. for ˜30 min. The reaction thinned to a thick black solution with gas evolution then became pasty again, and was heated continuously at 90° C. for an additional 30 min and checked by TLC. An additional quantity of phosphorous oxychloride (100 mL, 1.07 mol) was added and the reaction was heated continuously for another 2 h. The reaction was complete (checked by TLC; complete consumption of starting material with some production of a polar impurity) so the excess POCl3 was removed under high vacuum to leave a solid mass of crude product. This solid mass was triturated with ethyl acetate (500 mL) at 0° C. for 3.5 h. The solid product was filtered and washed with cold ethyl acetate (250 mL). Mother liquors contained essentially no product and were discarded. The weight of this crude solid salt was ˜208 grams. This salt was dissolved in a mixture of cold ethyl acetate (1000 mL) and water (1000 mL) and neutralized to pH=6.75 with NaHCO3 (209 g, 2.49 mol, 3.75 eq based on starting material). The phases were split, and the aqueous phase was back extracted with ethyl acetate (500 mL) and combined with the first product containing the ethyl acetate phase. The ethyl acetate was removed under reduced pressure to yield 110.8 g crude residue. In order to remove the polar impurity, this residue was dissolved in a mixture of ethyl acetate 200 mL and heptanes 100 mL and passed through a silica gel plug (500 g) and eluted with a mixture of ethyl acetate/heptanes 1:1. The product containing fractions was concentrated to a residue to provide pinkish-yellow solids. These solids were recrystallized from hot (˜75° C.) heptanes (1000 mL) and cooled to rt then to 0° C. Filtration and washing with cold heptanes (250 mL) followed by drying under vacuum provided purified 1J as a off-white crystalline solid. (98.02 g, 506 mmol, 76.5%).
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:17]([C:22](O)=[O:23])#[C:18][C:19]([OH:21])=[O:20]>>[CH2:11]([N:10]1[C:22](=[O:23])[C:17](=[CH:18][C:19]([OH:21])=[O:20])[S:9][C:8]1=[N:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCNC(=S)NCCCCCC
Reactant: O=C(O)C#CC(=O)O
Product: CCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCC
Yield: 31.6 %

Procedure:
Prepared by the method described in Example 1 from N,N'-dihexylthiourea (114.2 g, 468 mmoles) and acetylenedicarboxylic acid (53.4 g, 468 mmoles). Recrystallization from acetonitrile gave the product (50.4 g) mp 66°-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[C:19]([C:25]([O:27][CH3:28])=[O:26])#[C:20][C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:24][O:23][C:21]([C:20]1[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]=1[C:25]([O:27][CH3:28])=[O:26])=[O:22]
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1ccccc1NCC(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)cn(-c2ccccc2OC)c1C(=O)OC

Procedure:
A solution of 7,4 g of 2-(2-methoxyphenyl)amino-1-phenyl-ethan-1-one and 11,3 ml of dimethyl acetylenedicarboxylate in 150 ml of toluene is refluxed for 12 hours and then the solvent is eliminated in vacuo. The residue remaining is taken up in ethyl acetate and washed with water. After the organic phase has been dried the solvent is distilled off in vacuo and the residue remaining is chromatographed on silica gel (n-hexane:ethyl acetate 80:20). 9,4 g of 2,3-di(methoxycarbonyl)-1-(2-methoxyphenyl)-4-phenyl-pyrrole are obtained as a colourless oil.
Reaction SMILES: [OH:1][C:2]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][C:5]2[CH2:6][C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13]Cl)[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1>>[OH:1][C:2]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][C:5]2[CH2:6][C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][N:27]([CH3:26])[CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=3)[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1Cc2cc(OCc3ccccc3)c(O)cc2CCN1CCCCl
Reactant: CNCCc1ccc(OC)c(OC)c1
Product: COc1ccc(CCN(C)CCCN2CCc3cc(O)c(OCc4ccccc4)cc3CC2=O)cc1OC

Procedure:
This compound was prepared analogous to Example 5(b) by reacting 1-(7-hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2-H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[NH:7][C:8]1[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=1[C:10]([NH:12][CH2:13][CH2:14][O:15][CH2:16][CH3:17])=[O:11])([O-:3])=[O:2].[H-].[Na+].CN(C)[C:29](Cl)=[O:30].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:10](=[O:11])[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH3:17])[C:29]2=[O:30])[CH:22]=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CCOCCNC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
3.3 g of 2-(m-nitroanilino)-N-(2-ethoxyethyl)benzamide was dissolved in 30 ml of dry tetrahydrofuran, and to the solution was added 1.0 g of approximately 50 % sodium hydride. After stirring the mixture for 30 minutes, 3.2 g of N,N-dimethylcarbamoyl chloride was further added dropwise under cooling, and the whole was refluxed for 4 hours. After the reaction was complete, the solvent was evaporated from the resulting mixture under reduced pressure. To the residue thus obtained was added water to yield a crude product. This product was recrystallized from ethanol to give 3.1 g of 1-(m-nitrophenyl)-3-(2-ethoxyethyl)quinazoline-2,4(1H, 3H)-dione as pale yellow prisms, melting at 161°-162° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[N+]([O-])(O)=[O:13]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:13])=[O:11]
Reactant: OCCCCCCCCCBr
Reactant: O=[N+]([O-])O
Product: O=C(O)CCCCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
9-Bromo-1-nonanol (4 g, 18 mmol) was placed in a flask, cooled on an ice bath, and concentrated nitric acid (40 mL) was slowly added. The solution was stirred at 0° C. for 30 minutes then allowed to warm to room temperature and stirring continued overnight. The solution was poured onto ice and extracted with DCM (3×150 mL). The combined extracts were washed with water (3×150 mL) and the solvent then removed in vacuo to give an oil 3.82 g (94%);
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15].[CH2:19]([SH:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>ClCCl>[CH3:18][O:17][C:13]([CH2:14][S:15][S:27][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:16]
Reactant: CCCCCCCCS
Reactant: COC(=O)CS
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Product: CCCCCCCCSSCC(=O)OC
Reaction time: 1.5 h

Procedure:
In a N2 purged flask there was dissolved Diethyl azodicarboxylate (5.0 g, 28.71 mmol) in dichloromethane (150 mL). A solution of Methyl thioglycolate (2.89 g, 27.27 mmol) in dichloromethane (50 mL) was then added dropwise at room temperature over 20 minutes. After 1.5 hours stirring, a solution of octanethiol (4.8 mL, 27.27 mmol) in dichloromethane (50 mL) was added dropwise over 20 minutes, and the resulting solution was stirred for an additional 12 hours at room temperature. The solvent was then removed under reduced pressure, and the resulting oil was then purified over flash silica with 5% ethyl acetate in hexanes to yield MeOC(O)CH2SSC8H17 as a clear, colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(NCc2ncc(C(F)(F)F)cc2Cl)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-aminomethyl-3-chloro-5-(trifluoromethyl) pyridine hydrochloride and DBU in DME. ES-MS m/e (%): 397 (M{37Cl}+H+, 30), 395 (M{35Cl}+H+, 100).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[CH3:24][S:21]([C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([OH:25])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18])(=[O:23])=[O:22]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A solution of 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.17 g, 3.01 mmol) in tetrahydrofuran (12 mL) was treated with a 0.8M aqueous lithium hydroxide solution (5.6 mL, 4.52 mmol). The reaction mixture was stirred at 25° C. for 3 h. The resulting reaction mixture was partitioned between water (75 mL) and ethyl acetate (75 mL) and then treated with a 1N aqueous hydrochloric acid solution (10 mL). The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (1.10 g, 98%) as a white foam which was used without further purification: mp 64-68° C. (foam to gel); FAB-HRMS m/e calcd for C16H22O6S2 (M+H)+ 375.0936, found 375.0932.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9](Cl)(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(OCC)C>C(N(CC)CC)C>[C:9]([C:5]1[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1)(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NC(=O)c1nc[nH]n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)c1nc(C(N)=O)n[nH]1
Reaction time: 24 h

Procedure:
To a cooled, stirred mixture of 3 g. of 1,2,4-triazole-3-carboxamide and 7.4 g. of palmitoyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred. at room temperature for 24 hours. The mixture is filtered and the solid is washed successively with diethyl ether, cold water, diethyl ether and then dried in vacuo for 4 hours. The solid is extracted with hot dry acetonitrile and cooled yielding a colorless solid. The solid is redissolved by heating the mixture and allowed to recrystallize from the clear, colorless solution. The product is collected, washed with acetonitrile and dried in vacuo for 3 hours, yielding 0.75 g., m.p. 145°-160° C. (dec.).
Reaction SMILES: BrBr.[OH-:3].[Na+].[Cl:5][C:6]1[C:11]([CH2:12][CH3:13])=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:15](=[O:17])C.O>O1CCOCC1>[Cl:5][C:6]1[C:11]([CH2:12][CH3:13])=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:15]([OH:17])=[O:3]
Reactant: CCc1c(F)ccc(C(C)=O)c1Cl
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1c(F)ccc(C(=O)O)c1Cl
Temperature: 10 °C
Yield: 88.2 %

Procedure:
Bromine (8.94 g) was added to an aqueous solution (35.6 mL) of sodium hydroxide (7.61 g) with stirring at 10° C., and a solution (37.4 mL) of 1-(2-chloro-3-ethyl-4-fluorophenyl)ethanone (3.74 g) in dioxane was added under ice-cooling (sodium chloride-ice bath). The mixture was warmed to room temperature and, after stirring for 1 hr, poured into water and partitioned with chloroform. The aqueous layer was adjusted to pH=3 with concentrated hydrochloric acid, and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as colorless crystals (yield: 3.33 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].Br[CH2:8][CH2:9][CH2:10][C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:8][CH2:9][CH2:10][C:11]#[N:12]
Reactant: Sc1cccs1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCSc1cccs1
Yield: 93.7 %

Procedure:
2.3 g of thiophen-2-thiol, 3.0 g of 4-bromobutyronitrile and 5.5 g of potassium carbonate were stirred in N,N-dimethylformamide at room temperature to give 3.4 g of 4-(2-thienylsulfanyl)butane nitrile. 3.4 g of 4-(2-thienylsulfanyl)butane nitrile was reacted with 5.4 g of N-iodosuccinimide in N,N-dimethylformamide, whereby 5.5 g of the title compound was obtained as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:15]=[C:14](Cl)[C:13]([F:17])=[CH:12][C:9]=1[C:10]#[N:11].[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[Cl:7][C:8]1[N:15]=[C:14]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[C:13]([F:17])=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c(C#N)cc1F
Temperature: 60 °C
Reaction time: 10 h
Yield: 59.8 %

Procedure:
Potassium carbonate (3.62 g) and 2,6-dichloro-5-fluoronicotinonitrile (5.00 g) were added to a THF (50 ml) solution containing tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (5.61 g), followed by reflux at 60° C. for 8 hours. Then, the solvent was distilled away at 70° C. 1,4-dioxane (100 ml) was added to the resulting solution, followed by stirring at 100° C. for 10 hours. The reaction solution was adjusted to room temperature. Ethyl acetate and 2M hydrochloric acid were added to the reaction solution. The organic layers were collected. The organic layers were washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 2:1). Diisopropyl ether was added to the obtained oily matter and a solid precipitate was collected by filtration. A white solid of tert-butyl ((1S,2R)-2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)cyclohexyl)carbamate (5.77 g) was thus obtained.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:11]([C:13]([OH:15])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:23]([O:25][CH:26](Cl)[CH3:27])[CH3:24]>C(Cl)Cl>[C:1]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:11]([C:13]([O:15][CH:23]([O:25][CH2:26][CH3:27])[CH3:24])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(c1ccccc1)C(O)C(=O)O)c1ccccc1
Reactant: CC(Cl)OC(C)Cl
Solvent: ClCCl
Product: CCOC(C)OC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1

Procedure:
The epoxide of the cis-cinnamate is then regioselectively opened to produce 3-phenyl isoserinamide. This 3-phenyl isoserinamide is hydrolyzed to produce 3-phenyl-isoserine, which in turn is reacted with benzoyl chloride to form N-benzoyl-3-phenyl-isoserine. Next, the N-benzoyl-3-phenyl-isoserine is reacted with 1-chloroethyl ether and a tertiary amine in methylene chloride to form N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine. Then, N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine is reacted with the alcohol shown below: ##STR8## This resulting intermediate is converted to taxol by hydrolytically removing the 1-ethoxyethyl and triethylsilyl protecting groups.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]1[N:16]([CH2:17][C:18](O)=[O:19])[C:15](=[S:21])[NH:14][N:13]=1>C1COCC1>[OH:19][CH2:18][CH2:17][N:16]1[C:12]([C:8]2[S:7][CH:11]=[CH:10][CH:9]=2)=[N:13][NH:14][C:15]1=[S:21]
Reactant: O=C(O)Cn1c(-c2cccs2)n[nH]c1=S
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCn1c(-c2cccs2)n[nH]c1=S

Procedure:
To a slurry of LAH (38.1 mg, 1.00 mmol) in anhydrous THF (8 ml) was drop wise added (3-thiophen-2-yl-5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-acetic acid (101 mg, 0.42 mmol) in anhydrous THF (4 ml). The mixture was reacted for 2 h and then quenched with saturated aq. Na2SO4 (10 ml). THF was removed under reduced pressure and the residue was made acidic with aq. HCl (3N) and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine (15 ml), dried (MgSO4) and concentrated under reduced pressure. The crude product was used without purification in the next step. 1H NMR (DMSO-d6), δ (ppm): 13.94 (s, 1H), 7.86 (d, 1H); 7.81 (d, 1H), 7.24 (dd, 1H), 5.09 (t, 1H), 4.16 (t, 2H), 3.76 (app. q, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:5][C:4]=1[CH3:10]
Reactant: O=S(=O)(O)Cl
Reactant: COc1c(C)cccc1C
Product: COc1c(C)cc(S(=O)(=O)Cl)cc1C
Yield: 62.6 %

Procedure:
The title compound was prepared from 2-methoxy-1,3-dimethylbenzene (6.81 g, 50 mmol) and chlorosulfonic acid (6.65 mL, 100 mmol), according to the procedure and in the same manner as described in Example 58, step b to yield 4-methoxy-3,5-dimethylbenzenesulfonyl chloride (7.43 g, 31.3 mmol, 63%) as a white solid;
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)nc(Cl)n1
Yield: 69.7 %

Procedure:
To a solution of 2,4-dichloro-6-methylpyrimidine (998 mg, 6.0 mmol) in tetrahydrofurane (30 mL) was added at 0° C. under stirring N,N-diisopropyl ethyl amine (853 mg, 6.6 mmol) and morpholine (627 mg, 6.6 mmol) and the reaction was stirred over night at 20° C. The solvent was evaporated under reduced pressure and the residue was taken up in water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel using heptane/ethyl acetate (7:3 v/v) as eluent to yield the title compound (893 mg, 70%) as white crystals. MS ISP (m/e): 214.1/216.2 (100/34) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=6.73 (s, 1H), 3.65 (m, 4H), 3.58 (m, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][C:6]([C:9]([O:11]C)=[O:10])=[N:5]2)[CH2:3][CH2:2]1.O[Li].O>C1COCC1.O>[CH:1]1([N:4]2[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[N:5]2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccn(C2CC2)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccn(C2CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate (2.5 g, 15 mmol) was dissolved in THF (40 ml) and H2O (10 ml). LiOH.H2O (1.50 g, 22.5 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and acidified to pH 2 using 1 N HCl. The mixture was extracted with EtOAc and the organic layer was concentrated. Yield 1.6 g. 1H-NMR (400 MHz; DMSO-d6): δ 0.96-1.02 (m, 2H), 1.04-1.09 (m, 2H), 3.79-3.84 (m, 1H), 6.66 (d, 1H), 7.88 (d, 1H), 12.6 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[OH-:16].[CH3:17][N+:18]([CH3:21])([CH3:20])[CH3:19]>CO>[F:1][C:2]1[C:7]([S:8]([O-:16])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].[CH3:17][N+:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: [OH-]
Agent: C[N+](C)(C)C
Solvent: CO
Product: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pentafluorobenzenesulfonyl chloride (25 g) was dissolved in 100 ml of methanol under ice cooling, and 100 g of a 25% aqueous solution of tetramethylammonium hydroxide was slowly added thereto, followed by stirring at room temperature for 3 hours. Thus, a solution of tetramethylammonium pentafluorobenzenesulfonate was obtained. This solution was used for salt interchange with a sulfonium salt and an iodonium salt.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:8][O:9][N+:10]=2[O-:11])[N:5]=[CH:6][N:7]=1.[H-].[Li+].[CH3:14]I>C1COCC1.C(OCC)(=O)C>[CH3:14][N:7]1[C:2](=[O:1])[C:3]2=[N+:10]([O-:11])[O:9][N:8]=[C:4]2[N:5]=[CH:6]1
Reactant: CI
Reactant: [O-][n+]1onc2ncnc(O)c21
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cnc2no[n+]([O-])c2c1=O
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A solution of 3.0 g (20 mmol) of 7-hydroxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide (C. Temple, C. L. Kussner, J. A. Montgomery, J. Org. Chem. 33 (1968) 2086) in 30 ml of THF is added dropwise to a suspension of 0.18 g (22.5 mmol) of lithium hydride in 20 ml of THF. The mixture is heated at 40° C. for 30 minutes, then 11.5 g (80 mmol) of methyl iodide in 10 ml of THF are added dropwise at room temperature and it is allowed to stand for 2 days. The mixture is diluted with 300 ml of ethyl acetate, washed three times with water, dried over magnesium sulphate and concentrated in vacuo. After recrystallisation from isopropanol, 1.9 g (57%) of 6-methyl-[1,2,5]oxadiazolo[3,4-d]pyrimidine-7(6H)-one-1-oxide are obtained.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[F:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>O1CCCC1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:47][C:46]2[CH:48]=[CH:49][C:43]([F:42])=[CH:44][CH:45]=2)=[O:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C(=O)Nc2ccc(F)cc2)cc1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
A mixture containing 4-acetyl-benzoic acid (4 g, 0.0243 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.13 g, 0.02673 mol), triethylamine (3.7 ml, 0.02673 mol), 1-hydroxybenzotriazole (3.62 g, 0.02673 mol) and 4-fluoroaniline (2.81 ml; 0.02916 mol) in 60 ml of tetrahydrofuran is stirred for 48 hours at 23° C. The reaction medium is filtered on frit and evaporated to dryness. The residue is taken up in a mixture of solvents : ethyl acetate-water: 50-50. The precipitate is filtered on frit, washed with isopropyl ether then isopentane. After drying, a white-coloured powder is obtained.