Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][Mg]Cl>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:1][C:2]1[N:7]=[C:6]([CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: C[Mg]Cl
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1nc(Cl)ncc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
A solution of 2,4-dichloro-5-fluoropyrimidine (2.5 g, 14.97 mmol) and iron(III) acetylacetonate (1.058 g, 2.99 mmol) in THF (100 mL) and NMP (10 mL) was chilled below 0° C. and methyl magnesium chloride (5.99 mL, 18.0 mmol, 3.0 M solution in THF) was added dropwise over 10 minutes. After stirring for 2 hours at 0° C., the mixture was quenched with 200 mL saturated NH4Cl and extracted twice with 200 mL EtOAc. The combined organic extracts were washed with 200 mL saturated NH4Cl and 200 mL brine, dried over Na2SO4 and concentrated. Purification by chromatography (Grace Reveleris 80 g column, eluted with 0-20% EtOAc/heptane, 35 mL/min) provided the title compound (1.13 g, 7.70 mmol, 51% yield). GC/MS (EI+) m/z 146.0 (M+); 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 2.55 (d, J=2.5, 3H); 13C NMR (101 MHz, CDCl3) δ 158.78, 158.61, 157.34, 154.92, 154.89, 154.74, 145.86, 145.63, 17.74, 17.73.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C:25]([C:26](=[O:34])[NH:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][C:23]([CH3:35])=[N:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:28]1([NH:27][C:26]([C:25]2[N:21]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:20][CH:19]=3)[N:22]=[C:23]([CH3:35])[CH:24]=2)=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)NC2CCCCC2)n(-c2ccc(OC3CCNCC3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[4-(5-cyclohexylcarbamoyl-3-methylpyrazol-1-yl)phenoxy]piperidine-1-carboxylic acid tert-butyl ester (482 mg, 1.00 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (2 mL). After the reaction was stirred at room temperature for 2 hours, it was quenched with saturated sodium bicarbonate and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried (MgSO4) and concentrated to give the crude product in quantitative yield. LC-MS (C22H30N4O2 calculated 382) m/z 383 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 67.7 %

Procedure:
To a solution of 5-benzyloxy-isophthalic acid dimethyl ester (D44) (24 g, 80 mmol, 1 equiv) in MeOH (300 ml) was added 1N aqueous NaOH solution (76 ml, 76 mmol, 0.95 equiv) and the resulting solution was stirred at room temperature for 17 h. A second portion of 1N aqueous NaOH solution (15 ml, 15 mmol, 0.2 equiv) was added and the solution stirred for another 6 h. Most of the MeOH was removed in vacuo and the residue was partitioned between AcOEt and 1N aqueous NaOH solution. The aqueous layer was extracted with AcOEt, acidified to pH 1 and re-extracted with AcOEt. The second organic extract was dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O to give 5-benzyloxy-isophthalic acid monomethyl ester (D46) (15.5 g, 68%) as a white solid. [M+H]+=2.86.0, RT=3.32 min
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:11]2.[BrH:20]>OS(O)(=O)=O.C(O)(=O)C.O>[Br:20][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:11]2
Reactant: Br
Reactant: COC(=O)c1ccc2cccc(N)c2c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2cccc(Br)c2c1
Temperature: 10 °C
Yield: 83 %

Procedure:
To a cooled (10° C.) stirred solution of NaNO2 (2.18 g, 31.5 mmol) in concentrated H2SO4 (28.3 mL) and glacial acetic acid (26.1 mL) (prepared by adding NaNO2 to cooled [10° C.] H2SO4, heating to dissolve, re-cooling and adding HOAc) was added a solution of 8-amino-2-naphthoic, methyl ester (VII) (5.72 g, 26.36 mmoles) in glacial acetic acid (88.7 mL) over 10 minutes. The resulting solution was then added slowly (over 10 minutes) to a heated (60° C.), stirred solution of CuBr (16.59 g, 43.31 mmoles) in concentrated HBr (160 mL). The mixture was warmed to 90° C. for 10 minutes, cooled, diluted with H2O (350 mL), and filtered to give 5.8 g (yield: 83%) of 8-bromo-2-naphthoic acid, methyl ester; 1H-NMR: δ9.00 (s, 1H), 8.10 (dd, J=7.5, 1.0 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.85 (d, J=6.5 Hz, 2H), 7.40 (dd, J=8.2, 7.5 Hz, 1H), 4.05 (s, 3H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[O:11]=[CH:12][C@H]([C@H]([C@H](CO)O)O)O>>[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH2:12][OH:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Product: O=C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
It is also known that both D-glucose and D-mannose can be epimerized in an aqueous solution containing about 17% by weight of D-glucose or D-mannose, based on total solution weight (i.e., 20% by weight of glucose, based on the weight of water) and a small amount of molybdic acid catalyst producing a solution containing 25 percent D-mannose, remainder D-glucose on the dry basis. This epimerization is described by V. Bilik, Chem. Zvesti, 26, 183-186 (1972) and in Czech patent 149,051 (June 15, 1973). No reaction took place when sodium molybdate was used as the catalyst. Bilik and co-workers have also found that various other sugars can be epimerized in the presence of molybdate ions in aqueous solution. For example, D-fructose gives a mixture of D-sorbose, D-tagatose, and D-psicose, and sucrose gives a mixture of D-mannose and D-sorbose in a similar reaction. [Chemical Abstracts, 80, 146433s (1974)]. Also, L-arabinose gives a mixture of L-arabinose and L-ribose [Czechoslovakian Patent 149,472, July 15, 1973; C.A. 81, 78189k (1974)]; L-mannose gives a mixture of L-glucose and L-mannose [C.A. 81, 91887f (1974)]; and D-galactose gives a mixture of D-talose and D-gulose in addition to D-galactose [C.A. 81, 152523h (1974)].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:7][CH:8]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CCc1cccc(CCCO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCc1cccc(CCCBr)c1
Reaction time: 5 h
Yield: 87.9 %

Procedure:
Compound 47-3 (3.53 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (6.19 g) and N-bromosuccinimide (4.20 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 5 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (4.29 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH:6]=[C:7]([CH:13]=O)[C:8]=1[O:9][CH2:10][C:11]#[N:12].[OH-].[Na+].Cl.[CH3:25][O:26][NH2:27]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH:6]=[C:7]([CH:13]=[N:27][O:26][CH3:25])[C:8]=1[O:9][CH2:10][C:11]#[N:12]
Reactant: COc1cc(NC(=O)OC(C)C)cc(C=O)c1OCC#N
Reactant: CON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=Cc1cc(NC(=O)OC(C)C)cc(OC)c1OCC#N
Reaction time: 12 h
Yield: 94.5 %

Procedure:
Isopropyl N-(3-methoxy-4-cyanomethoxy-5-formylphenyl)carbamate (0.59 g) was dissolved in ethanol (20 ml). To the solution was added an aqueous solution (10 ml) containing sodium hydroxide (0.32 g) and methoxyamine hydrochloride (0.66 g). After being allowed to stand for 12 hours, the reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The resultant solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give isopropyl N-(3-methoxy-4-cyanomethoxy-5-methoxyiminomethylphenyl)carbamate (Compound No. 78) (0.62 g) in a yield of 94.5%.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=O)[O:4][C:2]2=O.[C:13]1(N)[CH:18]=[CH:17][CH:16]=C[C:14]=1[NH2:19]>C(O)(=O)C.O>[CH:11]1[C:1]2[C:2](=[O:4])[N:19]=[C:14]3[CH:13]=[CH:18][CH:17]=[CH:16][C:5]3=[N:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CC(=O)O
Solvent: O
Product: O=c1nc2ccccc2nc2ccccc12
Temperature: 75 °C
Yield: 96 %

Procedure:
A mixture of isatoic anhydride (1 mol) and 1,2 phenylenediamine (1.1 mol) in aglacial acetic acid (60%) was heated at 75° C. for 3 hrs. The resulting mixture was diluted with water and solid filtered to obtained dibenzo[b,e][1,4]-diazepine-11-one in 96% yield.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.C([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])C>O1CCCC1>[CH3:8][N:7]1[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=[C:2]1[N:18]1[C@@H:19]2[CH2:20][CH2:10][CH2:4][CH2:5][C@H:6]2[O:9][CH2:22][CH2:21]1
Reactant: CCN(CC)CC
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Solvent: C1CCOC1
Product: Cn1c(N2CCO[C@@H]3CCCC[C@H]32)nc(-c2ccncn2)cc1=O
Yield: 128.1 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.34 g, 1.53 mmol), (4aRS,8bRS)-trans-octahydrobenzo[1,4]oxazine hydrochloride (0.3 g, 1.69 mmol) and triethylamine (0.5 g, 4.94 mmol) in tetrahydrofuran (20 ml) was stirred for 10 hours at 100° C. The solution was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 1-methyl-2-((4aRS,8aRS)-trans-octahydro-benzo[1,4]oxazin-4-yl)-1H-[4,4′]bipyrimidinyl-6-one (0.32 g, 0.98 mmol, 64%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:22][C:23](=O)NC[C:26]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[CH3:40][N:41]([CH:43]=[O:44])[CH3:42]>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:40]4[N:41]([CH3:42])[C:43](=[O:44])[N:22]([CH3:23])[CH2:21][C:26]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)NC4)cc2)CCC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN1Cc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-6-yl)phenyl)cyclobutyl)carbamate (46 mg, 0.10 mmol) in dry DMF (1 ml) at −78 C was added sodium hydride (3.9 mg, 0.10 mmol) and methyliodide (6.1 μl, 0.10 mmol) under nitrogen. The bath was removed and the resulting mixture was stirred for 1 h at room temperature. The mixture was cooled down to −78 C. Sodium hydride (3.9 mg, 0.10 mmol) and methyliodide (6.10, μl, 0.10 mmol) were added under nitrogen. The bath was removed and the resulting mixture was stirred for 1 h at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 50% EtOAc in cyclohexane) to give the title compound (30 mg, 61%). 1H NMR (500 MHz, CDCl3): 7.20-7.19 (7H, m), 7.13-7.11 (2H, m), 7.02 (1H, s), 5.00 (1H, br s), 4.56 (2H, s), 3.27 (3H, s), 3.03 (3H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.40-1.10 (9H, br)
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH2:18][C:19]3[N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:21](=[O:41])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:25]([C:35]3[S:36][CH:37]=[C:38]([CH3:40])[N:39]=3)=[CH:24][CH:23]=4)C3C(=CC=CC=3)C=2C=CC=1.N1CCCC1.O>CN(C)C=O>[NH2:17][CH2:18][C:19]1[N:20]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:21](=[O:41])[C:22]2[C:27]([C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:26][C:25]([C:35]1[S:36][CH:37]=[C:38]([CH3:40])[N:39]=1)=[CH:24][CH:23]=2
Reactant: Cc1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OCC4c5ccccc5-c5ccccc54)c(-c4ccccc4)c3c2)n1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: Cc1csc(-c2ccc3c(=O)n(CC(C)C)c(CN)c(-c4ccccc4)c3c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 9H-fluoren-9-ylmethyl[2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.38 g, 0.6 mmol) in N,N-dimethylformamide (10 ml) was added pyrrolidine (0.5 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The residue was purified by silica gel column chromatography to give 3-(aminomethyl)-2-isobutyl-6-(4-methyl-1,3-thiazol-2-yl)-4-phenyl-1(2H)-isoquinolinone (0.13 g, 54.2%) as crystals.
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:26][O:27][CH3:28])[C:12]([NH:14][C@H:15]2[C@H:18]([S:19][CH3:20])[N:17]([S:21]([O-:24])(=[O:23])=[O:22])[C:16]2=[O:25])=[O:13])[N:10]=1)=O.[Na+:29].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:26][O:27][CH3:28])[C:12]([NH:14][C@H:15]2[C@H:18]([S:19][CH3:20])[N:17]([S:21]([O-:24])(=[O:23])=[O:22])[C:16]2=[O:25])=[O:13])[N:10]=1.[Na+:29]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1SC)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1SC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 0.15 g of the above-mentioned sodium (3R,4S)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-methylthio-2-oxoazetidine-1-sulfonate in 4 ml of water is added under ice-cooling 0.044 g of sodium monomethyldithiocarbamate, and the mixture is stirred for one hour at room temperature. The same procedure as Example 3B yields 0.057 g of sodium (3R,4S)-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-4-methylthio-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.Cl[C:13]1[S:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:18]1([C:15]2[N:14]=[C:13]([N:1]3[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]3)[S:17][N:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Clc1nc(-c2ccccc2)ns1
Reactant: CCOC(=O)C1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 75.7 %

Procedure:
A mixed solution of ethyl isonipecotate (0.782 ml, 5.08 mmol), 5-chloro-3-phenyl-1,2,4-thiadiazole (1.00 g, 5.08 mmol) and triethylamine (0.708 ml, 5.08 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 30 minutes. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to yield 1.22 g (75.8%) of the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:32])([F:31])[C:18]1[N:23]=[CH:22][C:21](/[CH:24]=[CH:25]\[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:31][C:17]([F:16])([F:32])[C:18]1[N:23]=[CH:22][C:21]([CH2:24][CH:25]([N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1
Reactant: CCOC(=O)/C=C\c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)nc1)n1c2c(c3cc(C)ccc31)CN(C)CC2

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, (Z)-ethyl 3-(6-(trifluoromethyl)pyridin-3-yl)acrylate and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.CCOC(C)=O.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)cc1C1(O)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C1=CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.2 %

Procedure:
To a solution of 1-benzyl-4-(5-fluoro-2-methoxy-phenyl)-4-hydroxypiperidine (1.01 g 3.20 mmole) in acetic acid (40 mL) at room temperature was added 2 drops of concentrated sulfuric acid. The resulting solution was heated to reflux, and the mixture stirred for 2 days. The mixture was cooled to room temperature and diluted with EtOAc (100 mL) and water (100 mL). The solution was basified with 50% NaOH solution until pH=10. The layers were separated and the organics washed with brine. The combined aqueous layers were extracted three times with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated. Flash chromatography (elution with 1:1 EtOAc-hexane) to give 0.62 g (65%) of 1-benzyl-4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridine as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:34]=[C:35]([S:39]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]3[C:16]([C:17]4[N:25]=[CH:24][N:23]=[C:22]5[C:18]=4[N:19]=[CH:20][N:21]5[CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][O:27]4)=[CH:15][CH:14]=[CH:13][N:12]=3)[C:2]=2[F:1])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 3-chloro benzene-1-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[F:16]C1C=C(C=CC=1F)C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([F:16])[CH:7]=1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccc(F)c(F)c1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 3,4-difluorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:29][C:28]=4[F:30])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)cc4F)c3O2)cc1
Yield: 81.5 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2,4-difluorophenylboronic acid (3.09 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.651 mmol), and potassium carbonate (4.51 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 afforded 4.43 g (82%) of (±)-[7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 116-118° C.; Anal. calcd. for C22H18F2O4S: C, 63.45; H, 4.36. Found: C, 63.3; H, 4.11.