Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][C:10]=2[F:24])[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[NH:3]1.Br[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH3:45])=[O:37].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[F:24][C:10]1[CH:11]=[C:12]([C:16]2[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:13]=[C:14]([F:15])[C:9]=1[CH2:8][N:7]1[C:6]2[S:25][C:26]([CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]=2[C:4](=[O:33])[N:3]([CH2:35][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])=[O:37])[C:2]1=[O:1]
Reactant: COc1ccccc1C(=O)CBr
Reactant: N#Cc1ccccc1-c1cc(F)c(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)Cn1c(=O)c2cc(CC(F)(F)F)sc2n(Cc2c(F)cc(-c3ccccc3C#N)cc2F)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a mixture of 4′-{[2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile (0.65 g), 2-bromo-1-(2-methoxyphenyl)ethanone (0.34 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.082 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.48 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([N+:13]([O-:15])=[O:14])=[C:4](Cl)[N:3]=1.[CH:17]1([C:20]2[NH:24][N:23]=[C:22]([NH2:25])[CH:21]=2)[CH2:19][CH2:18]1.O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([NH:25][C:22]2[CH:21]=[C:20]([CH:17]3[CH2:19][CH2:18]3)[NH:24][N:23]=2)[N:3]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: CCOC(=O)c1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(Cl)nc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
To a THF (20 ml) solution of ethyl 2,6-dichloro-5-nitropyrimidine-4-carboxylate (1.0 g, 3.80 mmol) was slowly added the 5-cyclopropyl-1H-pyrazol-3-amine (0.48 g, 3.85 mmol) in THF (5 ml) at 0° C. The reaction was stirred at 0° C. for 10 minutes, treated with water (50 ml), and then extracted with DCM (3×50 ml), dried, filtered, and concentrated to give the title compound (1.2 g). MS: Calcd.: 352; Found: [M+H]+ 353.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:26]([CH3:28])[CH3:27])=[NH:15])([CH3:3])[CH3:2].[Cl:29][CH:30](Cl)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:26]([CH3:28])[CH3:27])[C:17]=1[NH:16][C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[N:15][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][Cl:29])=[CH:32][CH:33]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=N)Nc1c(C(C)C)cccc1C(C)C
Reactant: Cc1ccc(C(Cl)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CC(C)c1cccc(C(C)C)c1NC(=NCc1ccc(CCl)cc1)Nc1c(C(C)C)cccc1C(C)C
Yield: 40.5 %

Procedure:
11.4 g (0.03 mole) of N,N'-bis-(2,6-diisopropylphenyl) guanidine, 5.7 g (0.033 mole) of α,α-dichloro-p-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of xylene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and then concentrated for the purpose of recovering the solvent and unreacted raw materials to obtain a slightly yellow crystal. The crystal was then recrystallized from benzene to obtain 6.3 g of white powder.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.C([Mg]Br)C.Br[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[N:35][CH:36]=1>C1COCC1.ClCCl.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:5]1[CH:6]=[C:2]([C:31]2[CH:32]=[CH:33][C:34]([CH3:37])=[N:35][CH:36]=2)[N:3]=[CH:4]1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-c2c[nH]cn2)cn1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of 4-iodo-1-trityl-1H-imidazole (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (10%) and 5-bromo-2-methylpyridine (1.2 eq) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane and washed with a EDTA buffer (at approximately pH 9), NaCl, dried over sodium sulfate, filtered and concentrated. The crude product was disolved in ethanol and concentrated HCl was added to the solution at room temperature. The reaction mixture was heated in a 50° C. oil bath for 2 hours. Upon cooling, the reaction was filtered and washed with ethyl ether to yield 5-(1H-imidazol-4-yl)-2-methyl-pyridine (63%). MH+(160)
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([OH:16])=[C:9]([O:14][CH3:15])[CH:10]=2)[CH:5]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH:2]=[CH2:3].FC(F)(F)C(O)=O>O=[V].Cl.Cl.Cl.C(Cl)Cl>[CH2:1]([N:4]1[CH:5]2[C:6]3=[C:7]([C:8]([OH:16])=[C:9]([O:14][CH3:15])[CH:10]=[C:11]3[CH2:12][CH2:13]1)[C:23]1[CH:22]=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[CH:19][C:18]=1[CH2:17]2)[CH:2]=[CH2:3]
Reactant: C=CCN1CCc2cc(OC)c(O)cc2C1Cc1ccc(OC)c(OC)c1
Agent: O=[V]
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN1CCc2cc(OC)c(O)c3c2C1Cc1cc(OC)c(OC)cc1-3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
22 g. (59.54 mmol) (+)-2-Allyl-7-hydroxy-6-methoxy-1-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline in a mixture of 190 ml. trifluoroacetic acid and 190 ml. anhydrous methylene chloride are mixed at -10° C., with the exclusion of moisture, with a solution of 6.0 ml. (11.04 g., 63.7 mmol) vanadium oxytrichloride in 190 ml. anhydrous methylene chloride. The reaction mixture is stirred for 30 minutes at -10° C., for 1 hour at 0° C. and for 2 hours at ambient temperature. Thereafter, the reaction mixture is concentrated to about one third of its volume by evaporation of the solvent in a vacuum at ambient temperature. The residue is mixed with ice water and extracted with chloroform. The chloroform phase is rendered basic with an aqueous solution of ammonia and worked up in the usual manner. By crystallisation from ethanol, there is obtained (+)-6-allyl-5,6,6a,7-tetrahydro-1-hydroxy-2,9,10-trimethoxy-4H-dibenzo(de,g)quinoline; m.p. 85°-93° C./134°-138° C.
Reaction SMILES: C([Li])CCC.C(C1N=CN([C:16](C2C=CC=CC=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C=1)(=O)CCC.[Cl-].[NH4+].O>C1COCC1.CCCCCC>[C:17]1([CH2:16][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: c1ccc(Cc2ccccc2)cc1
Yield: 200 %

Procedure:
A solution of 4.30 g (25.8 mmols) of diphenylmethane in 50 ml of THF is prepared in inert atmosphere (nitrogen) then cooled in an ice bath. First 16.7 ml of butyllithium of a 1.7M solution in hexane and then, drop by drop, a solution of 4.90 g (12.9 mmols) of the previous ketone 3 in 50 ml of THF, are added slowly. The resultant mixture is stirred for 2 hours at room temperature and then 50 ml of a saturated aqueous solution of ammonium chloride and 100 ml of water are added. Extraction with ethyl acetate followed by evaporation of the previously dried extracts yields alcohol 4 which is recrystallised in cyclohexane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:21]([CH3:22])[CH3:20])[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1Cl
Reactant: CNC
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1N(C)C

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B8) (3.5 g, 12.2 mmol) and dimethylamine (11 ml, 33% in EtOH, 61.0 mmol) in DMSO (35 mL) at 50° C. according to the general procedure C. Obtained as a yellow solid (3.50 g, 97%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14]Br)=[CH:9][CH:8]=1>CCOCC.ClCCl>[C:7]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:8]=[CH:9][C:10]([C:13](=[O:16])[CH2:14][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a cooled (0° C.) solution of morpholine (5.99 g, 68.7 mmol) in ether (20 mL) was added the solution of 1-(4-biphenylyl)-2-bromoethanone (9.47 g, 34.4 mmol) in a mixture of ether (100 mL) and dichloromethane (100 mL) dropwise at 0° C. After the addition was over, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (150 mL) and extracted with 5% NaHCO3 (150 mL) and brine (100 mL). The organic layer was dried (MgSO4) and concentrated to give 9.70 g (100%) of the title compound as a white solid. MS (ES) m/e 281.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[CH3:14][C:15]([CH3:17])=[O:16]>[NH4+].[Cl-]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([OH:16])([CH3:17])[CH3:14])=[N:3][CH:4]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CC(C)(O)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a suspension of 2,5-dibromopyridine (1.0 eq.) in Tol (0.1M) at −78° C. was added dropwise n-BuLi (1.07 eq.). The mixture was stirred at −78° C. for 3 h then acetone (1.2 eq.) was added. The final mixture was stirred for an extra 2 h at −78° C., poured in saturated aqueous NH4Cl and extracted with Tol (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 4:1) afforded the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C:11]([CH2:14][NH:15][C:16](=[O:37])[C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][C:25]5[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]#[N:36])=[CH:28][C:26]=5[N:27]=4)=[CH:19][CH:18]=3)([CH3:13])[O:10][C:9]2=[O:38])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:45][C:46]([F:58])([F:57])[O:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1B(O)O>O1CCCC1.O.C(P([C-]1C=CC=C1)C(C)(C)C)(C)(C)C.[CH-]1C=CC=C1.[Fe+2].[Pd]>[C:35]([C:29]1[CH:30]=[C:31]([CH:32]([CH3:34])[CH3:33])[C:25]2[O:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([NH:15][CH2:14][C:11]4([CH3:13])[O:10][C:9](=[O:38])[N:8]([C:5]5[CH:4]=[CH:3][C:2]([C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=6[O:47][C:46]([F:45])([F:58])[F:57])=[CH:7][N:6]=5)[CH2:12]4)=[O:37])=[CH:18][CH:19]=3)=[N:27][C:26]=2[CH:28]=1)#[N:36]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc(Cl)cn5)C(=O)O4)cc3)oc12
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4(C)CN(c5ccc(-c6ccccc6OC(F)(F)F)cn5)C(=O)O4)cc3)oc12
Temperature: 100 °C
Yield: 25.1 %

Procedure:
To a mixture of N-{[3-(5-chloropyridin-2-yl)-5-methyl-2-oxo-1,3-oxazolidin-5-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (26 mg, EXAMPLE 50) and potassium carbonate (35 mg) in 0.5 ml of tetrahydrofuran and 0.5 ml of water was added 2-trifluoromethoxyphenylboronic acid (10 mg) and palladium di-tert-butylphosphinoferrocene (7 mg). The mixture was heated via microwave for 10 min at 100° C. The sample was cooled to room temperature, and was purified via column chromatography on a Biotage Horizon 40M column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 4 column volumes to provide the title compound as an off-white solid (8 mg, 24%). Mass spectrum (ESI) 656.4 (M+1). 1H NMR (500 MHz, CDCl3):): δ 8.40 (d, J=2.0 Hz, 1H), 8.31 (d, J=8.3 Hz, 2H), 8.25 (d, J=8.7 Hz, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.92 (s, 1H), 7.82 (dd, J=8.7, 2.3 Hz, 1H), 7.51 (s, 1H), 7.40 (m, 4H), 6.82 (t, J=6.3 Hz, 1H), 4.30 (d, J=10.7 Hz, 1H), 4.13 (d, J=10.8 Hz, 1H), 3.94 (dd, J=14.5, 6.3 Hz, 1H), 3.86 (dd, J=14.5, 6.5 Hz, 1H), 3.47 (sept, J=6.9 Hz, 1H), 1.65 (s, 3H), 1.45 (d, J=6.9 Hz, 6H).
Reaction SMILES: O1CCOCC1.[PH2](O)=O.C(N1CCCCC1)C.CSC(O[C@@H:23]1[C@H:27](OC(SC)=S)[C@@H:26]([CH2:33][OH:34])[O:25][C@H:24]1[N:35]1[C:44]2[N:43]=[CH:42][N:41]=[C:39]([OH:40])[C:38]=2[N:37]=[CH:36]1)=S.CCCCCC.C(B(CC)CC)C>C(OCC)(=O)C.O1CCCC1>[C@@H:24]1([N:35]2[C:44]3[N:43]=[CH:42][N:41]=[C:39]([OH:40])[C:38]=3[N:37]=[CH:36]2)[O:25][C@H:26]([CH2:33][OH:34])[CH:27]=[CH:23]1
Reactant: CSC(=S)O[C@@H]1[C@H](OC(=S)SC)[C@@H](CO)O[C@H]1n1cnc2c(O)ncnc21
Agent: CCB(CC)CC
Agent: CCN1CCCCC1
Agent: O=[PH2]O
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC[C@@H]1C=C[C@H](n2cnc3c(O)ncnc32)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To a 1,4-dioxane solution containing N-ethylpiperidine hypophosphite (1.25 mL, 2.2 mmol) at a concentration of 1.764 mol/L, a mixed solution of a tetrahydrofuran solution (2 mL) of 2′,3′-bis-O-[(methylthio)thiocarbonyl]inosine (99 mg, 0.22 mmol) and a triethylborane hexane solution (0.22 mL, 0.22 mmol) at a concentration of 1.0 mol/L was added, and the obtained mixture was stirred at room temperature for one hour. The obtained reaction mixture was diluted with ethyl acetate. The resultant organic layer was washed with brine solution, and thereafter dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After purification by chromatography (using as eluting solutions a mixed solvent of hexane and ethyl acetate (3:7), ethyl acetate, and a mixed solvent of dichloromethane and methanol (10:1) successively in this order), 47 mg of the intended product was obtained in a yield of 92%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([O:14]C(OC)=O)=[N:7][S:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])=[O:4].ClCCl.CO.S(=O)(=O)(O)O>O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:14])=[N:7][S:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])=[O:4]
Reactant: COC(=O)Oc1nsc(S(C)(=O)=O)c1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(O)nsc1S(C)(=O)=O
Temperature: 65 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
The 5-Methanesulfonyl-3-methoxycarbonyloxy-isothiazole-4-carboxylic acid methyl ester/dichloromethane extracts were combined, then displaced with methanol (150 mL, 15 volumes). A solution of 98% sulfuric acid (50 mL, 5 volumes) in water (100 mL, 10 volumes) was added and the mixture was heated at 65° C. for 6 hours. The foamy slurry became a clear solution with some insoluble white solids over time. The mixture was cooled to 25° C. and stirred for 16 hours. Most of the methanol was removed under vacuum. The aqueous residue was extracted once with 100 mL dichloromethane, then twice with 50 mL dichloromethane. The combined dichloromethane extracts were dried over anhydrous magnesium sulfate and filtered. The dichloromethane was displaced with hexanes (100 mL, 10 volumes) and stirred at 25° C. until solids formed. The solids were filtered, and the filter cake was rinsed with hexane and dried to give 9.27 g of 3-Hydroxy-5-methanesulfonyl-isothiazole-4-carboxylic acid methyl ester (80% yield). 1H NMR (DMSO-d6): δ 13.07 (s, 1H); 3.83 (s, 3H); 3.55 (s, 3H). MS (API-ES pos): 238 (M+H)+; 206 (M−MeO)+, base.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](OS(C3C=CC(C)=CC=3)(=O)=O)[N:9]=2)=[CH:4][CH:3]=1.[CH3:32][NH:33][S:34]([CH3:37])(=[O:36])=[O:35].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([N:33]([CH3:32])[S:34]([CH3:37])(=[O:36])=[O:35])[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(OS(=O)(=O)c2ccc(C)cc2)nc1C(C)C
Reactant: CNS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 85 °C
Yield: 63 %

Procedure:
In a 50 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.1 g (2.5 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine, 0.55 g (5.0 mmol.) of N-methylmethanesulfonamide, 0.69 g (5.0 mmol.) of potassium carbonate (available from Wako Junyaku Co., Ltd., special grade), 0.32 g (1.0 mmol.) of tetrabutylammonium bromide, 20 mL of toluene and 5 mL of water. The mixture was heated to 85° C. for 28 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the reaction mixture were added 10 mL of water and 7 mL of acetone, and the organic liquid portion was separated. The organic liquid portion was analyzed by high performance liquid chromatography. It was confirmed that 0.6 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine was produced. The yield was 63% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][C:9](=[O:37])[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[C:28](C)(C)[O:29][SiH2]C(C)(C)C)=[O:22])=[CH:5][CH:4]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.C(Cl)(Cl)Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:37])[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][OH:29])=[O:22])=[CH:38][CH:39]=1
Reactant: COc1ccc(COC(=O)Nc2cc(OC)c(OC)cc2C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(COC(=O)Nc2cc(OC)c(OC)cc2C(=O)N2CCCC2CO)cc1

Procedure:
The TBDMS ether 10 (0.37 g, 0.66 mmol) in THF (20 mL) was deprotected (Method A: Bu4NF (0.8 ml, 0.8 mmol)) to give the product (flash column chromatography 80% EtOAc/20% n-hexane, then EtOAc) as a colourless oil (0.29 g, 97%). [α]D22.1−69.6° (c=0.23, CHCl3), 1H NMR (CDCl3) δ 8.72 (s, 1H), 7.76 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 6./90 (d, J=8.6 Hz, 2H), 6.80 (s, 1H), 5.10 (m, 2H), 4.40 (m, 1H), 4.30 (m, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.80 (m, 4H), 3.7 (m, 1H), 3.58 (m, 1H), 3.45 (m, 1H), 2.15 (m, 1H), 1.90 (m, 1H), 1.70 (m, 2H). IR (neat) 3338, 2958, 2837, 1726, 1599 cm−1.
Reaction SMILES: [Cl:1][C:2]([Cl:24])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:3]([OH:5])=[O:4].[C:25](Cl)(=O)C(Cl)=O>CO>[CH3:25][O:4][C:3](=[O:5])[C:2]([Cl:24])([Cl:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C(Cl)(Cl)CCCCCCCCCCCCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CO
Product: COC(=O)C(Cl)(Cl)CCCCCCCCCCCCc1ccccc1
Yield: 56.8 %

Procedure:
1.98 g (5 mmol) 16 was stirred for 2 hours at 40° C. with 1.27 g (10 mmol) oxalyl chloride in 20 ml absolute methanol analogously to 103 (example 54). 1.1 g (57) 57 was obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][C:17]2[O:18]CC(C)(C)[N:21]=2)=[CH:14][CH:13]=1.S(=O)(=O)(O)[O-].[Na+].CN1CCCC1=O>O.C1(C)C(C)=CC=CC=1>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:16]([C:15]3[CH:24]=[CH:25][C:12]([Cl:11])=[CH:13][CH:14]=3)[C:17](=[O:18])[NH:21]2)=[CH:6][CH:7]=1
Reactant: CC1(C)COC(Cc2ccc(Cl)cc2)=N1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2cc(Cl)ccc2cc1-c1ccc(Cl)cc1

Procedure:
17.5 g of 2,4-dichlorobenzaldehyde, 22.4 g of 2-(4-chlorobenzyl)-4,4-dimethyl-2-oxazoline, 1 g of sodium bisulphate, 50 ml of 1-methyl-2-pyrrolidinone and 30 ml of xylene are heated at a bath temperature of 170° to 220° C., using a water separator, until 3.2 ml of water and 20 ml of xylene have been separated off. After cooling the reaction mixture, methanol is added and the title compound (m.>300° C.) is collected by filtration (yield: 24.8 g).
Reaction SMILES: O.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Zr+4:18].C(CC(=O)C)(=O)C.[CH3:26][CH:27]([O:31][C:32]([CH3:34])=[O:33])[CH2:28][O:29][CH3:30]>C(O)(C)C>[CH3:26][CH:27]([O:31][C:32]([CH3:34])=[O:33])[CH2:28][O:29][CH3:30].[Zr:18]
Reactant: [Zr+4]
Agent: CC(C)[O-]
Solvent: COCC(C)OC(C)=O
Solvent: CC(=O)CC(C)=O
Solvent: O
Product: [Zr]
Reaction time: 2 h

Procedure:
A mixture of purified water (2.7 g) and isopropyl alcohol (50 g) was dropped to a mixture of zirconium tetraisopropoxide (32.7 g), isopropyl alcohol (50 g) and acetylacetone (50 g). After completion of dropping, the mixture was agitated for 2 hours, subjected to hydrolytic condensation and heated to reflux for 2 hours. PGMEA (200 g) was added thereto and was concentrated under reduced pressure to obtain a PGMEA solution of a zirconium-containing condensate (B-II) (250 g). The solid content concentration of the zirconium-containing condensate was 10.5%.