Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[C:7]3[N:39]=[C:38]4[N:40]=[C:31]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=54)[N:30]=[C:28]4[NH:29][C:21]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=54)=[N:20][C:18]4=[N:19][C:11]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=54)=[N:10][C:9]=2[NH:8]3)[CH:6]=1.[Cl:41][S:42]([OH:45])(=O)=[O:43].S(Cl)([Cl:48])=O>O>[CH:2]1[CH:1]=[CH:6][C:5]2[C:4](=[C:9]3[N:10]=[C:11]4[N:19]=[C:18]([C:17]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=54)[N:20]=[C:21]4[NH:29][C:28]([C:27]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=54)=[N:30][C:31]4=[N:40][C:38]([C:37]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=54)=[N:39][C:7]=2[NH:8]3)[CH:3]=1.[S:42]([Cl:41])([Cl:48])(=[O:45])=[O:43]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)Cl
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: O
Product: O=S(=O)(Cl)Cl
Temperature: 77.5 °C
Reaction time: 1 h

Procedure:
An unsubstituted metallic phthalocyanine compound is added by small portions in three times to ten times amount (by weight) of chlorosulfonic acid while maintaining at 18° C. or less. After stirring at that temperature for 1 hour, the temperature is increased at a rate of 0.5 to 1° C. per minute, and the mixture is reacted at a temperature of 130 to 135° C. for from 4 to 6 hours. Thereafter, the mixture was cooled to 70 to 85° C., thionyl chloride in an amount of twice to six times the amount of the unsubstituted metallic phthalocyanine is added dropwise while maintaining at from 70 to 80° C. over 10 to 15 hours. After stirring for several hours at that temperature, the mixture was cooled to 15 to 20° C. and continuously stirred for from 10 to 15 hours. The reaction mixture is discharged by small portions into iced water in an amount of 50 times to 200 times the amount of the metallic phthalocyanine. The resulting deposit is filtrated and washed with iced water until becoming neutral, followed by drying, to obtain a metallic phthalocyanine sulfonylchloride.
Reaction SMILES: [CH:1]1([C:8]2[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1(=[O:33])[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]2[CH2:23]1.C1(C)C=CC=CC=1>O1CCCC1>[CH:1]1([C:8]2[N:9]=[C:10](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:33])[CH2:23][C:24]4[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=4[C:26]([OH:28])=[O:27])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCCCC3)cs2)c1

Procedure:
A solution of 2.1 g of (E)-3-[2-[4-(cycloheptyl)-2-thiazolyl]ethenyl]benzeneamine, 1.25 g of homophthalic anhydride and 30 ml of toluene was heated to reflux for 0.5 hr. Cooling and filtration yielded 2.31 g of (E)-2-[2-[3-[2-[4-(cycloheptyl)-2-thiazolyl]ethenyl]phenyl=amino]-2-oxoethyl]benzoic acid; m.p. 189°-190° C. from tetrahydrofuran.
Reaction SMILES: COC1C(OC)=NS(=O)N=1.CN.CO[C:15]1[C:19]([NH:20][CH3:21])=[N:18][S:17](=[O:22])[N:16]=1.[CH3:23][N:24]([CH2:26][C:27]1[O:31][C:30]([CH2:32][S:33][CH2:34][CH2:35][NH2:36])=[CH:29][CH:28]=1)[CH3:25]>>[CH3:25][N:24]([CH2:26][C:27]1[O:31][C:30]([CH2:32][S:33][CH2:34][CH2:35][NH:36][C:15]2[C:19]([NH:20][CH3:21])=[N:18][S:17](=[O:22])[N:16]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CNC1=NS(=O)N=C1OC
Agent: CN
Agent: COC1=NS(=O)N=C1OC
Product: CNC1=NS(=O)N=C1NCCSCc1ccc(CN(C)C)o1

Procedure:
Reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, Step A] with one equivalent of methylamine and treatment of the resultant 3-methoxy-4-methylamino-1,2,5-thiadiazole 1-oxide with one equivalent of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine yields the title compound, which is identical to the product prepared in Example 18.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[CH:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1>CN(C)C=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:6]2[C:2](=[O:1])[N:3]([C:7]3[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=3)[C:10]([O:12][CH3:13])=[O:11])[CH:4]=[N:5]2)=[CH:22][CH:23]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccnc(-n2cn[nH]c2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-n2cnn(Cc3ccc(F)cc3)c2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate (1.68 g, 7.63 mmol) in N,N-dimethylformamide (76 mL) was added sodium hydride (60% dispersion in mineral oil, 0.67 g, 16.80 mmol) at 0° C. The resulting reaction mixture was stirred for 1 hour at 0° C., followed by the addition of 1-(bromomethyl)-4-fluorobenzene (3.23 g, 17.09 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 48 hours and concentrated in vacuo to dryness to give methyl 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)isonicotinate, and used in the further reaction without purification
Reaction SMILES: C(=O)C1OC=CC=1.[O:8]=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11]>>[CH2:9]([OH:8])[C@@H:10]([C@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Solvent: O=Cc1ccco1
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
In addition, the strain of the present invention has high tolerance to the toxic inhibitor furfural, which is often existed in the pretreated lignocellulosic hydrolysate. The fermentation experiments with a synthetic xylose solution supplemented with furfural show that the strain can grow in the xylose solution containing 3 g/L of furfural and produce xylitol, and the yield is very similar to that of the xylose fermentation without furfural.
Reaction SMILES: [OH-].[Na+].[O:3]=[CH:4][C@@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6].C(=O)C1OC=CC=1>>[CH2:4]([OH:3])[C@@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O=Cc1ccco1
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 0.25 h

Procedure:
The fermentation medium is a silvergrass hydrolysate pretreated by dilute acid. For pretreatment, the concentration of the dilute acid is 1-4%, the operation temperature is 130° C., and the reaction time is 15 min at this temperature. In this case, NaOH is added to adjust the pH value of the hydrolysate to be 6.0, the fermentation temperature is controlled at 30° C., the agitation of the incubator is maintained at 100 rpm, and the ratio of the inocula size of the culture and the volume of the fermentation medium is 1:6 (v/v). The content of xylose in the silvergrass hydrolysate is 17.5-23.14 g/L, the content of the inhibitor furfural is 0.17-0.67 g/L, the amount of xylitol produced is 5.59-6.13 g/L, and the overall utilization of xylose is 97%, as shown in Table 3.
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[F-].[K+].[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C@@H:21]1[C@@H:26]([NH:27]C(=O)OC(C)(C)C)[CH2:25][C@@H:24]([N:35]2[CH2:42][C:41]3[C:37](=[N:38][N:39]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:40]=3)[CH2:36]2)[CH2:23][O:22]1.C(N(CC)CC)C>ClCCl.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C@@H:21]1[C@@H:26]([NH2:27])[CH2:25][C@@H:24]([N:35]2[CH2:42][C:41]3[C:37](=[N:38][N:39]([S:43]([CH3:46])(=[O:45])=[O:44])[CH:40]=3)[CH2:36]2)[CH2:23][O:22]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Agent: O=S(=O)(O)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)n1cc2c(n1)CN([C@H]1CO[C@H](c3cc(F)ccc3F)[C@@H](N)C1)C2
Temperature: 32.5 °C
Reaction time: 8 h

Procedure:
Benzenesulfonic acid (32.95 kg, 271 mol) was dissolved in dichloromethane (1020 kg) under nitrogen. Then, 880 g of water was added such that the solution KF was 0.2%. Next, tert-butyl {(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate (38.4 kg, 100 mol) was added in three equal portions over 30 min. The reaction was then aged overnight at room temperature. Next, water (733 kg) was added over 1 h and the reaction stirred rapidly for 1 h. The layers were then separated, discarding the resulting organics layer. To the aqueous layer was charged dichloromethane (510 kg) followed by triethylamine (22.4 kg, 592 mol). After agitation, the layers were separated and the aqueous extracted with dichloromethane (510 kg). The combined organics were washed with 7% aqueous NaHCO3 (2×410 kg) and 5% brine (386 kg). The organics were then dried with Na2SO4, filtered, and treated with activated carbon (6.2 kg of C-941). The carbon was filtered off and the filtrate was concentrated under vacuum to 154-193 L. This solution was then warmed to 30-35° C. to dissolve solids (additional dichloromethane may be added to dissolve solids). Next, iso-propylacetate (338 kg) was added and the solution stirred at room temperature for 1.5 h. Then, n-heptane (159 kg) was charged to the vessel drop-wise and stirred for 3 h. The slurry was then filtered and the cake washed with n-heptane. This wet cake was then recrystallized again by dissolving it into dichloromethane and adding iso-propylacetate and n-heptane as before, filtering, and washing with n-heptane. The solids were dried under vacuum at 40-50° C. overnight to give crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine was washed with cold 2:1EtOAc/hexanes to give the title compound as an off-white solid. 1H NMR (500 MHz, CD3OD): 1.71 (q, 1H, J=12 Hz), 2.56-2.61 (m, 1H), 3.11-3.18 (m, 1H), 3.36-3.40 (m, 1H), 3.48 (t, 1H, J=12 Hz), 3.88-3.94 (m, 4H), 4.30-4.35 (m, 1H), 4.53 (d, 1H, J=12 Hz), 7.14-7.23 (m, 2H), 7.26-7.30 (m, 1H), 7.88(s, 1H). LC-MS: 399.04 [M+1].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl.O>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH2:27][O:28][CH3:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(OCc2ccccc2)ccc1C=O
Yield: 78.7 %

Procedure:
To a solution of 4-benzyloxy-2-hydoxy-benzaldehyde (44.9 g, 197 mmol) synthesized in step (a) of Example 197 in dichloromethane (200 ml) were added diisopropylethylamine (52.0 ml, 300 mmol) and methoxymethyl chloride (20.5 ml, 270 mmol) at 0° C. with stirring, and the resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with dichloromethane (200 ml×2). The organic layer was washed successively with water (300 ml×1) and saturated aqueous sodium chloride solution (300 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford-the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-1:1) as the eluent to afford the title compound (42.2 g, yield: 79%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[CH2:12]([Sn:16]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])Cl)[CH2:13][CH2:14][CH3:15]>O1CCCC1.[Cl-].[Na+].O>[CH3:1][N:2]1[C:6]([Sn:16]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][N:4]=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1ccnn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Temperature: -78 °C
Yield: 65.7 %

Procedure:
A solution of 1-methyl-1H-[1,2,3]triazole (350 mg) in dry tetrahydrofuran (5.0 ml) was added dropwise under nitrogen to a stirred, cooled (-78° C.) solution of n-butyl lithium (2.81 ml of 1.6M solution in hexanes) in dry tetrahydrofuran (10 ml). After 1 hour tributylchlorostannane (1.46 g) was added. The reaction was maintained at -78° C. for 30 min. and then allowed to warm to room temperature over 2 hours. The reaction mixture was diluted with brine (10 ml) and extracted into ethyl acetate (50 ml). The organic layer was separated, washed with brine (50 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography (20% ethyl acetate/n-hexane), to give 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole as a yellow oil (1.03 g). 1H NMR (360 MHz,CDCl3)δ0.87 (9H, m), 1.15 (6H, m), 1.28 (6H, m), 1.36 (6H, m), 4.02 (3H, s), 7.60 (1H, s); MS m/z CI+ 372 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[O:14])[CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:14])[CH:3]=1
Reactant: CCOc1nc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)cc(N)c1C#N
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1nc(C(=O)NCC2CCNCC2)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
The compound prepared in Example 225 (3.579 g) was suspended in dichloromethane (50 mL) and trifluoroacetic acid (10.00 mL) added and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was poured onto saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was saturated with sodium chloride. The desired material crystallized from the aqueous and was isolated by filtration to obtain the title compound (2.752 g) with the following physical data.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[C:3]([Cl:9])[CH:2]=1.O1CCOCC1.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C(NCC)C>C(OCC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:9][C:3]1[CH:2]=[CH:1][C:6]([CH2:7][O:8][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][O:16]2)=[CH:5][N:4]=1
Reactant: OCc1ccc(Cl)nc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Clc1ccc(COC2CCCCO2)cn1
Temperature: 55 °C
Reaction time: 2 h
Yield: 124.3 %

Procedure:
A mixture of 44.3 g of 6-chloro-3-pyridine-carbinol, 300 ml of dioxan and 104.3 g of 3,4-dihydro-2H-pyran was treated with 3 g of p-toluenesulfonic acid monohydrate and stirred at 55° C. for 2 hours. The reaction mixture was treated with 10 ml of diethylamine and, after cooling, taken up in diethyl ether. Repeated washing with water, drying over sodium sulfate and concentration in a vacuum yielded 87.3 g of crude 2-chloro-5-[(tetrahydro-2-pyranyloxy)methyl]pyridine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[C:25]([CH2:33][CH3:34])=[N:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH2:33]([C:25]1[C:24]([O:23][C:21]2[CH:22]=[CH:17][N:18]=[C:19]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:20]=2)=[CH:29][CH:28]=[C:27]([N+:30]([O-:32])=[O:31])[N:26]=1)[CH3:34]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (863 mg, 4.15 mmol), 3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (892 mg, 3.19 mmol), K2CO3 (1.322 mg, 9.57 mmol) and Pd(PPh3)4 (184 mg, 0.159 mmol) in dioxane (6 mL) and water (1.5 mL) was sparged with Ar, heated at 80° C. for 24 h, then cooled to RT and stirred for 24 h. The mixture was treated with EtOAc, washed with satd. NaHCO3 (1×), then brine (1×), dried over Na2SO4 and concentrated to dryness to afford 2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (100% yield assumed) as a thick oil. Material carried on to the next step without purification. MS (ESI) m/z: 326.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: ClCCl
Product: Oc1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 50 °C
Reaction time: 1.33 h

Procedure:
1-(4-fluorophenyl)-5-methoxy-1H-indazole (147f, 3.32 g, 13.7 mmol) in CH2Cl2 (40 mL, dried over 4 Å mol sieves). Borontribromide solution (1M in dichloromethane, 35 mL, 35 mmol) was added and the mixture was stirred at 50° C. for 80 min. The reaction mixture was cooled to r.t., diluted with dichloromethane and washed with ice-cold sat. aqueous NaHCO3. Crude title compound crystallised from the organic phase at 8° C. Re-crystallization from methanol-water afforded 1-(4-fluorophenyl)-1H-indazol-5-ol as light grey needles (1.88 g). From the mother liquor was obtained by crystallization (methanol-water) additional title compound (0.7 g). Total yield 2.58 g (82%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][C:10]([F:14])=[C:9]([F:15])[C:8]=1[CH3:16].[C:17](=[O:19])=[O:18].Cl>COCOC.O>[CH3:16][C:8]1[C:7]([F:6])=[C:12]([F:13])[C:11]([C:17]([OH:19])=[O:18])=[C:10]([F:14])[C:9]=1[F:15]
Reactant: O=C=O
Reactant: Cc1c(F)c(F)cc(F)c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: COCOC
Product: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -70 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium (2.7M in n-hexane, 21 cm3) was added dropwise to a stirred solution of 2,3,5,6-tetrafluorotoluene (9.0 g) in dry dimethoxymethane cooled to -70° C. under a nitrogen atmosphere and the mixture stirred for one hour. Carbon dioxide was then passed into the mixture for 3 hours during which time a white solid precipitate formed. After allowing the mixture to attain the ambient temperature (ca. 22° C.) it was poured into water. The resultant mixture was acidified with dilute hydrochloric acid and extracted with diethyl ether. The ethereal extract was washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent yielded a semi solid residue which on trituration with petroleum ether (boiling range 40°-60° C.) gave 4-methyl-2,3,5,6-tetrafluorobenzoic acid (2.5 g) white crystals, mp 168° C. (Infra red C=O, 1700 cm-1.)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=[O:8].[CH3:10]N(C=O)C.C(N(C(C)C)C(C)C)C.CI>C(OCC)(=O)C.O>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cn1cccc1C(=O)O
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cccn1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 1-methylpyrrole-2-carboxylic acid (28.66 g., 0.229 mol) in 75 ml. DMF at 0° was added N-ethyl diisopropylamine (39.4 ml., 0.229 mol) followed by CH3I (14.27 ml., 0.229 mol). The reaction mixture was stirred 16 hours at room temperature, diluted with equal volumes each of ethyl acetate and water, the pH adjusted from 3.4 to 8.5, and the layers evaporated. The aqueous layer was washed 1×100 ml. fresh ethyl combined, washed 2×100 ml. H2O and 1×100 ml. brine, dried over Na2SO4 and stripped to yield title product as an oil, 24.83 g.; 1H-nmr (CDCl3) delta 3.75 (s, 3H), 3.87 (s, 3H), 5.97 (m, 1H), 6.62 (m, 1H), 6.78 (m, 1H).
Reaction SMILES: C[O-].[Na+].ClC1C=CC=CC=1.CO[C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15].[CH3:19][C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21]>CO>[CH3:17][O:16][C:14](=[O:15])[C:13]([CH2:19][C:20](=[O:21])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CO
Product: COC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
198 g of methanolic sodium methyate solution (30% strength by weight) are added to 400 g of chlorobenzene. The methanol is distilled off at 65° C. in the course of 1 hour. The mixture is cooled to 10° C. and 118 g (1 mol) of molten oxalic acid dimethyl ester are introduced in the course of 1 hour. Thereafter, 100 g (1 mol) of pinacolin are allowed to run in and the mixture is subsequently stirred at room temperature for 15 minutes. It is heated, and the methanol formed in the reaction is distilled off in the course of 2 hours. Neutralisation with sulphuric acid, separation of the phases and distillation of the organic phase gives 165 g of pivaloylpyruvic acid methyl ester (87.8% of the theoretical yield). Purity: 99.0%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1OCc1ccccc1

Procedure:
4-bromo-2-fluorophenol (2.557 g, 13.39 mmol) and (bromomethyl)benzene (1.590 ml, 13.39 mmol) in DMF (20 ml) were treated with K2CO3 (3.70 g, 26.8 mmol) overnight. The reaction was then diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4 and concentrated to provide the title compound. LCMS (APCI) m/e 282 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Under a nitrogen stream, 4-bromo-2-fluorophenol (14.9 g, 78 mmol) and potassium carbonate (13.0 g, 94 mmol) were dissolved in N,N-dimethylformamide (100 mL), followed by addition of benzyl bromide (10.2 mL, 86 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the solvent was concentrated under reduced pressure. The aqueous phase was extracted with ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography (ethyl acetate/hexane:0/100-5/95) to give the title compound (21.9 g, 100%).