Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[CH:10]([CH3:12])[CH3:11].[Br:26]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[Br:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][N:9]([CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)N(CCOCCCCO)C1CCN(Cc2ccccc2)CC1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)N(CCOCCCCBr)C1CCN(Cc2ccccc2)CC1

Procedure:
4-[N-(7-Hydroxy-3-oxahept-1-yl)-N-(isopropyl)amino]-1-benzylpiperidine (3.7 g, 10.6 mmol) was treated with dibromotriphenylphosphorane (11.2 g, 26.6 mmol) in dichloromethane for 2 h. The reaction mixture was then was washed with 1 N sodium hydroxide, saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give the title intermediate, which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].Cl.[NH2:9][OH:10].CCN(C(C)C)C(C)C>CCO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[N:9][OH:10])[NH2:7]
Reactant: N#Cc1nccs1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NO)c1nccs1
Yield: 93.1 %

Procedure:
Hydroxylamine hydrochloride (9.03 g, 130 mmol) was added to a solution of 1,3-thiazole-2-carbaldehyde (14.71 g, 130 mmol) and pyridine (10.5 mL, 130 mmol) in DCM (100 mL). The reaction mixture was stirred overnight at room temperature and then washed twice with water. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 15.26 g of 1,3-thiazole-2-carbaldehyde oxime (yield 92%). 1,3-thiazole-2-carbaldehyde oxime (15.23 g, 119 mmol, 1 equiv) was dissolved in 80 mL of dioxane and then TEA (41.4 mL, 2.5 equiv) was added. The reaction mixture was cooled to 0° C. and then trifluoroacetic anhydride (18.3 mL, 1.1 equiv) was added dropwise to the reaction. The solution was stirred overnight at room temperature and then evaporated. The residue was dissolved in DCM and then washed twice with water. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 1,3-thiazole-2-carbonitrile. This compound was used in the next step without further purification. 1,3-thiazole-2-carbonitrile (13.11 g, 119 mmol, 1 equiv), hydroxylamine hydrochloride (12.4 g, 1.5 equiv) and DIEA (33 mL, 1.6 equiv) were mixed in absolute EtOH (150 mL). The reaction mixture was refluxed 4 h and then the solvent was evaporated under reduced pressure. The residue was dissolved in AcOEt, washed twice with water and once with brine. The organic layer was dried over MgSO4 and then evaporated under reduced pressure to give 15.86 g of 1,3-thiazole-2-amidoxime (yield 93% over two steps).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.Cl.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([O:30][NH2:31])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ON1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([O:30][N:31]2[C:37](=[O:38])[C:36]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]3[C:34]2=[O:43])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NOC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCC(ON2C(=O)c3ccccc3C2=O)C1
Reaction time: 4 h
Yield: 90.7 %

Procedure:
10.05 g of diethylazodicarboxylate were added at 25° C. over 30 minutes to a solution of 10.8 g of the product of Step A, 8.24 g of N-hydroxyphthalimide and 13.25 g of triphenylphosphine in 225 ml of tetrahydrofuran and the mixture was stirred for 4 hours. Then, the solvent was evaporated under reduced pressure and the residue was chromatographed on silica (eluant: ethyl acetate-hexane 1-1) to obtain 13 g of the expected product in the form of 2 diastereoisomers.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[Br:6][C:7]1[N:8]=[C:9](S(C)(=O)=O)[C:10]2[N:11]([C:13]([I:16])=[CH:14][N:15]=2)[CH:12]=1>CN(C)C=O>[Br:6][C:7]1[N:8]=[C:9]([NH:4][CH2:3][CH2:2][CH2:1][NH2:5])[C:10]2[N:11]([C:13]([I:16])=[CH:14][N:15]=2)[CH:12]=1
Reactant: CS(=O)(=O)c1nc(Br)cn2c(I)cnc12
Reactant: NCCCN
Solvent: CN(C)C=O
Product: NCCCNc1nc(Br)cn2c(I)cnc12
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 1.26 mL propane-1,3-diamine in 8 mL 2.0 g N,N-dimethylformamide was added a solution of (4.98 mmol) 6-bromo-3-iodo-8-(methylsulfonyl)imidazo[1,2-a]pyrazine which was prepared according to intermediate example 60c in 20 mL N,N-dimethylformamide at 40° C. during 1.5 hours. The mixture was stirred at 40° C. for additional 1.5 hours. The solvent was removed and the residue was purified by chromatography to give 1.52 g (77%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: BrCc1ccccc1
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OCc1ccccc1
Yield: 74 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.4 g (1.10 mmol) thereof was dissolved in 5 ml of acetone, and 0.21 g (1.21 mmol) of benzyl bromide as a reaction reagent (XII) and 0.15 g (1.10 mmol) of potassium carbonate as a base were added. The resultant mixture was refluxed under heat for 3 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. Its organic layer was separated, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate=2:3) to give 0.37 g (yield 74%) of 4-methoxy-5-methyl-6-(5-benzyloxy-1-ethylpyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 62) as an end compound which comes under the general formula (XI). Table 21 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (I).
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:5]=2[CH:6]=[O:7])[CH2:3][CH2:2]1.Cl([O-])=[O:21].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[CH:1]1([C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:17])([F:18])[F:19])[C:5]=2[C:6]([OH:21])=[O:7])[CH2:3][CH2:2]1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 2-cyclopropyl-4,6-bis-trifluoromethyl-benzaldehyde (intermediate AM, 1.01 g, 3.58 mmol) was dissolved in 8.5 mL tert-butylalcohol and 4.5 mL 2-methyl-2-butene. At 0° C. a solution of sodium chlorite (340 mg, 3.76 mmol) and sodium dihydrogenphosphat (451 mg, 3.76 mmol) in 3 mL water was added. The reaction mixture was stirred at room temperature overnight. The solvents were evaporated off. The residue was taken up in 1N NaOH and extracted twice with tert-butyl methyl ether. The aqueous phase was adjusted to pH 2 by addition of 25% HCl and extracted twice with tert-butyl methyl ether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude material, off-white solid (1.01 g, 54%) was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.O.[NH2:19][NH2:20]>C(O)C>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:19][NH2:20])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: NN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: O
Solvent: CCO
Product: NNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
1.181 g (5.00 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was placed into a 25 ml flask equipped with a magnetic stirring bar. About 5 ml absolute ethanol was added and then 2.50 g (50.00 mmol) of hydrazine hydrate was added and the solution was stirred at room temperature in a closed flask. A large amount of precipitate formed after about 30 minutes and the solution was allowed to stand overnight. The solution was filtered by vacuum and the white solid was washed with ethanol and then with ether. Upon drying, 0.890 g of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid hydrazide (AIT-0056) as a white solid was obtained. Yield: 80%.
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH:6]=[C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:4]=1)[CH3:2].[CH3:12]O.N1CC[CH2:16][CH2:15]1.Cl>CC(C)=O>[C:8]([C:5]1[CH:6]=[C:7]([CH2:15][CH3:16])[C:3](=[C:1]([CH3:12])[CH3:2])[CH:4]=1)([CH3:10])([CH3:9])[CH3:11]
Reactant: CO
Reactant: C1CCNC1
Reactant: CCC1=CC(C(C)(C)C)=CC1
Agent: Cl
Solvent: CC(C)=O
Product: CCC1=CC(C(C)(C)C)=CC1=C(C)C
Temperature: 25 °C
Reaction time: 144 h
Yield: 74 %

Procedure:
To a 100 ml three-neck flask equipped with a magnetic stirrer chip and a three-way cock, 3.12 g (20.8 mmol) of 1-ethyl-3-tert-butylcyclopentadiene, 30 ml of methanol, 19 ml of acetone and 20 ml of pyrrolidine were charged under a nitrogen atmosphere, and stirred at room temperature for 6 days. The reaction solution was poured into 200 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted three times with 100 ml of ether. The obtained organic layers were combined, washed once with a saturated aqueous solution of sodium hydrogencarbonate, twice with water, and once with saturated brine, dried over magnesium sulfate, and purified by column chromatography to obtain 2.91 g of a orange solution. The yield was 74%. Identification was done by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=3)=[CH:24][N:23]=2)=[CH:18][CH:17]=1)[C:3]([NH:5][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7])=[O:4].[C:42]([C:46]1[S:50][C:49]([C:51](O)=[O:52])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[C:42]([C:46]1[S:50][C:49]([C:51]([NH:1][C@@H:2]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=4)=[CH:24][N:23]=3)=[CH:18][CH:17]=2)[C:3]([NH:5][C@@H:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH3:7])=[O:4])=[O:52])=[CH:48][CH:47]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](N)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N[C@H](C)C(=O)OC(C)(C)C)cc3)nc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
Prepared using General Procedure 7. To a stirred solution of tert-butyl ((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate (418 mg, 0.75 mmol), 5-(tert-butyl)thiophene-2-carboxylic acid (137 mg, 0.75 mmol) in DMF (8 mL) was added TEA (208 μl, 1.49 mmol). The mixture was cooled to 0° C. and HATU (298 mg, 0.78 mmol) was added in 2 portions over 5 mins. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EA (150 mL) and washed with saturated aqueous NaHCO3 (100 mL), 1N HCl (100 mL), and brine (100 mL). The organic layer was dried over MgSO4 then concentrated. The crude product was purified by chromatography 0-30% ACN in DCM to afford 382 mg (69%) of tert-butyl ((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate as a white solid. LCMS-ESI (m/z) calculated for C42H54N4O5S: 726.4; no m/z observed, tR=3.47 min (Method 11).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[C:13]([O-])([O-])=O.[K+].[K+].C.[I].CCOC(C)=O>CN(C=O)C>[CH3:13][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: C
Agent: [I]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 128.4 %

Procedure:
To a suspension of 20.0 g of 3-(trifluoromethoxy)phenol and 23.3 g of K2CO3 (anhydrous) in DMF (100 ml) was added 23.9 g of iodine methane under ice cooling, then the reaction mixture was warmed to room temperature, and was stirred at room temperature for 13 hours. To the reaction solution was added EtOAc (100 ml) and purified water (150 ml), and the resulting mixture was stirred for 30 minutes. After liquid separation, the aqueous layer was extracted with EtOAc (50 ml×2), the combined organic layer was washed with purified water (100 ml×3) and with saturated brine (50 ml) and dried overover MgSO4, then, the drying agent was separated by filtration, and the solvent was removed under reduced pressure to obtain 27.7 g of the title compound (crude form, yellow oil). The present compound was used in the next reaction without purification.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: NC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To 350 mg of N,N-dimethylformamide were added 100 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-aminoazetidine dihydrochloride and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 1 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 86 mg of the title compound as a colorless powder.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br>CCCCC>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][O:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CC(C)(C)OC(=O)N1CCCC(OCc2ccc(F)c(F)c2)C1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To sodium hydride (60% w/w dispersion in oil, 0.62 g, 16.4 mmol) washed in pentane was added N,N-dimethylformamide (20 ml) and then 1,1-dimethylethyl 3-hydroxypiperidine-1-carboxylate (Preparation 117, 3.0 g, 14.9 mmol). The reaction mixture was stirred for 1 h, before adding 3,4-difluorobenzyl bromide (2.0 ml, 16.4 mmol) and stirring the reaction mixture for 18 h. The reaction mixture was concentrated in vacuo and the crude residue was dissolved in dichloromethane and washed with brine and dried (MgSO4) before concentrating in vacuo. The crude residue was purified by flash chromatography to give the title compound (4.58 g, 94%).
Reaction SMILES: C[Si]([O:5][Si](C)(C)C)(C)C.[K].C([O:13][C:14]([C:16]1[C:17](Cl)=[N:18][C:19]([S:22][CH3:23])=[N:20][CH:21]=1)=[O:15])C>COCCOC>[OH:5][C:17]1[C:16]([C:14]([OH:13])=[O:15])=[CH:21][N:20]=[C:19]([S:22][CH3:23])[N:18]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: C[Si](C)(C)O[Si](C)(C)C
Agent: [K]
Solvent: COCCOC
Product: CSc1ncc(C(=O)O)c(O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A slurry of potassium trimethylsilyl oxide (90% tech., 40 g, 0.31 mol) in 1,2-dimethoxyethane (300 mL) was added, slowly over 20 min, to a solution of ethyl-4-chloro-2-methylthio-5-pyrimidinecarboxylate (Aldrich, 15 g, 64 mmol) in 1,2-dimethoxyethane (100 mL). Said addition, being mildly exothermic, may warrant the use of an ice bath to maintain ambient temperature conditions during addition. After addition was complete, the resulting suspension was stirred at ambient temperature for 1 h, then warmed to reflux for 36 h, then allowed to cool to ambient temperature. Reaction mixture was quenched with 1 M HCl(aq), then extracted with ethyl acetate and dried using sodium sulfate to produce a crude solid (11 g). Said crude solid was then recrystallized in ethyl acetate to afford 4-hydroxy-2-methylsulfanylpyrimidine-5-carboxylic acid as a white solid (8.8 g, 47 mmol, 73% yield). MS (−ESI) m/z 185 (M−, 100). An aliquot of this material (3.00 g, 16.1 mmol) was diluted with thionyl chloride (90 mL) followed by DMF (0.20 mL) and the resulting solution was warmed to reflux. After 1 hour at reflux, the solution was allowed to cool to ambient temperature and was concentrated in vacuo to afford a beige solid which was triturated once from hot toluene and then once again from hot hexanes (i.e., in both instances the soluble material was the desired fraction). This afforded, after concentration in vacuo, the titled compound as a white solid (3.90 g, 15.6 mmol, 97% yield). 1H NMR (300 MHz, CDCl3) δ 9.15 (s, 1H), 2.63 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OC1C=[CH:15][C:11]([C:12](O)=[S:13])=[CH:10]C=1C.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[OH:21][CH2:20][C:19]1[CH:18]=[CH:22][C:12]([SH:13])=[C:11]([CH3:15])[CH:10]=1
Reactant: Cc1cc(C(O)=S)ccc1O
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(CO)ccc1S
Temperature: 60 °C
Reaction time: 21 h

Procedure:
95% LiAlH4 (0.55 g, 14 mmol) is introduced in absolute THF (10 ml) into a three-necked flask which is heated and flushed with argon. A solution of 4-hydroxy-3-methylthiobenzoic acid (1.37 g; 7.4 mmol) in absolute THF (15 ml) is added dropwise to this initial mixture with ice-cooling in the course of 5 min such that only moderate evolution of gas takes place. After addition is complete, the cooling is removed and the reaction mixture is stirred at RT for 30 min and at 55-65° C. for a further 21 h. After the reaction mixture has cooled to RT, it is treated carefully with ice water with ice-cooling. The basic Al(OH)3 precipitate is dissolved by addition of 10% strength sulfuric acid and the aqueous, acidic solution (pH=1) is extracted with diethyl ether (150 ml). The phenolic product is extracted from the combined ethereal extract using 2 portions of sodium hydroxide solution (10%, 50 ml). The alkaline sodium hydroxide extract is adjusted to pH=7 using hydrochloric acid (20% strength), the precipitate is taken up using diethyl ether (50 ml), and the neutral aqueous solution is extracted with diethyl ether (100 ml). The combined, ethereal extract is washed with saturated NaCl solution, dried over Na2SO4 and concentrated: a crystalline, white residue remains.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:27](=O)([O-])[O-:28].[K+].[K+]>CN(C=O)C>[CH2:6]([N:13]1[C:17]([C:18]([F:20])([F:21])[F:19])=[CH:16][C:15]([C:22]2[O:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=2)=[N:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1cc(-c2ccco2)nn1Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2cc(C(F)(F)F)n(Cc3ccccc3)n2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 ml of dry DMF were initially charged at 10° C., 1.9 g (12.4 mmol) of phosphorus oxychloride were added dropwise and the mixture was stirred for 30 min. A solution of 3 g (10.3 mmol) of 1-benzyl-3-(2-furyl)-5-trifluoromethylpyrazole in 10 ml of DMF was added dropwise, and the mixture was stirred at RT overnight. The mixture was poured into ice-water and adjusted to pH 9 using potassium carbonate solution. The precipitated product was filtered off with suction and dried in a vacuum drying cabinet at 50° C. This gave 3.3 g (100%) of the title compound. m.p.: 76.5-77.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][NH:27][O:28][CH3:29].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:13]=1)[C:8]([N:27]([O:28][CH3:29])[CH3:26])=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)c1cc(OCCCOC2CCCCO2)cc(C(=O)O)c1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc(OCCCOC2CCCCO2)cc(C(C)(C)C)c1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
3-tert-Butyl-5-[3-(tetrahydropyran-2-yloxy)propoxy]benzoic acid (O4.059; 4.90 g) and N,O-dimethylhydroxylamine hydrochloride (1.42 g) were dissolved in DMF (80 ml) and admixed with Hünig's base (4.81 ml) and TOTU (4.78 g). After stirring for 2 h, the mixture was left to stand overnight. Then the DMF was drawn off, the mixture was partitioned between EA and saturated sodium hydrogencarbonate solution, and the EA phase was removed, dried over magnesium sulfate, filtered and concentrated. 5.49 g of the title compound were obtained.