Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][Cl:15])[C:8]([OH:10])=[O:9])[N:6]=1.[C:16](OC(=O)C)(=[O:18])C.C(O)=O>O1CCCC1>[CH:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][Cl:15])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(C(=NOCCCl)C(=O)O)cs1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1nc(C(=NOCCCl)C(=O)O)cs1
Yield: 80.3 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 15 g.), acetic anhydride (24.5 g.), formic acid (11.0 g.) and tetrahydrofuran (50 ml.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 13.4 g.), mp 155° C. (dec.).
Reaction SMILES: [CH:1]1([N:7]([CH3:18])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(C(OCC)=O)=CC=1.C1C(=O)N([Br:38])C(=O)C1>>[CH:1]1([N:7]([CH3:18])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][Br:38])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)N(C)C2CCCCC2)cc1
Agent: CCOC(=O)c1ccc(C)cc1
Product: CN(C1CCCCC1)S(=O)(=O)c1ccc(CBr)cc1
Yield: 90.1 %

Procedure:
Utilising the procedure described in Example 1(a) employing N-cyclohexyl-N-methyl 4-methylbenzenesulphonamide (20.0 g, 0.075 mol) in lieu of ethyl 4-methylbenzoate and two equivalents of NBS (27.0 g, 0.15 mol) yielded a crude product of N-cyclohexyl-N-methyl 4-bromomethylbenzenesulphonamide (23.4 g, 90%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([OH:21])=O)=[O:5].[OH:30][C@@H:31]([CH3:34])[CH2:32][NH2:33]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:16])([CH3:17])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19]([NH:33][CH2:32][C@@H:31]([OH:30])[CH3:34])=[O:21])=[O:5]
Reactant: C[C@H](O)CN
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: C[C@H](O)CNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and commercially available (S)-2-hydroxypropylamine using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.01 (d, J=6.1 Hz, 3H), 1.48 (s, 6H), 1.46 (s, 6H), 3.07-3.20 (m, 2H), 3.65-3.73 (m, 1H), 4.68 (d, J=4.4 Hz, 1H), 7.68-7.81 (m, 4H), 11.60 (br s, 1H). MS (ESI+) m/z 489 (M+H)+. Anal. calcd. for C22H24F4N2O4S: C, 54.09; H, 4.95; N, 5.73. Found: C, 53.91; H, 4.89; N, 5.38.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH2:23])[CH:19]=4)[N:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:27]([CH:24]5[CH2:26][CH2:25]5)=[O:28])[CH:19]=4)[N:14]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CO2
Reactant: O=C(O)C1CC1
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)C4CC4)ccc3n1)CO2

Procedure:
The title compound was prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-quinoline-2,6-diamine (Example 173) (154 mg, 0.5 mmol) and commercially available cyclopropanecarboxylic acid (40 ul, 0.5 mmol) in accordance with the general method 14 described in example 119 and was obtained as an off-white solid (68 mg, 36%); MS: m/e=376.3 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:11]C)[C:6]([O:9]C)=[CH:7][CH:8]=1)[CH3:2].C(O)(=O)C.Br>O>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:7][CH:8]=1)[OH:9])[CH3:2]
Reactant: CCc1ccc(OC)c(OC)c1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(O)c(O)c1
Yield: 89 %

Procedure:
A mixture of 10.0 g (60.2 mM) of 4-ethylveratrole, 38.4 g (639 mM) of acetic acid and 115.0 g (668 mM) of 47% hydrobromic acid was heated under reflux for 4 hours with stirring. After cooling to the room temperature, 100 ml of water was added and the resultant mixture was extracted three times with each 110 ml of ether. The ether extract was successively washed with 110 ml of water, 150 g of 5% aqueous sodium thiosulfate solution and further twice with each 110 ml of water. The resulting ether solution was dried with anhydrous sodium sulfate, filtered, concentrated and distilled under vacuum to obtain 7.4 g (53.6 mM) of 4-ethylcatechol as a light yellow liquid having a boiling point of 111°-112° C./4 mmHg.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[N:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)C(C)C)C>CC#N>[Br:1][C:2]1[C:3]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:4][C:5]([NH:8][NH:9][C:26](=[O:27])[CH2:25][C:22]2[CH:23]=[N:24][C:19]([C:18]([F:17])([F:30])[F:29])=[CH:20][CH:21]=2)=[N:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)nc1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(C(F)(F)F)nc1)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Temperature: 20 °C
Reaction time: 15 h
Yield: 92.7 %

Procedure:
To a suspension of 5-bromo-4-(4-chlorophenyl)-2-hydrazinylpyridine (37 mg, 0.12 mmol), 2-(6-(trifluoromethyl)pyridin-3-yl)acetic acid (26 mg, 0.12 mmol) and bromotripyrrolidinophosphonium hexafluorophosphate (PyBop, 70 mg, 0.13 mmol) in CH3CN (1.0 mL) was added (i-Pr)2EtN (32 mg, 0.25 mmol) at 20° C. The reaction mixture was stirred at 20° C. under argon for 15 h, then concentrated in vacuo. The residue was dissolved in EtOAc (15 mL). The organic solution was successively washed with saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using reverse phase preparative HPLC (Conditions: Phemomenex Luna 5μ C18 30×75 mm; Eluted with 0% to 100% B, 10 min gradient, 100% B hold for 2 min, (A=90% H2O, 10% CH3CN, 0.1% trifluoroacetic acid and B=10% H2O, 90% CH3CN, 0.1% trifluoroacetic acid); Flow rate at 40 mL/min, UV detection at 220 nm), followed by basification with 1N aqueous NaOH to pH 12 and extraction with EtOAc to afford 54 mg (92%) of the title compound as a white solid. LC/MS (method B): retention time 1.91 min, [M+H]+=487.0.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[OH:9][C:10]1([CH3:18])[CH2:14][CH2:13][C:12](=O)[C:11]1([CH3:17])[CH3:16]>C(O)C.O>[OH:9][C:10]1([CH3:18])[CH2:14][CH2:13][C:12](=[N:7][OH:8])[C:11]1([CH3:17])[CH3:16]
Reactant: NO
Reactant: CC1(O)CCC(=O)C1(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(O)CCC(=NO)C1(C)C
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Sodium acetate (7.57 g, 92 mmol) and hydroxylamine hydrochloride (6.01 g, 87 mmol) were added to a solution of 3-hydroxy-2,2,3-trimethylcyclopentanone (8.20 g, 57.7 mmol, from Step 1) in ethanol (80 mL) and water (16 mL). The resultant mixture was heated to 80° C. for 15 h, then cooled to room temperature. After removal of ethanol in vacuo, the aqueous residue was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated to give crude 3-hydroxy-2,2,3-trimethylcyclopentanone oxime (9.05 g). 1H NMR (400 MHz, methanol-d4) δ ppm 2.29-2.80 (2 H, m), 1.63-1.94 (2 H, m), 1.22 (3 H, s), 1.08 (3 H, s), 0.99 (3 H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:30]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N(CC)CC)C.NCCN(CCN)CCN>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[C:35]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:36])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Agent: NCCN(CCN)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)C(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (15 mg, 0.038 mmol), prepared in Step A of Example 13a, pyrrolidine-1-carbonyl chloride (5 eq), and triethylamine (5 eq) in CH2Cl2 (1-2 mL) was stirred at room temperature for 72 h. Additional pyrrolidine-1-carbonyl chloride (5 eq) and triethylamine (5 eq) were added and the reaction was stirred for 24 h followed by addition of tris (2-aminoethyl)amine on polymer support. The reaction was stirred for 24 h and the resin was removed by filtration with the aid of CH2Cl2. The organic solution was washed sequentially with 5.5% aqueous HCl and saturated NaHCO3 solution. The organic solution was concentrated and was used in Step B without further purification.
Reaction SMILES: C[C:2]1([C:11]2[CH:16]=[CH:15][C:14](C(F)(F)F)=[CH:13][CH:12]=2)OC2C=CC=CC=2[O:3]1.[N+]([O-])(O)=[O:22].O>ClC(Cl)C>[O:22]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:2][O:3]1
Reactant: O=[N+]([O-])O
Reactant: CC1(c2ccc(C(F)(F)F)cc2)Oc2ccccc2O1
Solvent: O
Solvent: CC(Cl)Cl
Product: c1ccc2c(c1)COO2
Temperature: 20 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of 2-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-benzodioxole (5.6 g) in dichloroethane (15 ml) was added over 10 minutes to vigorously stirred nitric acid (50% w/v, 25 ml) keeping the temperature at 15°-20° C. by means of a cooling bath. The resulting reaction mixture was stirred for a further 1 hour at 20° C., poured into water (200 ml) and extracted with methylene chloride (3×100 ml). After drying over anhydrous sodium sulphate, the extract was evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methylene chloride as eluant, affording the pure product benzodioxole as a pale yellow oil (5.3 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2([C:11]#[N:12])[CH2:10][CH2:9]C2)=[C:4]([I:15])[CH:3]=1.C1(C#N)CC1.BrC1C=CC(CBr)=C(I)C=1>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[C:4]([I:15])[CH:3]=1
Reactant: N#CC1(Cc2ccc(Br)cc2I)CCC1
Agent: BrCc1ccc(Br)cc1I
Agent: N#CC1CC1
Product: N#CC1(Cc2ccc(Br)cc2I)CC1
Yield: 55 %

Procedure:
The title compound (2.1 g, 55% yield) was prepared as described for 1-(4-Bromo-2-iodobenzyl)cyclobutanecarbonitrile (Intermediate 37) starting from cyclopropanecarbonitrile (1.96 mL, 26.6 mmol) and 4-bromo-1-(bromomethyl)-2-iodobenzene (see Caruso, A; Tovar, J., D. J. Org. Chem. 2011, 76, 2227-2239) (4.0 g, 10.6 mmol): 1H NMR (400 MHz, CDCl3) δ ppm 1.02-1.07 (m, 2H), 1.33-1.37 (m, 2H), 2.98 (s, 2H), 7.35 (d, 1H), 7.51 (dd, 1H), 8.02 (d, 1H); MS (CI) m/z 362 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>ClCCl>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 22.9 %

Procedure:
To a solution of 10.0 mg (0.0437 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole in 3.0 mL dichloromethane were added 6.2 mg (0.0874 mMol) ethyl isocyanate. The reaction was mixed for 48 hours and to it were then added 0.15 gm (0.0874 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the filtrate washed with 1N hydrochloric acid. The aqueous phase was washed several times with dichloromethane and was then made basic with dilute aqueous sodium hydroxide. The aqueous phase was then extracted several times with an equal volume of dichloromethane. These organic extracts were dried over sodium sulfate and then concentrated under reduced pressure to give 3.0 mg (23%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][CH:9]=[CH:10][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12
Reactant: O=C(O)c1cnc(Cl)c2[nH]ccc12
Reactant: C1COCCN1
Product: O=C(c1cnc(Cl)c2[nH]ccc12)N1CCOCC1

Procedure:
Prepared from 7-chloro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid in a similar manner to Example 19 (e) using morpholine instead of tetrahydro-pyran-4-ylmethylamine to give the title compound (32 mg).
Reaction SMILES: Cl.[F:2][C:3]1([F:38])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])[C:14](=[O:37])[CH:13]=3)=[CH:11][C:5]=2[O:4]1>C(O)C.O>[F:38][C:3]1([F:2])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C:12]3[C:17]([F:18])=[CH:16][N:15]([CH2:19][CH2:20][C@@:21]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:22]([NH:24][OH:25])=[O:23])[C:14](=[O:37])[CH:13]=3)=[CH:11][C:5]=2[O:4]1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc3c(c2)OC(F)(F)O3)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[C@@](CCn1cc(F)c(-c2ccc3c(c2)OC(F)(F)O3)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
Aqueous HCl (1.42 mL, 1.42 mmol) was added to a solution of (2R)-4-[4-(2,2-Difluoro-1,3-benzodioxol-5-yl)-5-fluoro-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (259 mg, 0.474 mmol) in ethanol (5 mL) and water (2 mL) and the reaction was stirred overnight at rt. The solid was collected via filtration, washed with water (5×3 mL) and dried under reduced pressure to afford the title compound (143 mg, 65.3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.07-2.24 (m, 1H) 2.36-2.49 (m, 1H) 3.11 (s, 3H) 3.68-3.86 (m, 1H) 3.98-4.13 (m, 1H) 6.58 (d, J=7.61 Hz, 1H) 7.36-7.49 (m, 1H) 7.55 (d, J=8.39 Hz, 1H) 7.68 (s, 1H) 8.06 (d, J=6.63 Hz, 1H) 9.24 (br. s., 1H) 11.08 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(C)(C)C.[ClH:32]>C(O)C.C(OCC)(=O)C>[ClH:32].[ClH:32].[NH2:7][C@@H:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[CH:15][CH:16]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1ccc(-c2ccncc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl[(1S)-1-benzyl-2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl]carbamate (800 mg) in ethanol (30 mL) was added 4N hydrogen chloride in ethyl acetate (5 mL) and the mixture was stirred at 60° C. for 1 hour. The solvents were removed by evaporation in vacuo and the residue was recrystallized from 2-propanol to afford (2S)-2-amino-3-phenyl-N-[4-(4-pyridinyl)phenyl]propanamide dihydrochloride (625 mg) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[O:55]1[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[CH2:57][CH:56]1[CH2:64][N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>ClCCl>[O:55]1[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[CH2:57][CH:56]1[CH2:64][N:65]1[CH2:70][CH2:69][N:68]([C:19](=[O:21])[CH2:18][O:17][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:6]=3)[CH2:12][CH2:13]2)[CH2:67][CH2:66]1
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: c1ccc2c(c1)CC(CN1CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(CC2Cc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (900 mg, 2.48 mmol) in dichloromethane (50 ml) was added EDAC.HCl (661 mg, 3.45 mmol), HOBt (464 mg, 3.43 mmol), triethylamine (463 mg, 4.58 mmol) and 1-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazine (500 mg, 2.29 mmol) in dichloromethane (1 ml) with stirring for overnight at room temperature. Then the mixture was diluted with dichloromethane (300 ml) and washed with water (100 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 0.5%-3% methanol in dichloromethane to afford 1-[4-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (462.4 mg, 36%); (ES, m/z): [M+H]+ 563.00; 1H NMR (300 MHz, CDCl3): δ 8.00 (d, J=8.7 Hz, 1H), 7.09-7.18 (m, 2H), 6.77-6.88 (m, 3H), 6.61 (dd, J=2.1 Hz, 8.7 Hz, 1H), 5.03 (broad s, 1H), 4.45 (d, J=6.9 Hz, 1H), 4.20 (s, 2H), 3.67-3.78 (m, 3H), 3.40-3.49 (m, 3H), 2.66-2.99 (m. 6H), 2.13-2.23 (m, 4H), 1.41-1.63 (m, 3H), 1.21-1.34 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[N:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:12]2[C:11]([CH3:10])=[N:15][C:14]([CH3:16])=[N:13]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(Cl)cc(Cl)n1
Reactant: Cc1n[nH]c(C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-n2nc(C)nc2C)cc(Cl)n1
Temperature: 100 °C

Procedure:
A mixture of 2,4-dichloro-6-methylpyridine (24-1, 2.15 g, 13.3 mmol), 3,5-dimethyl-1H-1,2,4-triazole (1.29 g, 13.3 mmol), and cesium carbonate (5.20 g, 16.0 mmol) in DMF (15 mL) was heated at 100° C. for 20 hours and cooled to room temperature. The mixture was diluted with ethyl acetate (250 mL) and washed with brine (4×250 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-90% ethyl acetate in hexanes) to afford 2-chloro-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-6-methylpyridine (24-2) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 1H), 7.29 (m, 1H), 2.64 (s, 3H), 2.62 (s, 3H), 2.41 (s, 3H). LRMS m/z (M+H) 223 found, 223 required. The regioisomer (24-3) was also obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.71 (m, 1H), 7.10 (m, 1H), 2.83 (s, 3H), 2.54 (s, 3H), 2.41 (s, 3H). LRMS m/z (M+H) 223 found, 223 required.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N:9]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: Cc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(N2CCCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 140 °C

Procedure:
2-Bromo-4-methylpyridine (400 mg, 2.326 mmol), tert-butyl 1,4-diazepane-1-carboxylate (2.1 g, 10.5 mmol) and potassium carbonate (2.8 g, 20 mmol) were combined in anhydrous DMF (20 ml) and heated under microwave heating at 140° C. for 5 hours. The mixture was poured into water and extracted with ethyl acetate (4×). The combined organic layers were washed with brine (2×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified two times by column chromatography (silica, gradient from 0 to 50% ethyl acetate in heptane) to yield 97 mg (0.33 mmol, 14%). MS (ESI) m/z=292.2 [M+1]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:8][CH:9]([CH3:27])[CH2:10][C:11]([O:13][CH2:14][CH2:15][O:16][C:17](ON1C(=O)CCC1=O)=[O:18])=[O:12]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:17]([O:16][CH2:15][CH2:14][O:13][C:11](=[O:12])[CH2:10][CH:9]([CH3:8])[CH3:27])=[O:18])[C:5]([OH:7])=[O:6]
Reactant: CC(C)CC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](CO)C(=O)O
Product: CC(C)CC(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 58.8 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (252 mg, 2.4 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 3-methylbutanoate (574 mg, 2.0 mmol) were reacted to provide 326 mg (59% yield) of the title compound (26) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.80 (m, 1H), 6.11 (m, 1H), 5.78 (br s, 1H), 4.41 (m, 1H), 4.04 (m, 1H), 3.94 (m, 1H), 2.01-2.24 (m, 3H), 1.48 (2d, 3H), 0.99 (2d, 6H). MS (ESI) m/z 278.04 (M+H)+; 295.09 (M+NH4)+; 300.04 (M+Na)+; 276.10 (M−H)−.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([OH:18])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl.O>CN(C=O)C>[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24][O:18][C:5]1[C:4]([Br:3])=[CH:13][C:12]2[C:11]([CH3:14])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:17])([CH3:16])[C:7]=2[CH:6]=1
Reactant: COCCOCCl
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C

Procedure:
720 mg (24 mmol) of sodium hydride (80% in oil) and 50 ml of DMF are introduced into a three-necked flask under a stream of nitrogen. A solution of 5.7 g (20 mmol) of 3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol dissolved in 75 ml of DMF are added dropwise and the mixture is stirred until the evolution of gas has ceased. 6.8 ml (59.3 mmol) of methoxyethoxymethyl chloride are then added at 0° C. and the mixture is stirred for four hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 16.6 g (91%) of the expected product are collected in the form of an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[O:11]1[CH2:13][CH:12]1[CH2:14][N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1>C(O)C>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23][CH2:24][N:15]1[CH2:14][CH:12]([OH:11])[CH2:13][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: c1ccc2c(c1)CCN(CC1CO1)C2
Solvent: CCO
Product: O=C1Cc2ccccc2N1CC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 33 %

Procedure:
To a solution of indolin-2-one (50.0 mg, 0.378 mmol) in ethanol (5 mL) was added 2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (85.0 mg, 0.451 mmol). The mixture was heated under microwave conditions at 120° C. for 0.5 h, concentrated and purified by preparative HPLC purification. (40.0 mg, yield 33.0%) MS (ESI+) e/z: 323.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.30-7.23 (m, 2H), 7.14-7.07 (m, 4H), 7.06 (d, J=7.5 Hz, 1H), 7.01 (t, J=5.8 Hz, 1H), 4.94 (d, J=7.8 Hz, 2H), 4.31-4.18 (m, 1H), 3.97-3.86 (m, 1H), 3.82-3.72 (m, 1H), 3.71-3.64 (m, 2H), 2.90-2.73 (m, 4H), 2.73-2.59 (m, 2H).