Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][CH3:18])[CH2:3][CH2:2]1.[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:26]([OH:28])=O)(=[O:22])=[O:21]>>[CH:1]1([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]([CH3:18])[C:26](=[O:28])[C:25]2[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1OC1CC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccccc1OC1CC1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-cyclopropoxy-phenyl)-pyridin-3-yl]-methyl-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow foam (65%). MS (ESI): m/z=491.125 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]#[N:21].C([O-])([O-])=O.[K+].[K+].Br[CH:29]1[C:34](=O)[CH2:33][CH2:32][N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:30]1.O>CN(C=O)C.CC(=O)OCC>[C:20]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[N:5][N:6]2[C:29]3[CH2:30][N:31]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:33][C:34]=3[NH:1][C:2]=12)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3c(C#N)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 34.6 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (1.5 g, 5.4 mmol) and K2CO3 (2.24 g, 16.3 mmol) in 50 mL of DMF at 80° C. was stirred under N2 for 45 min before tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (4.5 g, 16.3 mmol) was added in one portion. Then the mixture was stirred at 80° C. for 1 hr. After cooling down to RT, 150 mL of water and 150 mL of EA was added. Aqueous phase was further extracted with EA (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to get crude product which was chromatographed on 15 g of silica gel using DCM/MeOH (400/1 to 200/1) as eluant to afford 850 mg (35%) of tert-butyl 3-cyano-2-(4-phenoxyphenyl)-5,6-dihydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-7(8H)-carboxylate as an off-white solid. MS (ESI) m/e [M+1]+ 455.9.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[CH2:22][C:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:26]=2[O:25][CH:24]=1.[Cl-].[NH4+]>CN(C=O)C>[C:9]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:8][CH2:22][C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:26]=3[O:25][CH:24]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc2c(CCl)coc12
Reactant: SC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc2c(CSC(c3ccccc3)c3ccccc3)coc12
Temperature: 25 °C
Yield: 84.6 %

Procedure:
Under argon atmosphere, diphenylmethanethiol (121 mg) was dissolved in DMF (2 ml) and the solution was stirred at room temperature. To this solution, potassium t-butoxide (81 mg) and 3-chloromethyl-7-methoxybenzofuran (118 mg) were added and the solution was stirred at room temperature. After confirming vanishment of the materials, the reaction solution was poured into saturated aqueous ammonium chloride solution (5 ml) and the resulting solution was extracted three times with ethyl acetate (10 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=20/1) using silica gel to obtain the desired compound (183 mg, yield: 85%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O.[NH2:29][C@H:30]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39]#[N:40])[CH2:35][CH2:34]1)=[O:32].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:39]([CH:36]1[CH2:37][CH2:38][N:33]([C:31]([C@H:30]([NH:29][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[N:3]=3)[N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)=[O:13])[C:41]([CH3:43])([CH3:42])[CH3:44])=[O:32])[CH2:34][CH2:35]1)#[N:40]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Reactant: CC(C)(C)[C@@H](N)C(=O)N1CCC(C#N)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
In a flask were combined 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.6 g, 4.3 mmol), 1-((R)-2-amino-3,3-dimethyl-butyryl)-piperidine-4-carbonitrile trifluoroacetate (crude from step 2), EDC (1.89 g, 9.9 mmol) and HOBt (1.67 g, 9.9 mmol). DMF (40 mL) was added followed by i-Pr2NEt (5.2 mL, 30.1 mmol). The reaction mixture was stirred at room temperature for overnight and then concentrated. The residue was taken up in EtOAc and 10% citric acid and the organic layer washed with 10% citric acid, sat. NaHCO3, sat LiCl and brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (40%-100% EtOAc/hexanes) to give 1.46 g (59%) of 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a beige foamy solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.Br[CH2:13][C:14]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:15]=1[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>C(O)C(C)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([S:11][CH2:13][C:14]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:15]=2[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(S)c1
Reactant: Cc1cccc(CBr)c1C(=O)OCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Product: COc1cccc(SCc2cccc(C)c2C(=O)OCC(C)C)c1
Reaction time: 0.25 h

Procedure:
A 10N solution of sodium hydroxide (0.32 mL, 3.2 mmol) is added slowly to a solution of 3-methoxybenzenethiol (0.42 g, 3.0 mmol) in isobutanol (2 mL) followed by a solution of isobutyl 2-bromomethyl-6-methyl-benzoate (0.96 g, 3.3 mmol, example 2) in isobutanol (2 mL). The reaction is allowed to stir 15 min and is then partitioned between ethyl acetate and dilute aqueous HCl. The organic phase is washed with water, dried over magnesium sulfate, concentrated and purified by column chromatography (silica, 40% dichloromethane in hexanes) to provide the title compound. MS (EI) 344 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].Br[CH2:31][CH:32]=[CH2:33]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:33][CH:32]=[CH2:31])[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:18])([CH3:17])[CH3:19])([CH3:15])[CH3:14])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexanecarboxylic acid ethyl ester (5.3 g, 18.50 mmol) in THF (56 ml) was cooled to −78° C. and then potassium hexamethyldisilazide (KHMDS) (74.0 ml, 37.0 mmol) (0.5M in toluene) was added slowly and reaction mixture was stirred at −78° C. for 10 min., then warmed to 0° C. for 5 mins and cooled back down to −78° C. 3-Bromo-propene (2.401 ml, 27.8 mmol) was added via syringe, and the reaction mixture was kept at −78° C. for another 10 mins before it was allowed to warm to room temperature overnight. The reaction mixture was quenched with aqueous ammonium chloride, and volatile solvents were removed under reduced pressure. The product was extracted from water with ether and concentrated. The crude oil was purified on biotage SP1, on column 65i, using gradient 5-35% EtOAc in heptane, with 25×150 tubes. Since the product as not UV active, it was detected by iodine staining. The product was a clear oil (4.88 g, 71%). LCMS [M+H]=327.2
Reaction SMILES: [H-].[Na+].[C:3]1(=[N:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl.C(O)(=O)/C=C/C([O-])=O>>[CH3:17][N:18]([CH2:19][CH2:20][O:16][N:15]=[C:3]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:22]
Reactant: ON=C1CCCCCCCCCCC1
Reactant: CN(C)CCCl
Agent: O=C([O-])/C=C/C(=O)O
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCON=C1CCCCCCCCCCC1

Procedure:
Starting from 2.4 g. (0.1 moles) of sodium hydride, 19.73 g. (0.1 moles) of cyclododecanone oxime and 11.8 g. (0.11 moles) of 1-dimethylamino-2-chloroethane the title compound is prepared as in Example 1. Yield: 19.5 g. (72.65%). Hydrogen fumarate, m.p.: 108°-110° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:20]I.O>CN(C=O)C>[CH3:20][N:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc([N+](=O)[O-])cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cn1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To 0.378 g (1.58 mmol) of the above nitro compound in DMF (6 mL) at 0° C. was added 0.067 g (2.80 mmol) of sodium hydride. After 20 min, 0.12 mL (1.93 mmol) of methyl iodide was added, and the mixture was stirred for 2 hrs. Water was added, and the mixture was extracted with EtOAc (×4). The combined organic layer was washed successively with 1M HCl, sat. NaHCO3 solution, and brine, dried (Na2SO4), and concentrated, to give 0.40 g (99% yield) of tert-butyl methyl(5-nitro-2-pyridinyl)carbamate: 1H NMR (CDCl3) δ9.19 (d, J=2.7 Hz, 1H), 8.36 (dd, J=9.4, 2.7 Hz, 1H), 8.14 (dd, J=9.4, 0.3 Hz, 1H), 3.50 (s, 3H), 1.57 (s, 9H); LCMS (APCI−) m/z: 253 (MH+, 100%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Oc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 67.8 %

Procedure:
A mixture of 2-bromo-1-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)ethanone (4.90 g, 14.0 mmol) and thiourea (1.07 g, 14.1 mmol) in 95% EtOH (20.0 mL) was heated at reflux for 100 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (3.10 g) as yellow solids in 68% yield: 1H NMR (500 MHz, CDCl3) 6.98 (m, 2 H), 6.88 (m, 2 H), 6.64 (s, 2 H), 6.27 (s, 1 H), 5.40 (s, 2 H), 3.81 (s, 3 H), 2.13 (s, 6 H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([Si](C)(C)C)([F:22])[F:21]>CN(C)C=O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[C:20]([F:22])([F:21])[F:19])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1ccc(C(F)(F)F)cc1)C(F)(F)F
Yield: 57.1 %

Procedure:
According to Reference Example 8-2, by use of 4-(trifluoromethyl)benzaldehyde (100 μL, 0.732 mmol), potassium carbonate (20.2 mg, 0.146 mmol), (trifluoromethyl)trimethylsilane (162 μL, 1.10 mmol) and N,N-dimethylformamide (2.0 mL), the mixture was stirred and reacted at room temperature for 1 hour. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 1-(trifluoromethyl)-4-(2,2,2-trifluoro-1-hydroxyethyl)-benzene (Compound CF) (102 mg, yield: 57%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.NC1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+:27]1[CH:32]=CC=C[CH:28]=1>>[N:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:32]=[N:27][CH:28]=1
Reactant: Nc1ccccc1
Reactant: c1cc[nH+]cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: c1ccc2ncncc2c1

Procedure:
With reference to Scheme 1 following, the present compounds are generally prepared by reaction of indole 1 and Meldrum's acid 2 and an aldehyde RCHO (formaldehyde, R=H) in the presence of proline [Diane S. Farlow, Michael E. Flaugh, Sharon D. Horvath, Edward R. Lavagnino, and Paul Pranc, Organic Preparations and Procedures Int. 13(1), 39 (1981)] to provide condensation adduct 3 which can be converted directly using Route C to quinazoline I by reaction with an o-aminobenzanilide 4 in the presence of pyridinium p-toluenesulfonate (PPTS) in refluxing pyridine. Alternatively, via Route A condensation adduct 3 can be decarboxylated in aqueous pyridine in the presence of copper powder to provide the intermediate indolylpropionic acid 5. The latter reacts with a methyl anthranilate 6 to form ester 7. Hydrolysis of ester 7 provides the corresponding carboxylic acid 8 which reacts at elevated temperature with an aniline hydrochloride via Route D or with an aniline in the presence of PPTS [Route E] to provide quinazoline I. Intermediate acid 8 can be prepared directly from adduct 3 by reaction with an anthranilic acid 9 in refluxing pypidine [Route B]. ##STR2##
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][N:16]([C:21](=[O:32])[CH2:22][N:23]1[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25])[CH2:17][C:18](O)=[O:19])(=[O:12])=[O:11])([O-:3])=[O:2].CN1CCOCC1.O>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:14][CH2:15][N:16]([C:21](=[O:32])[CH2:22][N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:17][C:18]1=[O:19])(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: Cc1cn(CC(=O)N(CCNS(=O)(=O)c2ccccc2[N+](=O)[O-])CC(=O)O)c(=O)[nH]c1=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2)c(=O)[nH]c1=O
Temperature: 0 °C
Yield: 97.9 %

Procedure:
To a solution of N-[2-(2-nitro-benzenesulfonylamino)-ethyl]-N-[(thymin-1-yl)-acetyl]-glycine (469 mg, 1.0 mmol) and N-mehtyl morpholine (330 μL, 3 mmol) in THF (10 mL) was added isobutylchloroformatre (205 mg, 1.5 mmol) at −20° C. The reaction mixture was allowed to warm to 0° C. for a period of 1 h. Then water (10 mL) was added to the reaction mixture to precipitate solid. The solid was filtered off, washed with water, dried in vacuo to give the tiltled compound (442 mg, 98%). 1H-NMR (500 MHz; DMSO-d6) δ 11.32 (s, 0.6H), 11.30 (s, 0.4H), 8.35 (m, 1H), 8.12 (dd, 1H), 8.04˜7.96 (m, 2H), 7.35 (s, 0.6H), 7.28 (s, 0.4H), 4.67 (s, 1.2H), 4.59 (s, 0.8H), 4.41 (s, 0.8H), 4.27 (s, 1.2H), 4.04 (m, 1.2H), 3.95 (m, 1.2H), 3.90˜3.85 (m, 1.6H), 1.75 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O.[Li+].[OH-]>C1COCC1.CO>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)COCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(COCC(=O)O)cc2)cc1
Temperature: 50 °C

Procedure:
To a solution of (R)-Ethyl 2-((4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)methoxy)acetate (125.6 mg, 0.329 mmol) in THF (0.5 mL), MeOH (0.5 mL), and H2O (1 mL) was added LiOH (23.65 mg, 0.988 mmol). The reaction was heated briefly to ˜50° C. and concentrated. The resulting aqueous mixture was acidified (HCl, 3 eq) and purified by HPLC to give the title compound. LCMS m/z=354.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (t, J=5.94 Hz, 3H), 1.53-1.70 (m, 1H), 1.86-2.13 (m, 2H), 2.16-2.28 (m, 1H), 2.91-3.13 (m, 2H), 3.16-3.27 (m, 2H), 3.51-3.71 (m, 3H), 4.09 (s, 2H), 4.58 (s, 2H), 7.37-7.47 (m, 4H), 7.61-7.70 (m, 4H), 9.26-9.84 (m, 1H), 12.68 (bs, 1H).
Reaction SMILES: O=[C:2]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:3]=[CH:4][CH:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.OS(O)(=O)=O>C(O)C.[Pd]>[C:16]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:14][CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(C=CC=CC(=O)c2ccccc2)cc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=C(O)c1ccc(CCCCCc2ccccc2)cc1
Reaction time: 4 h
Yield: 53.7 %

Procedure:
4-(5-Oxo-5-phenyl-penta-1,3-dienyl)-benzoic acid (13.9 g, 50 mmol) is dissolved in ethanol (280 mL). Concentrated H2SO4 (1 mL) and 5% palladium on carbon (2.8 g) are added and the mixture hydrogenated at 50° C. and 60 psi for 4 h. The reaction is filtered, diluted with water (1000 mL), and extracted several times with diethyl ether. The combined organic extracts are washed with 2 N NaOH. The aqueous portion is acidified with concentrated hydrochloric acid and extracted with diethyl ether. The ether extracts are washed with water, dried over Na2SO4, and evaporated to obtain a solid. The solid is recrystallized from hexanes to obtain 7.2 g (54%) of white crystals. m.p.=80-80.5° C.; Anal. Calcd for C18H20O2: C, 80.56; H, 7.51. Found: C, 80.75; H, 7.34.
Reaction SMILES: C([Li])CCC.CCCCCC.C([Mg]Cl)CCC.[Br:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21](Br)[CH:20]=1.[I:28]Cl>C1(C)C=CC=CC=1.C(Cl)Cl.O>[Br:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([I:28])[CH:20]=1
Reactant: COc1cc(Br)cc(Br)c1
Reactant: ClI
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cc(Br)cc(I)c1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
A 1.6 M solution of n-butyllithium in hexane (5.65 mL, 9.04 mmol) was dissolved in dry toluene (50 mL) under dry argon and cooled to −5° C. Then a 2M solution of n-butylmagnesium chloride (2.26 mL, 4.52 mmol) was added slowly with the temperature held below 0° C. over a period of 15 min. Stirring was continued for 45 min at −5° C., followed by drop wise addition of a solution of 1,3-dibromo-5-methoxy-benzene (3.00 g, 11.3 mmol) in toluene (30 mL) with the temperature held below 0° C. The mixture was stirred for 45 min at −5° C. A solution of iodine chloride (1.83 g, 11.3 mmol) in methylene chloride (20 mL) was added in the described manner and stirring continued for additional 20 min at −5° C. The mixture was warmed to room temperature. Water (50 mL) and toluene (50 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of Na2S2O3 (2×30 mL), water and brine (30 mL). The organic layer was dried (MgSO4) and concentrated to give the crude product which was purified by flash chromatography on silica gel (100 g, AcOEt/heptane 1:9). 1-Bromo-3-iodo-5-methoxy-benzene (2.12 g, 60%) was obtained as a yellow oil, which crystallized quickly upon standing.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22](Cl)=[O:23]>C(Cl)Cl>[F:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:21]=1[C:22]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:23]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(C(=O)c2c(F)cccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride (1.0 g, 6.5 mmol) in methylene chloride (32 mL) at rt were successively added DIPEA (1.4 mL, 7.8 mmol) and 2,6-difluorobenzoyl chloride (0.82 mL, 6.5 mmol). The resulting heterogeneous mixture was stirred at rt for 2 d. The resulting mixture was washed with 1 N aq. sodium hydroxide (3×10 mL) and the combined basic aqueous portion was back-extracted with methylene chloride (2×10 mL). The organic extracts were combined and washed with 10% aq. citric acid (2×10 mL), brine (20 mL), and dried over anhyd sodium sulfate. Concentration under vacuum afforded the title compound a as a pale yellow solid (1.29 g, 83%). 1H NMR (400 MHz, d3-MeOD): δ 7.60 (m, 1 H), 7.18-7.09 (m, 2 H), 4.09 (t, J=6.4 Hz, 2 H), 3.70 (t, J=6.3 Hz, 2 H), 2.62 (t, J=6.4 Hz, 2 H), 2.48 (t, J=6.3 Hz, 2 H).
Reaction SMILES: N1C=CC(=O)NC1=[O:3].O=C[C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])[OH:12].O=C[C@@H]([C@H]([C@@H](CO)O)O)O>>[O:3]=[C:11]([OH:12])[C@@H:13]([C@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C(O)[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
The resulting strains H3679 and H3680 were cultured on SC-medium lacking uracil for plasmid selection, with 10 g I−1 glucose and 20 g I−1 xylose as carbon sources. The strains were cultured in 250 ml Erlenmeyer flasks in 50 ml medium with 250 rpm agitation at 30° C. Strain H3679 expressing the gene CC_1225 produced 3.3 g xylonic acid I−1 extracellularly in 75 h (FIG. 14). Strain H3680 (control strain) produced no xylonic acid when grown under the same conditions.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[C:7]([CH3:12])=[CH:8][CH:9]=[C:10]([CH3:11])[C:4]=2[O:3]1.[CH3:14][O:15]C(Cl)Cl>ClCCl>[CH3:1][C:2]1([CH3:13])[CH2:6][C:5]2[C:7]([CH3:12])=[C:8]([CH:14]=[O:15])[CH:9]=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1ccc(C)c2c1CC(C)(C)O2
Reactant: COC(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C=O)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 110 g of the 2,3-dihydro-2,2,4,7-tetramethylbenzofuran in 500 ml of absolute dichloromethane was added 68.5 ml of titanium chloride(IV) and 56.5 ml of α,α-dichloromethyl methyl ether at 0° C. With stirring at room temperature for 45 minutes and refluxing for 15 minutes, the reaction mixture was quenched with 1 l of water and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product. Final purification was carried by recrystallization to afford 104 g of 2,3-dihydro -2,2,4,7-tetramethyl-benzofuran-5-carboxaldehyde as a white solid.