Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])=[CH:6][C:5]=1[CH:22]=[N:23][O:24][CH3:25].[N+:26](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:26][N:12]1[C:13]([C:17]([F:18])([F:19])[F:20])=[CH:14][C:15](=[O:16])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[C:5]([CH:22]=[N:23][O:24][CH3:25])[CH:6]=2)[C:11]1=[O:21]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)ccc1Cl
Temperature: 50 °C
Reaction time: 6 h
Yield: 29.5 %

Procedure:
0.38 g (16 mmol) of sodium hydride in 50 ml of anhydrous dimethylformamide was treated dropwise at 0°-5° C. with a solution of 5.0 g (14 mmol) of 3-(4-chloro-3-methoxyiminomethylphenyl)-2,4-dioxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine in 50 ml of anhydrous dimethylformamide. A solution of 2.8 g (14 mmol) of 2,4-dinitrophenoxyamine in 50 ml of anhydrous dimethylformamide was added dropwise to this mixture after 10 minutes, after which it was stirred for 60 hours at 20°-25° C. and for 6 hours at 50° C. For working up, the cooled reaction mixture was poured into 800 ml of ice water. The aqueous phase was extracted three times with 200 ml of ethyl acetate each time. The ethyl acetate extracts were then dried over sodium sulfate and concentrated. After chromatographic purification of the crude product on silica gel (eluent: cyclohexane/ethyl acetate/triethylamine 79:20:1), 1.5 g (29%) of a colorless oil were obtained.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[S:11]1[CH:15]=[CH:14][N:13]2[CH:16]=[N:17][CH:18]=[C:12]12.[OH-].[Na+]>ClCCl>[CH:4]([C:18]1[N:17]=[CH:16][N:13]2[CH:14]=[CH:15][S:11][C:12]=12)=[O:5]
Reactant: c1cn2cncc2s1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ncn2ccsc12
Reaction time: 0.5 h

Procedure:
DMF (15.48 ml) was added to 80 ml of dichloromethane. A solution of 18.32 ml of phosphorus oxychloride in 80 ml of dichloromethane was dropwise added thereto under ice cooling. A reaction was allowed to proceed at room temperature for 30 min. A solution of imidazo[5,1-b]thiazole in 40 ml of dichloromethane was added dropwise thereto. The mixture was heated under reflux for 2.5 hr. The reaction solution was poured into ice. The reaction solution was adjusted to pH 9.8 by the addition of a 5 N aqueous sodium hydroxide solution, followed by extraction five times with 200 ml of dichloromethane. The extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (eluting with dichloromethane:ethyl acetate=5:1, ethyl acetate alone, and then dichloromethane:methanol=10:1) to give 2.37 g of 7-formylimidazo[5,1-b]thiazole.
Reaction SMILES: O=[C:2]1[CH:7]([C:8](OCC)=[O:9])[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3]1.O.[NH2:21][NH2:22]>C(O)C>[O:9]=[C:8]1[C:7]2[CH2:6][CH2:5][N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:3][C:2]=2[NH:22][NH:21]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c([nH][nH]c2=O)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 1-tert-butyl 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (5.0 g, 18.43 mmol) in ethanol (10 mL) was added hydrazine monohydrate (1.04 g, 20.27 mmol) via syringe. The resulting solution was heated to 80° C. and stirred overnight. A white precipitate formed after stirring overnight. The reaction was cooled to rt and solvent was decanted from the reaction mixture, the solids were dried under vacuum to provide the desired product (3.8 g, 86%). MS (ESI) mass calcd. C11H17N3O3, 239.2. m/z found, 240.2 [M+H]+. 1H NMR (500 MHz, MeOD) δ 4.40 (s, 2H), 3.67-3.54 (m, 2H), 2.40 (t, J=5.6 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[SH:17].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Cl.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.[K]>CN(C)C=O.O>[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[S:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:30]1[C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]2[C:26]1=[O:36]
Reactant: Sc1ccc2ccccc2c1
Reactant: ClCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCSc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
Potassium carbonate (8.29 g) was added to a solution of 2-naphthalenethiol (8.01 g) and 1-bromo-6-chlorohexane (9.98 g) in N,N-dimethylformamide (65 ml). The mixture was stirred at room temperature for 3 hours. Then potassium phthalimide (9.26 g) was added to the mixture, and the resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), and the solvent was distilled off under reduced pressure to obtain N-[6-(2-naphthylthio)hexyl]phthalimide (18.56 g, 95.3%), which was then recrystallized from ethyl acetate-hexane. Colorless plate, mp: 109°-110° C.
Reaction SMILES: COC1C=CC(NC2OC3C=C(C(C)C#N)C=CC=3N=2)=CC=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][C:29]=1[OH:30].C(O[C:41]([S-])=[S:42])C.[K+].C(O)C>O>[S:42]=[C:41]1[NH:23][C:24]2[CH:25]=[C:26]([CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][C:29]=2[O:30]1
Reactant: CCOC(=S)[S-]
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Agent: COc1ccc(Nc2nc3ccc(C(C)C#N)cc3o2)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)c1ccc2oc(=S)[nH]c2c1

Procedure:
2-[2-(4-methoxyanilino)-6-benzoxazolyl]propionitrile (i) A stirred mixture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (8.4 g.), potassium ethylxanthate (6.33 g.), ethanol (38 ml.) and water (6.5 ml.) was heated under reflux for 4 hours. The solution was evaporated to half volume and diluted with water (65 ml.). The mixture was acidified with 2N-hydrochloric acid and extracted several times with ether. The ethereal solution was washed with water, then dried with anhydrous sodium sulphate, and evaporated to give ethyl 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl)propionate as an oil. Dry chlorine was passed into a solution of the thione (9 g.) in freshly dried and distilled chloroform (150 ml.) with stirring for 4 hours. The solution was then washed with water, N-sodium hydroxide solution, then water (3x). The dried (Na2SO4) organic solution was evaporated to yield ethyl 2-(2-chloro-5-benzoxazolyl]propionate as a brown oil which was shown to be a single compound by thin layer chromatography. (j) A mixture of the 2-chloro compound (12.5 g.) of Example 3 (i) and p-chloroaniline (25 g.) was heated on a steam bath for one hour. The reaction mixture was dissolved in chloroform and the solution was washed with 2N hydrochloric acid (2x), water, 2N sodium hydroxide solution (2x) and water (3x). The chloroform solution was stirred with charcoal and anhydrous sodium sulphate, then filtered and evaporated. The residue was purified using prep t.l.c. plates to give ethyl-2-[2-(4-chloroanilino) -5-benzoxazolyl]propionate, mpt 135°-7° C., which was characterised by ir uv and nmr spectroscopy and by micro analysis which gave C 62.45% H 5.11% N 7.97% C18H17ClN3O2 requires C 62.70% H 4.93% N 8.13%
Reaction SMILES: C([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([CH3:16])=[CH2:15])[CH:9]=1)(=O)CC.[OH-:17].[K+].[CH2:19](O)C>[Pd]>[CH:14]([C:10]1[CH:9]=[C:8]([CH:7]([CH3:19])[C:6]([OH:5])=[O:17])[CH:13]=[CH:12][CH:11]=1)([CH3:15])[CH3:16]
Reactant: CCO
Reactant: C=C(C)c1cccc(CCOC(=O)CC)c1
Reactant: [OH-]
Agent: [Pd]
Agent: [K+]
Product: CC(C)c1cccc(C(C)C(=O)O)c1
Temperature: 25 °C

Procedure:
A mixture of 2-[3′-(isopropenyl)phenyl]ethyl propionate, obtained by the method reported above (1 g; 4.6 mmol), 95% ethyl alcohol (10 ml) and Pd/C 10% (100 mg) are subjected to catalytic hydrogenation at r.t. and atmospheric pressure until the initial reagent disappears (2 h). The catalyst is filtered off on Celite and, after evaporation of the filtrate, a transparent oil is obtained (0.99 g; 4.5 mmol) that is hydrolysed in a 1N solution of KOH in ethyl alcohol (10 ml) at T=80° C. for 2 h. After cooling at r.t. the solvents are evaporates at reduced pressure; the residue is taken up with EtOAc (20 ml) and it is extracted with H2O (3×10 ml); the aqueous phase is acidified to pH=2 with 2N HCl and counter-extracted with EtOAc (2×10 ml); the organic extracts are combined and washed with a saturated solution of NaCl, are dried over Na2SO4 and evaporated at reduced pressure to give 2-[(3′-isopropyl)phenyl]propionic acid (0.75 g; 3.6 mmol)
Reaction SMILES: [C:1]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:14]Br>C(Cl)Cl>[CH2:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([Br:14])[C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCCCCCCCCC1
Reactant: BrBr
Solvent: ClCCl
Product: O=C1CCCCCCCCCCC1Br

Procedure:
reacting cyclododecanone with elemental bromine in boiling methylene chloride to form α-bromocyclododecanone;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[OH:36])[CH:31]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:31][C:30]4[CH:33]=[CH:34][C:35]([OH:36])=[C:28]([Cl:27])[CH:29]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc(O)c(Cl)c3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.045 mmol) was reacted with 3-chloro-4-hydroxybenzaldehyde to provide 22 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].C([O:15][C:16]([CH3:18])=[CH2:17])(=O)C.C[O-].C([Sn+](CCCC)CCCC)CCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1>[CH3:11][N:6]1[C:7]2[C:3](=[C:2]([CH2:17][C:16]([CH3:18])=[O:15])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: C=C(C)OC(C)=O
Reactant: Cn1ccc2c(Cl)cccc21
Agent: CCCC[Sn+](CCCC)CCCC
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[O-]
Solvent: Cc1ccccc1
Product: CC(=O)Cc1cccc2c1ccn2C
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.852 g (5.14 mmol) of 4-chloro-1-methylindole in 15 mL dry toluene, 0.85 mL (7.73 mmol) isopropenyl acetate and 2.3 mL (8 mmol) tributyltin methoxide were added. The solution was heated to 100° C. After 15 min, 0.24 g (0.61 mmol) 2-dicyclohexylphospino-2′-(N,N-dimethylamino)biphenyl and 0.14 g (0.153 mmol) tris(dibenzylidineacetone)dipalladium were added and heating was continued. After 2 h the solution was cooled, filtered through a pad of CELITE diatomaceous earth and the filtrate was concentrated to ca. 5 mL. This solution was purified on a silica column using a gradient of 5-20% EtOAc/hexane to obtain the title compound. 1H NMR: (500 MHz, CDCl3): δ 2.14 (s, 3H), 3.84 (s, 3H), 3.97 (s, 2H), 6.51 (d, 1H), 7-7.3 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][NH2:8].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:3]3[S:4][CH:5]=[CH:6][C:2]=3[CH3:1])=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: Cc1ccsc1CN
Product: Cc1ccsc1CNC(=O)c1sc(-n2ccc(OCc3ccccc3)cc2=O)nc1C
Yield: 52 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (3-methylthiophen-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 52% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, J=5.8 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.45-7.30 (m, 5H), 7.24 (d, J=5.1 Hz, 1H), 6.79 (d, J=5.1 Hz, 1H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.22 (d, J=2.7 Hz, 1H), 5.15 (s, 2H), 4.45-4.43 (m, 2H), 2.53 (s, 3H), 2.17 (s, 3H); MS (ES+) m/z 452.1 (M+1).
Reaction SMILES: C1C2C(COC([NH:18][CH:19]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:54][C:55]3[N:56]([CH2:60][C:61]([N:63]([CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:62])[CH:57]=[CH:58][N:59]=3)[CH2:28][C:29]3[N:30]([CH2:34][C:35](=[O:53])[N:36]([CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:31]=[CH:32][N:33]=3)[C:20]([OH:22])=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][C@@H:19]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:28][C:29]1[N:30]([CH2:34][C:35]([N:36]([CH2:37][C:38]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:44])[CH2:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:53])[CH:31]=[CH:32][N:33]=1)[CH2:54][C:55]1[N:56]([CH2:60][C:61](=[O:62])[N:63]([CH2:72][C:73](=[O:74])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH2:64][C:65](=[O:71])[O:66][C:67]([CH3:69])([CH3:68])[CH3:70])[CH:57]=[CH:58][N:59]=1)[C:20]([OH:22])=[O:21]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Yield: 79.1 %

Procedure:
A solution of 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (190 mg, 0.173 mmol) and piperidine (0.50 mL) in DMF (0.50 mL) was stirred at room temperature for 1 hrs. The solvent was evaporated under reduced pressure to give a crude product. The crude product was purified by Biotage SP4 with a gradient method of 5-50% methanol in DCM to give (S)-2-amino-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (0.120 g, 79%). 1H NMR (400 MHz, DMSO-d6) □6.92 (s, 2H), 6.76 (s, 2H), 5.01 (s, 4H), 4.32 (s, 2H), 4.31 (s, 2H), 3.92 (s, 4H), 3.44 (s, 4H), 3.01-2.99 (m, 1H), 2.30 (t, J=7.2 Hz, 2H), 1.60-1.57 (m, 2H), 1.43 (s, 18H), 1.35 (m, 18H). 1.30-1.12 (m, 4H); MS (ESI), 439.4 (M/2+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[C:10]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24](=O)/[CH:25]=[CH:26]/N(C)C)[CH:21]=[CH:20][C:19]=1[O:31][CH3:32])(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].[OH-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.C(O)(=O)C>[C:10]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][C:3]3[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][C:2]=3[N:1]=2)[CH:21]=[CH:20][C:19]=1[O:31][CH3:32])(=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccc(C(=O)/C=C/N(C)C)cc1COC(=O)C(C)(C)C
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2ccc3c(=O)[nH]c(=O)[nH]c3n2)cc1COC(=O)C(C)(C)C
Temperature: 99 °C
Reaction time: 0.83 h
Yield: 91.7 %

Procedure:
6-Aminouracil (2.50 g, 19.1 mmol) was added to glacial acetic acid (24.6 mL) and water (6.1 mL) and the mixture heated to 99° C. A solution of 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-methoxybenzyl pivalate (3.1 g, 9.5 mmol) in DMSO (9.2 mL) was then added over 280 minutes. The reaction was stirred at 99° C. for a further 50 minutes and cooled to 0° C. A solution of potassium hydroxide (24 g, 363.6 mmol) in water (48 mL) was then added to achieve a pH of around 7.0. Aqueous potassium carbonate was then added to afford a pH of around 10. After an hour at RT, a beige solid was filtered off, washed three times with aqueous potassium carbonate and pulled visibly dry on the filter. The beige solid was then added to a solution of citric acid (7.1 g) in water (44 ml) and the mixture maintained at 20° C. for 60 minutes. The resulting creamy white solid was isolated by filtration and washed with water until neutral pH of the wash liquors was obtained. The solid was dried to constant weight in vacuo thus affording 3.34 g of desired product (3).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[Cl:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:21]=1[C:30](Cl)=[O:31].O>C1(C)C=CC=CC=1>[Cl:19][C:20]1[N:24]([CH3:25])[N:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[C:21]=1[C:30]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:12])[CH3:1])=[O:31]
Reactant: Cn1nc(C(F)(F)F)c(C(=O)Cl)c1Cl
Reactant: CC1(C)CCc2c(N)cccc21
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)(F)F)c(C(=O)Nc2cccc3c2CCC3(C)C)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.1 %

Procedure:
To a solution of 1.61 g of 1,1-dimethyl-4-aminoindane and 2 ml of pyridine in 50 ml of toluene was added drop by drop with stirring at room temperature a solution of 2.47 g of 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride in 10 ml of toluene, followed by stirring at room temperature for 12 hours. Thereafter, the reaction solution was poured into a cold water to result in separation into two layers. The aqueous layer was extracted with ethyl acetate. The resultant organic layer was dried over anhydrous magnesium sulfate and the soluent was distilled off. The residue was recrystallized using toluene to obtain 3.01 g of 5-chloro-1-methyl-3-trifluoromethyl-N-(1,1-dimethylindane-4-yl)pyrazole-4-carboxamide having a melting point of 119.9° C.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[Cl:40][C:41]1[CH:51]=[CH:50][C:44]([CH2:45][S:46](Cl)(=[O:48])=[O:47])=[CH:43][CH:42]=1>>[Cl:40][C:41]1[CH:51]=[CH:50][C:44]([CH2:45][S:46]([N:37]2[CH2:38][CH2:39][N:34]([C:26]3[CH:27]=[C:28]([F:33])[C:29]([O:31][CH3:32])=[CH:30][C:25]=3[F:24])[CH2:35][CH2:36]2)(=[O:48])=[O:47])=[CH:43][CH:42]=1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Reactant: O=S(=O)(Cl)Cc1ccc(Cl)cc1
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1cc(F)c(N2CCN(S(=O)(=O)Cc3ccc(Cl)cc3)CC2)cc1F
Yield: 100.6 %

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (228 mg) and 4-chlorobenzylsulfonyl chloride (338 mg), respectively, to provide crude 1-(4-chlorobenzylsulfonyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (419 mg).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18](O)[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1N=[C:29](Cl)[C:28](F)=CN=1.[CH2:33](C1C=CC(N)=CC=1)[CH3:34]>>[CH2:33]([C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:28][CH3:29])=[CH:18][CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)=[CH:3][CH:2]=1)[CH3:34]
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: CCc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CCc1ccc(Nc2ncc(F)c(Nc3ccc(CC)cc3)n2)cc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-ethylaniline were reacted to yield N2,N4-bis(4-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 8.83 (bs, 1H), 7.77 (d, 1H. J=3.9 Hz), 7.48 (d, 2H, J=8.7 Hz), 7.40 (d, 2H, J=8.7 Hz), 7.31 (bs, 1H), 7.18 (d, 2H, J=8.7 Hz), 7.11 (d, 2H, J=8.7 Hz), 2.68-2.61 (m, 4H), 1.28-1.21 (m, 6H); LCMS: ret. time: 29.17 min.; purity: 100%; MS (m/e): 337 (MH+).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[NH2:13][C:14]1[C:41]([F:42])=[CH:40][C:17]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=3)[C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:22][CH2:21]2)=[O:19])=[CH:16][C:15]=1[F:43].[CH:44]1([CH2:47][NH2:48])[CH2:46][CH2:45]1.C(N(C(C)C)C(C)C)C>ClCCl>[C:33]([NH:32][C:30](=[O:31])[C:29]1[CH:37]=[CH:38][CH:39]=[C:27]([CH2:26][N:23]2[CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:17]3[CH:40]=[C:41]([F:42])[C:14]([NH:13][C:1]([NH:48][CH2:47][CH:44]4[CH2:46][CH2:45]4)=[O:12])=[C:15]([F:43])[CH:16]=3)[CH2:25][CH2:24]2)[CH:28]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cc(F)c(N)c(F)c3)CC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCC1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cc(F)c(NC(=O)NCC4CC4)c(F)c3)CC2)c1
Reaction time: 2 h
Yield: 118.1 %

Procedure:
To a stirred solution of bis(trichloromethyl) carbonate (0.353 mmol, 105 mg) in dichloromethane (10 mL) was added a solution of 3-((4-(4-amino-3,5-difluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.929 mmol. 400 mg) and N-ethyl-N-iosopropylpropan-2-amine (0.3 mL) in dichloromethane (10 mL) (dropwise). After 2 hours stirring, a solution of cyclopropylmethylamine (1.022 mmol, 0.089 mL, 72.7 mg) and N-ethyl-N-isopropylpropan-2-amine (0.222 mL) in dichloromethane (10 mL) was added. The reaction mixture was stirred for 24 hours. Chromatography on silica (eluting with dichloromethane then dichloromethane/methanol (1% to 5%)) gave the title compound (220 mg). MS (ESI) m/z 528.3 [M+H]+
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>CO.[Pd]>[OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([NH:14][S:18]([CH3:17])(=[O:20])=[O:19])[CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H](O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(C[C@H](O)C(=O)O)ccc1O
Reaction time: 24 h
Yield: 60.2 %

Procedure:
A solution of (S)-2-hydroxy-3-(4-hydroxy-3-nitrophenyl)propanoic acid (9.2 g, 41 mmol) in 150 mL of methanol was hydrogenated, after addition of 0.5 g of 10% palladium on carbon, for 24 h at 45 psi using a Parr shaker. After filtration through Celite under a blanket of nitrogen gas, the volatiles were removed using a rotary evaporator. The flask was flushed with nitrogen before addition of 30 mL of dry pyridine. Once the stirred suspension formed a homogeneous solution, the flask was cooled-under nitrogen to −20° and methanesulfonyl chloride (5.0 g, 44 mmol) was added over 5 min. After stirring for 1 h at −20°, the flask was placed in a −12° freezer for 24 h. To quench the reaction, 50 mL of water was added and the volatiles were removed using a rotary evaporator with a bath temperature of 50°. A second 50 mL portion of water was added and removed as previously described. The resultant crude red oil was chromatographed on Mitsubishi Chemical Industries CHP-20P resin (75-150 micron) using 15-25% methanol/water to elute the product. After evaporative removal of methanol, the residual solution was lyophilized to yield 6.8 g (63%) of (S)-2-hydroxy-3-(4-hydroxy-3-(methylsulfonyl)aminophenyl)propanoic acid.