Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=O)C1C=CC=CC=1.C1C2NC3C(=CC=CC=3)C=2CC(C(N)=O)N1.C(OC(N1[C@H](C(O)=O)CC2C3C(=CC=CC=3)NC=2C1)=O)C1C=CC=CC=1>>[CH2:12]1[C:13]2[NH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH2:22][C@@H:23]([C:24]([NH2:26])=[O:25])[NH:11]1
Reactant: NC(=O)C1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Agent: NC(=O)C1Cc2c([nH]c3ccccc23)CN1
Agent: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=O)OCc1ccccc1
Product: NC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1

Procedure:
In the same manner as described above (1) and (2) using (3S)-2-benzyloxycarbonyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, there is obtained (3S)-1,2,3,4-tetrahydro-β-carboline-3-carboxamide as powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH3:11].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:11][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: C1COCCN1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1ccc(CN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
2-Fluoro-4-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.82 g, 10 mmol), and benzoyl peroxide (0.1 g, 0.4 mmol) were dissolved in CCl4 (50 mL). The mixture was heated at reflux, and irradiated with light (100 W bulb) for 4 hours. The reaction mixture was filtered and concentrated. The residue was dissolved in THF (50 mL) and morpholine (1.9 g, 22 mmol) was added to this solution. The mixture was stirred at ambient temperature for 1 hour, and then filtered. The filtrate was evaporated. The title compound was isolated by column chromatography in an amount of 710 mg (30% yield).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].I[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CN(C=O)C.C(Cl)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.[Cu](I)I.O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]2[C:3]([OH:5])=[O:4])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
Proline (3.5 g, 30.4 mmol), 4-iodonitrobenzene (7.2 g, 28.9 mmol), Pd(PPh3)4 (1.7 g, 5 mol %), copper iodide (0.3 g, 5 mol %), benzyltriethylammonium chloride (11.9 g, 52 mmol), triethylamine (8.3 ml, 60 mmol) and potassium carbonate (4.2 g, 30 mmol) were pre-mixed in DMF (60 ml)/water (6 ml). The reaction was heated at 80° C. for 8 hours. The DMF was removed in vacuo and the remaining black gum was dissolved in DCM, acidified with 2.0 N HCl (50 ml), extracted with DCM (3×100 ml), dried and solvent removed in vacuo to yield a black tar. The tar was dissolved in a minimum amount of DCM (7 ml) and loaded onto a 50 g silica column, the system was eluted with 20% EtOAc/isohexane, then 60% EtOAc/iso-hexane and finally 100% EtOAc. The title compound was obtained as an orange gum. NMR (299.954 MHz, CDCl3) 8.13 (d, 2H), 6.52 (d, 2H), 4.41 (d, 1H), 3.66 (t, 1H), 3.49 (q, 1H), 2.47-2.29 (m, 2H), 2.25-2.12 (m, 2H); m/z 237.
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])=[C:11]([F:29])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[OH:30][CH2:31][C:32]([CH2:37]O)([CH2:35][OH:36])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[OH:30][CH2:31][C:32]([CH2:35][OH:36])([CH2:33][OH:34])[CH2:37][O:7][C:6](=[O:8])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][C:11]([F:29])=[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:28])[C:2]=1[F:1]
Reactant: O=C(O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: OCC(CO)(CO)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F)OCC(CO)(CO)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a stirred solution of 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetic acid (I(b)) (700 mg, 1.73 mmol, 1.0 eq) in DMF (30 mL) was added pentaerythritol (470 mg, 3.45 mmol, 2.0 eq), TEA (699 mg, 6.91 mmol, 4.0 eq) and HATU (985 mg, 2.60 mmol, 1.5 eq). The resulting mixture was stirred at room temperature overnight under N2. The reaction was diluted with water then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (DCM:MeOH=100:1-20:1) to give the title compound as a colourless oil (370 mg, 41%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:25](Cl)(=[O:27])[CH3:26]>O1CCCC1>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][N:21]([C:25](=[O:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(=O)Cl
Reactant: CC(C)NCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)C(C)C
Temperature: 0 °C
Yield: 177.5 %

Procedure:
1-Boc-4-[2-(isopropylamino-methyl)-phenyl]-piperazine (0.325 g, 0.975 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to about 0° C. TEA (0.54 mL, 3.9 mmol) was added followed by dropwise addition of acetyl chloride (0.2 mL, 2.93 mmol). The solution was allowed to warm to r.t. The solvents were removed under reduced pressure, and the resulting oil was purified using silica chromatography (ethyl acetate) to afford the title compound (0.650 g, 82%) as an oil.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9](I)[CH:8]=1.B(F)(F)F.CCOCC.[N:24]1[O:25][CH2:26][CH:27]2[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:29][C:28]=12>O1CCCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:28]23[CH2:29][N:30]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:31][CH:27]2[CH2:26][O:25][NH:24]3)[CH:8]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: O=C(OCc1ccccc1)N1CC2=NOCC2C1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CC2CONC2(c2cc(Br)ccc2F)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
A 1.6 M hexanes solution of n-butyl lithium (25.4 mL, 40.6 mmol) is added drop wise to a −78° C. solution of 4-bromo-1-fluoro-2-iodobenzene (12.22 g, 40.6 mmol) in tetrahydrofuran (60 mL) to give a yellow solution that is stirred at −78° C. for 15 minutes. Boron trifluoride etherate (5.14 mL, 40.6 mmol) is added to a separate −78° C. solution of benzyl 3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (5 g, 20.3 mmol) in tetrahydrofuran (60 mL) and the mixture is stirred at −78° C. for 5 minutes. This solution is added to the previously prepared −78° C. organolithium mixture via cannula. The combined mixture is stirred for 30 minutes at −78° C. The mixture is quenched with saturated aqueous ammonium chloride and warmed to room temperature. The mixture is extracted with ethyl acetate (3×) and the organic extracts are combined, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 35 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (2.27 g, 27%). ES/MS (m/e): (79Br/81Br) 421/423 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-:12].[K+]>CO.O>[OH:12][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:9]=1[C:8]([OH:7])=[O:11]
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)C(=O)OC2
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(CO)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
A colorless, homogeneous solution of 6-methylisobenzofuran-1(3H)-one (0.95 g, 6.41 mmol), KOH (0.576 g, 10.26 mmol) in methanol (20.52 mL) and water (5.13 mL) was refluxed. After two hr, the reaction was cooled to room temperature, concentrated in vacuo, and acidified with 1 M aqueous KHSO4 to pH ˜3. The mixture was extracted with EtOAc (4×50 mL). The combined extract was dried over MgSO4 and concentrated in vacuo to give the desired product (0.632 g, 3.81 mmol, 59.4% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([O-])=[O:25])=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:24](=[O:25])[C:23]5[CH:27]=[CH:28][C:20]([N:19]([CH3:29])[CH3:18])=[CH:21][CH:22]=5)=[CH:10][CH:9]=4)[CH:5]=[N:6]3)=[CH:12][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(C(=O)[O-])cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc(-n3ncc4cc(NC(=O)c5ccc(N(C)C)cc5)ccc43)cc2)cc1

Procedure:
Compound 373 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-dimethylaminobenzoate. 1H NMR (500 MHz, Acetone-d6) δ 9.44 (s, 1H), 9.38 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.08 (d, J=9 Hz, 2H), 7.95 (d, J=9 Hz, 4H), 7.81 (m, 2H), 7.76 (d, J=9 Hz, 2H), 6.79 (d, J=9 Hz, 4H), 3.06 (s, 6H), 3.05 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=O>C(O)(=O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[N:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3cccnc3)ccnc12

Procedure:
As for Example 2, 1.04 g. of 3-amino-4-carboethoxypyrazole is heated at reflux temperature for 16 hours with 1.18 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one in 25 ml. of glacial acetic acid to give 1.30 g. of the product of the example as colorless needles, m.p. 170°-171° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17](=O)[NH2:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:20])[CH3:7]>N1C=CC=CC=1>[CH2:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]=[C:9]1[CH3:20])[CH3:7]
Reactant: CCn1c(C)nc2cc(C(N)=O)ccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCn1c(C)nc2cc(C#N)ccc21
Temperature: 60 °C
Yield: 61 %

Procedure:
42.4 ml (0.44 mole) of phosphorus oxychloride were added to a stirred and ice-cooled solution of 81.2 g (0.4 mole) of compound IV in 160 ml of pyridine. The temperature reached 45° C. Thereupon the mixture was heated to 60° C. The reddish-brown oil obtained was poored immediately in 1 kg of an ice-water mixture with stirring. The precipitate was filtered, washed with ice-cold water and dried. The crude product obtained was crystallized from pyridine (1.5 ml/g) and water (9 mg/g). Melting point: 162° C. Yield: 61% (452 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:21][CH:20]=2)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+]>CO.O>[C:26]1([C:22]2[CH:23]=[C:24]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:3]([OH:32])=[O:2])=[O:14])=[CH:25]3)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccccc3)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1cc2cc(-c3ccccc3)ccc2[nH]1
Temperature: 50 °C
Yield: 24.4 %

Procedure:
A solution of (R)-2-(5-phenyl-indol-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 46 (0.195 g, 0.455mmole) in methanol (20 ml) was treated with a solution of lithium hydroxide monohydrate (23 mg, 0.55 mmole) in water (1 ml) and heated to 50° C. for 7 hrs, cooled to room temperature, acidified, evaporated, extracted with EtOAc, washed, dried, and evaporated. The residue was purified by chromatography to give about 46 mg of (R)-2-(5-phenyl-indol-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid 47, mp. 168–174°.
Reaction SMILES: F[O:2][C:3]([O:6]F)([F:5])[F:4].[F:8][C:9]([F:13])=[C:10]([F:12])[F:11]>N#N>[F:4][C:3]1([F:5])[O:6][C:9]([F:13])([F:8])[C:10]([F:12])([F:11])[O:2]1
Reactant: FC(F)=C(F)F
Reactant: FOC(F)(F)OF
Agent: N#N
Product: FC1(F)OC(F)(F)C(F)(F)O1
Temperature: -80 °C

Procedure:
Into a multineck glass reactor equipped with: magnetic entrainment mechanical stirrer, reflux cooler, thermocouple, inner plunging pipes for introducing the reagents, and maintained at a temperature of -80° C., there were simultaneously fed-after having introduced 75 ml of FC 75-0.5 l of bis(fluoroxy)difluoromethane at a flowrate of 0.3 l/h diluted with N2 (0.5 l/h) and 5.0 g of tetrafluoroethylene (3.0 g/h).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([OH:23])=O)[CH:11]=2)=[CH:7][C:6]=1[F:26])=[O:4].S(Cl)(Cl)=O.[NH2:32][C:33]1[CH:37]=[C:36]([CH3:38])[O:35][N:34]=1>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:38][C:36]1[O:35][N:34]=[C:33]([NH:32][C:21]([C:12]2[CH:11]=[C:10]([O:9][C:8]3[CH:24]=[CH:25][C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:27])=[C:6]([F:26])[CH:7]=3)[C:15]3[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:14]=3[CH:13]=2)=[O:23])[CH:37]=1
Reactant: Cc1cc(N)no1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cc(Oc3ccc(C(=O)N(C)C)c(F)c3)c3c(c2)OC(C)(C)C3)no1
Temperature: 40 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To a solution of 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (66 mg, 0.177 mmol) in 3 mL of CH2Cl2 was added thionyl chloride (0.0154 mL, 0.212 mmol), followed by 3 drops of DMF. The mixture was refluxed for 1.5 h, then concentrated and dried under vacuum. The residue was dissolved in 3 mL of CH2Cl2, added 3-amino-5-methylisoxazole (22.6 mg, 0.230 mmol) at 0° C., followed by DMAP (52 mg, 0.354 mmol). The mixture was stirred at 0° C. to room temperature for 1 hr and heated at 40° C. overnight, then concentrated and purified by flash column chromatography with 40-55% EtOAc in hexanes to give a white solid (8 mg, 10% yield). 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1 H) 7.38 (t, J=8.08 Hz, 1 H) 7.11 (d, J=1.77 Hz, 2 H) 6.76-6.84 (m, 2 H) 6.70 (dd, J=10.61, 2.27 Hz, 1 H) 3.13 (s, 3 H) 2.98 (br. s., 3 H) 2.91 (s, 2 H) 2.42 (s, 3 H) 1.50 (s, 6 H); LCMS for C24H24FN3O5 m/z 454.00 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][CH3:14])[CH:7]=1)=[O:5].[Br:19]Br>C(Cl)Cl.N1C=CC=CC=1>[Br:19][C:10]1[CH:11]=[C:6]([C:4](=[O:5])[C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Cl:1])[CH:7]=[C:8]([CH2:13][CH3:14])[C:9]=1[OH:12]
Reactant: BrBr
Reactant: CCc1cc(C(=O)c2ccccc2Cl)ccc1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc(C(=O)c2ccccc2Cl)cc(Br)c1O
Reaction time: 48 h
Yield: 93 %

Procedure:
At ambient temperature, to a stirred solution containing 4-(2-chlorobenzoyl)-2-ethylphenol (13.62 g, 52.24 mmol) and pyridine (0.25 mL, 3.23 mmol) in CH2Cl2 (870 mL) was added dropwise bromine (3.3 mL, 62.29 mmol). After 48 h, the reaction was washed with 10% aq. Na2SO4 (1×180 mL), H2O (2×350 mL), brine (1×300 mL), dried (Na2SO4) and concentrated to give 16.50 g (93%) of the title compound. 1H NMR: consistent.
Reaction SMILES: [CH:1]1([N:7]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])[CH:8]2[CH2:14][CH:13]3[N:15](C(OC(C)(C)C)=O)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(NCC)=O)C>Cl.C(OCC)C>[CH:10]12[NH:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][CH:8]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:23]([N:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[O:24])[CH2:9]2
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: CCNC(=O)NCC
Agent: Cl
Solvent: CCOCC
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.0 g of tert-butyl 3-{cyclohexyl[(diethyl-amino)carbonyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate mixed with diethylurea are placed in 37 ml of 2N hydrochloric acid in diethyl ether. The reaction medium is stirred at ambient temperature for 16 h. After evaporation to dryness, the residue is taken up with a 1N aqueous hydrochloric acid solution. Extraction is carried out with ethyl acetate and a 1N aqueous sodium hydroxide solution is then added up to a pH of 10. Extraction is carried out with ethyl acetate until the aqueous phase is completely depleted. The organic phase is washed with H2O and then with a saturated aqueous sodium chloride solution. After drying over MgSO4 and concentration to dryness, 1.8 g of N-8-azabicyclo[3.2.1]oct-3-yl-N-cyclohexyl-N′,N′-diethylurea are obtained.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2)cs1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(CBr)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of N-(4-{2-[4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (50 mg) prepared in a similar manner according to Step 3 of the following Production Example 16, carbon tetrabromide (72 mg) and dichloromethane (1 ml) was added triphenylphosphine (71 mg), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was purified by flash column chromatography on silica gel with 1% methanol/chloroform as an eluent. The crystalline residue was collected and washed with diisopropyl ether to give N-(4-{2-[4-(bromomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (48 mg).
Reaction SMILES: CO.[F:3][C:4]1[CH:26]=[CH:25][C:7]([NH:8][C:9]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[NH2:22][C:20]1[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:9]([NH:8][C:7]2[CH:25]=[CH:26][C:4]([F:3])=[CH:5][CH:6]=2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(N)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
To a mixed solution of methanol 5.0 mL and ethyl acetate 5.0 mL of tert-butyl 2-(4-fluoroanilino)-4-nitrobenzoate 1.0 g, was added 5% palladium-carbon 0.20 g, and it was stirred under hydrogen atmosphere at room temperature for 6 hours. Insoluble matter was filtrated, the solvent was removed under reduced pressure to give tert-butyl 4-amino-2-(4-fluoroanilino)benzoate 0.90 g of white solid.
Reaction SMILES: [Se](=O)=O.[F:4][C:5]([F:45])([C:41]([F:44])([F:43])[F:42])[C:6]([F:40])([F:39])[C:7]([P:10]([C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])([C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])(F)F)([F:9])[F:8]>>[P:10]([C:7]([C:6]([C:5]([C:41]([F:42])([F:43])[F:44])([F:4])[F:45])([F:39])[F:40])([F:8])[F:9])([C:26]([C:27]([C:28]([C:29]([F:32])([F:31])[F:30])([F:34])[F:33])([F:36])[F:35])([F:38])[F:37])[C:13]([C:14]([C:15]([C:16]([F:19])([F:18])[F:17])([F:21])[F:20])([F:23])[F:22])([F:25])[F:24]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)P(F)(F)(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=[Se]=O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)P(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2.14 g (19.3 mmol) of selenium dioxide, SeO2, are added to 12.445 g (17.1 mmol) of tris(nonafluorobutyl)difluorophosphorane, (C4F9)3PF2, in a 100 ml glass round-bottomed flask and warmed (120° C. oil-bath temperature). An intensive reflux condenser is connected downstream of the flask. The suspension is stirred at 120° C. for 3 h. After this time, no weight loss, but complete consumption of (C4F9)3PF2 and formation of (C4F9)3P═O can be detected. The entire suspension is condensed at 80° C. in vacuo (10−3 mbar). Clear and colourless (C4F9)3P═O (7.426 g; 10.5 mmol; 62%) in 87% purity can be isolated.
Reaction SMILES: CS(O)(=O)=O.FC(F)(F)S(O)(=O)=O.N[C@H](C(O)=O)CCSC.C[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1>>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(C)=O)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Product: CC(=O)c1ccc(O)cc1
Yield: 30 %

Procedure:
In this connection, the demethylation of compounds of relatively simple structure by means of a couple sulfonic acid/derivative of the sulfide type, for instance methanesulfonic acid or trifluoromethanesulfonic acid and methionine, is known. This method is reported in particular in J. C. S. Perkin I. pp. 2288-2289 (1977). The results obtained with this method are usually very varied (yield of demethylated compounds varies from 30 to 90%) and may be poor. This is the case for p-methoxyacetophenone: no reaction is recorded at 20° C. and only 30% yield of p-hydroxyacetophenone is obtained after 72 hours at 60° C.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH2:11])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:11][C:6]1[C:5]([CH2:4][OH:3])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCOC(=O)c1cccnc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1CO
Reaction time: 1.5 h
Yield: 79 %

Procedure:
To a solution of 2-aminonicotinic acid ethyl ester (1.74 g, 10.5 mmol) in anhydrous THF (35 mL) was added a solution of lithium aluminum hydride (0.60 g, 15.7 mmol) in THF (17 mL) at 0° C. over 15 min and the mixture stirred for 1.5 h. To the reaction was added sequentially 0.6 mL H2O, 0.6 mL 15% aqueous NaOH and 1.8 mL H2O and the resultant slurry was filtered. The filtrate was dried (MgSO4), filtered, concentrated and purified by column chromatography (10% MeOH/CH2Cl2) to give 2-amino-3-hydroxymethylpyridine (1.03 g, 79%) as a yellow crystalline solid. 1H NMR (CDCl3) δ 3.14 (br s, 1H (OH)), 4.60 (s, 2H), 5.00 (br s, 1H (NH)), 6.59 (t, 1H, J=6.0 Hz), 7.28 (d, 1H, J=7.5 Hz), 7.94 (d, 1H, J=7.5 Hz).