Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[O:30]=[C:31]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([C:41](O)=[O:42])[C:35]=2[CH2:34][CH2:33][N:32]1[CH:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][CH3:47].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:41]([C:36]1[C:35]2[CH2:34][CH2:33][N:32]([CH:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][CH3:47])[C:31](=[O:30])[C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:42])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cccc2C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 24 h

Procedure:
Poured into a suspension of 150 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 101 mg of 1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 4 mg of hydroxybenzotriazole and 76 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 6 cm3 of dichloromethane is 0.217 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The solution is kept stirring for 24 h at a temperature close to 20° C. 15 cm3 of water are added to the reaction medium. The organic phase is washed with 5 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The product obtained is purified by flash chromatography over silica (column: 15 g; particle size: 120-40 μm, spherical; flow rate: 10 cm3/min; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 140 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]-cyclopropyl}amino)propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a colorless oil.
Reaction SMILES: C1(CO[C:9](=[O:27])[NH:10][C@H:11]2[CH2:14][N:13]([C:15]([NH:17][P:18]([N:23]([CH3:25])[CH3:24])([N:20]([CH3:22])[CH3:21])=[O:19])=[O:16])[C:12]2=[O:26])C=CC=CC=1.[C:28]1([CH2:34]C(Cl)=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Pd].C(N(CC)CC)C>[CH3:25][N:23]([P:18]([NH:17][C:15]([N:13]1[CH2:14][C@H:11]([NH:10][C:9](=[O:27])[CH2:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]1=[O:26])=[O:16])([N:20]([CH3:21])[CH3:22])=[O:19])[CH3:24]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CN(C)P(=O)(NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)N(C)C
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CN(C)P(=O)(NC(=O)N1C[C@H](NC(=O)Cc2ccccc2)C1=O)N(C)C

Procedure:
By a procedure analogous to that used in the second part of Example IV, (S)-[1-[[[bis-(dimethylamino)phophinyl]amino]carbonyl]2-oxo-3-azetidinyl]carbamic acid phenylmethyl ester, produced as in the previous Example, is hydrogenated in the presence of 10% Pd on carbon catalyst, and the intermediate thus obtained is acylated by reaction with phenylacetyl chloride and triethylamine to obtain the title compound.
Reaction SMILES: O[N:2]=[CH:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:14])[O:9][N:8]=1)([CH3:6])[CH3:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[C:3]([C:4]([CH3:6])([CH3:5])[C:7]1[CH:11]=[C:10]([NH:12][C:13]([C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[O:14])[O:9][N:8]=1)#[N:2]
Reactant: CC(C)(C=NO)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C#N)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Temperature: 100 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
79.0 mg (0.23 mmol) of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid [3-(2-hydroxyimino-1,1-dimethyl-ethyl)-isoxazol-5-yl]amide are added to 1.00 mL trifluoroacetic anhydride and stirred at 100° C. for 3 h. The solvent is removed under reduced pressure. The residue is purified by HPLC-MS to afford 32.6 mg of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid[3-(cyano-dimethyl-methyl)-isoxazol-5-yl]amide. Yield: 44%; ESI-MS: 333 [M+H]+; HPLC (Rt): 0.66 min (method F); 1H-NMR (400 MHz, DMSO-d6): 1.31-1.53 (m, 2H), 1.57-1.65 (m, 1H), 1.69 (s, 6H), 1.69-1.81 (m, 4H), 2.01-2.14 (m, 1H), 2.50-2.66 (m, 2H), 3.08-3.14 (m, 1H), 3.20-3.32 (m, 2H), 3.47-3.52 (m, 1H), 3.77-3.88 (m, 2H), 6.46 (s, 1H), 9.70 (s, 1H) ppm.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12]>C(O)C>[NH2:10][C:4]1[N:3]=[C:2]([NH:14][CH2:13][CH2:11][OH:12])[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=1
Reactant: Nc1nc(Cl)c(N)c(Cl)n1
Reactant: NCCO
Solvent: CCO
Product: Nc1nc(Cl)c(N)c(NCCO)n1
Temperature: 105 °C
Reaction time: 0.33 h
Yield: 69.3 %

Procedure:
A mixture of 4,6-dichloropyrimidine-2,5-diamine (28 g, 156 mmol), ethanolamine (18 ml, 312 mmol) and ethanol (250 ml) were heated at 100-110° C. for 16 hours. The mixture was cooled and solvent was removed. To the residue methanol (100 ml) was added and stirred for 20 minutes. The solid was filtered off to obtain 2-[(2,5-diamino-6-chloro-pyrimidin-4-yl)amino]ethanol (22.0 g, 70%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][S:14]2(=[O:19])=[O:18])=[C:9]([F:20])[CH:8]=1)[CH3:6])C.[Li+].[OH-].Cl>C1COCC1.O>[O:19]=[S:14]1(=[O:18])[CH2:15][CH2:16][CH2:17][N:13]1[C:10]1[CH:11]=[CH:12][C:7]([CH:5]([CH3:6])[C:4]([OH:21])=[O:3])=[CH:8][C:9]=1[F:20]
Reactant: CCOC(=O)C(C)c1ccc(N2CCCS2(=O)=O)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)O)c1ccc(N2CCCS2(=O)=O)c(F)c1
Reaction time: 0.25 h
Yield: 85.8 %

Procedure:
2-[4-(1,1-Dioxo-[1,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid ethyl ester (448 mg, 1.42 mmol) was dissolved in a 2:1 mix of THF/water (2.8 mL+1.4 mL) and stirred for 15 min. 3 equivalents of LiOH (98 mg, 4.26 mmol), which is also dissolved in a 2:1 THF/water mix (1 mL+0.5 mL), are added to this solution. The reaction mixture was stirred overnight under reflux. While cooling, the aqueous phase is set to pH 1 using 4 N aq. HCl and repeatedly extracted with ethyl acetate (3×10 mL). The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to afford 2-[4-(1,1-dioxo-[1,2]thiazolidin-2-yl)-3-fluoro-phenyl]-propionic acid (350 mg, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH3:18])=[C:16]([NH:19][C:20]2[CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=[CH:22][C:21]=2[N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.Br[C:42]1[CH:47]=[CH:46][N:45]=[C:44]([NH2:48])[CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:48][C:44]1[CH:43]=[C:42]([C:24]2[CH:23]=[CH:22][C:21]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[C:20]([NH:19][C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[C:17]=3[CH3:18])[CH:25]=2)[CH:47]=[CH:46][N:45]=1
Reactant: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCOCC1
Reactant: Nc1cc(Br)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2ccccc2c1Nc1cc(-c2ccnc(N)c2)ccc1N1CCOCC1
Temperature: 120 °C

Procedure:
A mixture of 2-(2-fluorophenyl)-3-methyl-N-(2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinolin-4-amine (44.0 mg, 0.082 mmol), 4-bromopyridin-2-amine (14.1 mg, 0.082 mmol), dichlorobis(triphenylphosphine)palladium(II) (5.73 mg, 8.16 μmol) and sodium carbonate (14.68 mg, 0.245 mmol) in 1,4-dioxane (2.00 mL) and water (0.500 mL) in a microwave vessel was purged with nitrogen then heated in a microwave at 120° C. for 60 min, after which time LC-MS indicated no starting material remained and desired product was present. The reaction was partitioned between 30 mL EtOAc and 20 mL water. The organic separation was stirred over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow film. The product was isolated by preparative scale reversed-phase HPLC, affording a colorless solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.11 (1H, d, J=8.2 Hz), 7.92 (1H, d, J=5.5 Hz), 7.84 (1H, d, J=8.6 Hz), 7.60-7.69 (1H, m), 7.56 (1H, td, J=7.4, 2.0 Hz), 7.34-7.51 (2H, m), 7.26 (1H, t, J=7.4 Hz), 6.99-7.21 (5H, m), 6.63 (2H, dd, J=7.4, 2.3 Hz), 6.43 (1H, br. s.), 4.44 (2H, d, J=1.2 Hz), 3.88 (4H, t, J=4.7 Hz), 2.94-3.23 (4H, m), 2.15 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=506.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5](Br)[CH2:6][N:7]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:8][CH:9](Br)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][N:7]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:8][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:34]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)C(Br)CN(CC(Br)C(=O)OCC)S(=O)(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccccc2)CC(C(=O)OCC)N1Cc1ccccc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
To a solution of (SR)-3-[benzenesulfonyl-((SR)-2-bromo-2-ethoxycarbonyl-ethyl)-amino]-2-bromo-propionic acid ethyl ester (CAS 58661-68-0) (13.8 g, 26.8 mmol) in toluene (54 ml) was added benzylamine (8.81 ml, 80.4 mmol) and the mixture was stirred at 90° C. for 1.5 h. Cooled to 23° C., filtered the solid off, washed with toluene and the filtrate was evaporated to leave a crude product which was purified by silica gel column chromatography with tert-butyl methyl ether and n-heptane 3:7 to give the title compound as light yellow crystals (7.0 g, 57%), MS (ISP) m/e=461.2 [(M+H)+].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=1.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>C1(C)C=CC=CC=1>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:28]3[S:27][CH:31]=[CH:30][N:29]=3)[CH:33]=2)=[N:3][CH:4]=1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Oc1cccc(-c2nccs2)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: Cc1ccccc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cccc(-c2nccs2)c1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1, 178 mg, 0.45 mmol), 3-(1,3-thiazol-2-yl)phenol (162 mg, 0.91 mmol) and 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP, 217 μL, 0.75 mmol) in toluene (2 mL) was stirred at 110° C. for 5 h. After removal of solvent, the residue was eluted on silica gel short column (hexane/ethyl acetate (4/1)) to afford 259 mg (quant.) of the title compound as a white amorphous: 1H-NMR (CDCl3) δ 8.57 (1H, d, J=2.7 Hz), 8.15–8.11 (2H, m), 7.97–7.94 (2H, m), 7.90–7.83 (3H, m), 7.58–7.38 (3H, m), 7.34–7.20 (2H, m), 5.42–5.32 (1H, m), 1.61–1.57 (12H, m); MS (ESI) m/z 536 (M+H)+, 534 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([CH3:10])=[CH2:9])=[C:5]([CH3:11])[S:4][C:3]=1[C:12]([OH:14])=O.[CH3:15][Li]>C(OCC)C>[CH3:1][C:2]1[C:6]([CH2:7][C:8]([CH3:10])=[CH2:9])=[C:5]([CH3:11])[S:4][C:3]=1[C:12](=[O:14])[CH3:15]
Reactant: C=C(C)Cc1c(C)sc(C(=O)O)c1C
Reactant: [Li]C
Solvent: CCOCC
Product: C=C(C)Cc1c(C)sc(C(C)=O)c1C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dimethyl-4-(2-methyl-allyl)-thiophene-2-carboxylic acid (475 mg, 2.26 mmol) in diethyl ether (15 mL), a solution of methyllithium (3.0 mL, 1.6 M in diethyl ether) is added at rt. The mixture is stirred at rt for 1 h before another portion of methyllithium (0.45 mL) is added. Stirring is continued for 1 h. The reaction is quenched by the addition of 1 N aq. NaH2PO4 solution. The mixture is diluted with diethyl ether, washed with 1 N aq. NaOH, dried over Na2SO4 and evaporated to give 1-[3,5-dimethyl-4-(2-methyl-allyl)thiophen-2-yl]-ethanone (395 mg) as a yellow oil; LC-MS: tR=1.03 min, [M+1]=209.14.
Reaction SMILES: O[C:2]1([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH3:14])=[CH:8][CH:9]=2)[C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH2:24][CH2:25][O:26]CC2C=CC=CC=2)=[C:3]1[C:34]([O:36][CH3:37])=[O:35].C(O)C>C(OC(=O)C)C>[OH:26][CH2:25][CH2:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH3:14])[CH:6]=2)[CH:2]([C:38]2[CH:43]=[CH:42][C:41]3[O:44][CH2:45][O:46][C:40]=3[CH:39]=2)[CH:3]1[C:34]([O:36][CH3:37])=[O:35]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCOCc1ccccc1)=C(C(=O)OC)C2(O)c1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCCO)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Reaction time: 48 h
Yield: 81.1 %

Procedure:
A mixture of methyl (1SR)-1-hydroxy-3-[2-(2-benzyloxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxy phenyl)-5-propoxyindene-2-carboxylate (88 g, 0.141 moles) 10% palladium on carbon (21 g), 0.65 L of absolute ethanol and 0.65 L of ethylacetate was hydrogenated at 50 psi, 55° C. for 48 hrs. The catalyst was filtered off, and the filtrate concentrated in vacuo to give an amorphous glass. Crystallization from 350 mL of absolute ethanol gave 59.5 g (81%) of white solid; m.p. 165-168° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])=[CH:29][C:25]=1[C:26]([OH:28])=O.[Br:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49](=[O:58])[C:50]2[CH:55]=[C:54]([NH2:56])[CH:53]=[CH:52][C:51]=2[Cl:57])=[CH:44][CH:43]=1>C1COCC1>[Cl:57][C:51]1[CH:52]=[CH:53][C:54]([NH:56][C:26](=[O:28])[C:25]2[CH:29]=[C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])[CH:31]=[CH:32][C:24]=2[Cl:23])=[CH:55][C:50]=1[C:49]([NH:48][C:45]1[CH:46]=[CH:47][C:42]([Br:41])=[CH:43][CH:44]=1)=[O:58]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1ccc(Cl)c(C(=O)Nc2ccc(Br)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ccc(Cl)c(C(=O)Nc3ccc(Br)cc3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of TBTU (108 mg, 0.338 mmol), TEA (0.128 mL), 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid (83 mg, 0.31 mmol) and 5 mL THF was stirred for 15 min at rt. Then N-(4-bromophenyl)-2-chloro-5-amino-benzoic acid amide (100 mg, 0.31 mmol, prepared analogously to 2d/2e) was added and it was stirred for 3 h at rt and for additional 3 h at reflux. The mixture was concentrated i.vac., EtOAc was added and the organic phase was washed with 1M NaOH, water, 2M aq. HCl-solution, water and brine and dried with Na2SO4. The crude mixture was concentrated i.vac. and purified by chromatography (silica gel, petrol ether/EtOAc 60/40→55/45) to furnish the title compound.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=C1N=CC=N1)=O.[C:20]([NH:23][NH2:24])(=O)[CH3:21].C(Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:21][C:20]1[O:12][C:10]([CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[N:24][N:23]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(=O)NN
Agent: BrC(Br)(Br)Br
Agent: O=C=C1N=CC=N1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnc(CNC(=O)OC(C)(C)C)o1
Reaction time: 0.5 h
Yield: 107.9 %

Procedure:
To a stirred solution of Boc-Glycine (1.75 g, 10.0 mmol) in CH2Cl2 at 0° C. was added carbonyl imidazole (1.7 g, 10.5 mmol) and the reaction was stirred for 30 min and then acetic hydrazide (740 mg, 10.0 mmol) was added. After 45 min, CBr4 (6.63 g, 20.0 mmol) and PPh3 (5.25 g, 20.0 mmol) were added and the reaction was stirred overnight at room temperature. The reaction mixture was concentrated partially and chromatographed (50% EtOAc in hexanes) to provide 2.3 g of tert-butyl (5-methyl-1,3,4-oxadiazol-2-yl)methylcarbamate with some triphenylphosphine oxide as impurity.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].C[Si]([N:15]=[N+:16]=[N-:17])(C)C>>[CH:5]1[CH:4]=[C:3]([N:8]2[NH:17][N:16]=[N:15][C:9]2=[O:10])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: O=c1nn[nH]n1-c1ccccc1Cl
Yield: 73.6 %

Procedure:
A mixture of 2-chlorophenylisocyanate (7 g) and trimethylsilyl azide (7.9 g) was refluxed under heating for either hours and then the mixture was evaporated to remove excess trimethylsilyl azide under reduced pressure distillation, followed by addition of methanol to the resulting residue. Thereafter, the methanol was distilled off under reduced pressure. The resulting residue was purified by flash column chromatography (eluent: hexane:ethyl acetate = 2:1) to obtain the desired 1-(2-chlorophenyl)-5(4H)-tetrazolinone (6.6 g) having a m.p. in the range of from 124° to 125.5° C., in a yield of 73% of theory.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:24]=[C:25]([CH3:27])[CH:26]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Cc1cc(N)cc(C(F)(F)F)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Cc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc(C(F)(F)F)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-amino-5-methylbenzotrifluoride were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.57 (bs, 1H), 9.39 (bs, 1H), 8.12 (d, 1H, J=3.6 Hz), 7.77 (s, 2H), 7.25-7.13 (m, 2H), 7.02 (s, 1H), 6.79 (d, 1H, J=9.0 Hz), 4.20 (s, 4H), 2.27 (s, 3H); LCMS: purity: 100%; MS (m/e): 421 (MH+)
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH2:15]([N:22]1[CH2:27][C@H:26]([CH3:28])[NH:25][C@@H:24]([CH3:29])[C:23]1=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:15]([N:22]1[CH2:27][C@H:26]([CH3:28])[N:25]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[C@@H:24]([CH3:29])[C:23]1=[O:30])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H]1N[C@@H](C)CN(Cc2ccccc2)C1=O
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2oc(N3[C@@H](C)CN(Cc4ccccc4)C(=O)[C@@H]3C)nc12
Temperature: 35 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (970 mg, 4.58 mmol) and (3S,5S)-1-benzyl-3,5-dimethylpiperazin-2-one (1.00 g, 4.58 mmol) in DMF (20 mL), was stirred in a 35° C. oil bath. After 16 h, the reaction mixture was heated to 55° C. After 3 h, potassium carbonate (630 mg, 4.58 mmol) was added. The reaction mixture was stirred for 2 h at 55° C. and then at ambient temperature for 17 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with 0.5 N HCl (25 mL), H2O (25 mL), brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by chromatography (silica gel, 10 to 80% EtOAc in hexanes) gave methyl 2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (1.08 g, 60%). 1H NMR consistent.
Reaction SMILES: [C:1]1([C:7]2([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]N1C(=O)CCC1=O>CC(N=NC(C#N)(C)C)(C#N)C.C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][CH2:9][CH2:10][O:11]2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(C2(c3ccccc3)OCCO2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(C2(c3ccccc3)OCCO2)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
To a round-bottom flask were added 12 (3.54 g, 14.7 mmol, 1.0 equiv.), N-bromosuccinimide (2.9 g, 16.2 mmol, 1.1 equiv.), AIBN (48 mg, 0.29 mmol, 0.02 equiv.), and CCl4 (60 mL, 0.25 M). The reaction mixture was stirred at reflux for 6.5 hours. The reaction mixture was cooled to room temperature. The succinimide was filtered and washed with CC14. The filtrate was concentrated and crystallized from EtOAc/hexanes to yield 13 (2.57 g, 55%) as a white solid. 1H-NMR (500 MHz, CDCl3) δ 7.56-7.53 (m, 4H), 7.38-7.35 (m, 4H), 7.33-7.29 (m, 1H), 4.48 (s, 2H), 4.08 (s, 4H). 13C-NMR (125 MHz, CDCl3): δ 142.4, 141.8, 137.4, 128.8, 128.1, 128.1, 126.5, 125.9, 109.0, 64.8, 33.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:19][C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][O:8][N:7]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCSCc1ccon1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCSCc1ccon1)c1ccccc1

Procedure:
3-[(2-Aminoethyl)thiomethyl]isoxazole is reacted with benzoyl isothiocyanate by the procedure of Example 18 to give N-benzoyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(3-isoxazolylmethylthio)ethyl]thiourea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl.CN(C=O)C.C(=S)=S>[F:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][C:12]=1[F:13])[C:7](=[O:9])[CH2:6][CH2:5]2
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: S=C=S
Product: O=C1CCc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3,4-difluorocinnamic acid (5.0 g, 26.9 mmol) in DCM (35 mL) at 0° C., was added DMF (1 drop) and oxalyl chloride (4.7 mL, 53.8 mmol). The reaction mixture was warmed to rt and stirred for 16 h. The solvents were removed in vacuo and the residue azeotroped with toluene (2×20 mL). The residue was redissolved in carbon disulfide (20 mL) and added to a solution of aluminum trichloride (12.4 g, 94.1 mmol) in carbon disulfide (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, heated to reflux for 4 h and then cooled to rt. The reaction mixture was poured into ice, extracted with EtOAc (2×500 mL) and the combined organic phase dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (EtOAc:isohexane 1:9) to give the title compound: δH (CDCl3) 2.73 (2H, t), 3.17 (2H, t), 7.32 (1H, t), 7.43 (1H, t).