Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:40]([O:42][C:43]([C@@H:45]1[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]1[C:54](=[O:63])[C@@H:55]([NH2:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:44])[CH3:41].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:40]([O:42][C:43]([C@@H:45]1[CH2:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]1[C:54](=[O:63])[C@@H:55]([NH:62][C:10](=[O:12])[C@@H:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:14])[CH3:13])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:44])[CH3:41]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
In a 50 mL round-bottomed flask, (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (1.52 g, 7.48 mmol, Eq: 1.5) and HATU (1.9 g, 5 mmol, Eq: 1) were combined with DCM (20 mL) to give a light yellow suspension. (S)-1-((S)-2-amino-2-phenyl-acetyl)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester hydrochloride (1.8 g, 5 mmol, Eq: 1) was added and followed by diisopropylethylamine (7 mL, 40 mmol, Eq: 8). The reaction was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo, and then dissolved in EtOAc (75 mL). The solution was washed with water and brine, dried and concentrated in vacuo. The crude material was purified by flash chromatography (10% to 30% EtOAc in hexanes) to afford (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-phenyl-acetyl}-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.3 g) as a white foam, m/z=510 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[CH:15][CH:14]=1)(C)(C)C>ClCCl>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc(-c2ccc(OC(C)(C)C)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2ccc(O)cc2)c1
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A solution of 4-tert-butoxybenzeneboronic acid (0.50 g), 3-bromoanisole (0.44 g), and tetrakis(triphenylphosphine)palladium(0) (0.09 g) in toluene (5 ml), ethanol(1.2 ml) and aqueous sodium carbonate (2 M, 2.4 ml) was heated at 100° C. for 19 hours. After cooling the reaction mixture was added to brine (50 ml) and ethyl acetate (50 ml). The organic layer was separated and dried over anhydrous magnesium sulfate. The solution was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with hexane:toluene 9:1 to give 4-tert-butoxy-3'-methoxybiphenyl (0.61 g). (MS (EI) 256 (M)+). Trifluoroacetic acid (5 ml) was added to a solution of 4-tert-butoxy-3'-methoxybiphenyl (0.60 g) in dichloromethane (20 ml) and the resulting solution stirred for 1 hour. The solution was then concentrated under reduced pressure. The residue was partitioned between a solution of saturated aqueous sodium hydrogen carbonate (25 ml) and ether (3×25 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane to give the sub-title compound as a solid (0.25 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:10]([O:14]C(OC(OC(C)(C)C)=O)=O)(C)(C)C>CN(C)C1C=CN=CC=1.C(#N)C.C(O)(=O)C.Cl>[O:9]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2][NH:1][C:10]1=[O:14]
Reactant: NCC1(O)CCCCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Product: O=C1NCC2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.65 g (5.0 mmol) of 1-(aminomethyl)-cyclohexanol, 1.2 g (5.5 mmol) di-tert.-butyldicarbonate ((Boc)2O) and 0.611 g 4-dimethylaminopyridine were dissolved in 50 ml acetonitrile and agitated overnight at room temperature. The mixture was then fully turned over, the residue was dissolved in 20 ml acetic acid and again turned over. The residue was taken up in 25 ml 1 M hydrochloric acid and extracted with 50 ml toluene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11]Br.[C-:13]#[N:14].[Na+]>O.CO>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][C:13]#[N:14]
Reactant: [C-]#N
Reactant: COc1cc(Cl)cc(CBr)c1Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Cl)cc(CC#N)c1Cl
Yield: 97.4 %

Procedure:
By the method of Example 1, Step C, 15.40 grams (0.057 mole) of 2,5-dichloro-3-methoxyphenylmethyl bromide and 3.63 grams (0.074 mole ) of sodium cyanide were reacted in 70 mL of water and 65 mL of methanol, yielding 12.0 g of 2,5-dichloro-3-methoxyphenylacetonitrile as an oil that solidified on standing, m.p. 53°-57° C. The NMR and IR spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[S:10]([Cl:9])(=[O:12])=[O:11]
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccc(Cl)cc1
Solvent: O
Product: O=S(=O)(Cl)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.4 %

Procedure:
4-Chlorophenol (4 g, 31.25 mmol) was added in portions to chlorosulfonic acid (10.3 mL, 156 mmol) while cooling in an ice bath. The resulting solution was stirred at 25° C. for 20 hrs. This was then added drop-wise to ice and water resulting in an emulsion. This was extracted with CHCl3, dried (Na2SO4) and concentrated in vacuo. Heptane was added and evaporated and replaced with cyclohexane. The resulting mixture was filtered and concentrated to give the title compound as an oil (2.16 g).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1.[CH3:15]I>C1COCC1.CCOCC>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH3:15])[CH:5]=1
Reactant: CI
Reactant: CC(C)(CO)c1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCC(C)(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a suspension of NaH (0.22 g, 9.00 mmol, 95%) in THF (30 mL) was added dropwise at ambient temperature the solution of 2-(3-bromo-phenyl)-2-methyl-propan-1-ol (1.7 g, 7.46 mmol) in THF (10 mL). After 10 min MeI (0.8 mL, 15 mmol) was added and the mixture stirred for 3 h at ambient temperature. The mixture was diluted with ether and washed twice with water. Organic layer was separated and concentrated to obtain the desired product (1.64 g, 91%) as a clear oil. NMR (DMSO-d6): 7.52 (m, 1H), 7.40 (m, 2H), 7.26 (m, 1H), 3.38 (s, 2H), 3.20 (s, 3H), 1.12 (s, 6H). MS (DCI): 260 (M+NH4).
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.[C:23]1(C)C=CC(NN)=CC=1>CCO.O>[C:4]1([CH3:23])[CH:3]=[CH:2][C:1]([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3([C:16]([F:18])([F:19])[F:17])[CH2:15][CH2:14]3)=[N:8]2)=[CH:6][CH:5]=1
Reactant: Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-n2nc(C3(C(F)(F)F)CC3)cc2N)cc1
Temperature: 80 °C
Yield: 57.4 %

Procedure:
To a solution of 3-oxo-3-(1-(trifluoromethyl)cyclopropyl)propanenitrile (500 mg, 2.8 mmol) (from Example 137A Step 2) in EtOH (10 mL) was added water (7.2 mL) and 1 M NaOH (2.8 mL) followed by p-tolylhydrazine hydrochloride (444 mg, 2.8 mmol) and the solution heated at 80° C. overnight. The solution was cooled to rt, diluted with water and extracted with 2 portions of EtOAc. The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude solid was purified using silica gel chromatography using a gradient of 5-25% EtOAc/hexane to give 1-p-tolyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (452 mg, 57% yield). LC-MS (ESI) m/z 282 (M+H)+
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([C:41]4[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=4)[CH2:36][CH2:37]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][S:15][CH2:16][C@@H:8]12
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CSCCN43)CC2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
(R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (80.0 mg, 0.318 mmol) was suspended in propionitrile (0.8 mL) and (cyanomethyl)trimethylphosphonium iodide (93.0 mg, 0.382 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (167 ul, 0.955 mmol). To the stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile (59.9 mg, 0.318 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was cooled to room temperature and left to sit 48 h. The precipitate was filtered off, washed with ethanol (5 mL) and dried in vacuum to afford the title compound (53.9 mg, 40.2%) as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 8.41 (d, J=1.8 Hz, 1H), 7.78 (d, J=1.8 Hz, 2H), 7.62 (dd, J=8.8, 2.3 Hz, 1H), 6.95 (br. s., 1H), 6.60 (d, J=8.8 Hz, 1H), 5.06 (dt, J=13.6, 2.8 Hz, 1H), 4.43 (dd, J=10.4, 3.3 Hz, 1H), 3.70 (br. s., 4H), 3.45 (br. s., 2H), 3.15 (td, J=12.9, 2.3 Hz, 1H), 3.00 (td, J=12.8, 2.8 Hz, 1H), 2.78-2.94 (m, 2H), 2.54 (br. s., 4H), 2.40 (dd, J=13.6, 1.5 Hz, 1H). [M+H] calc'd for C21H23N7OS, 422; found, 422.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([C:27]#[CH:28])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:34]1([NH2:40])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C)C=O>[C:34]1([NH:40][C:21]([C:20]2[C:15]([NH:14][C:13]([C:12]3[N:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[N:9]=[C:10]([C:29]([F:31])([F:32])[F:30])[CH:11]=3)=[O:22])=[C:16]([C:27]#[CH:28])[CH:17]=[C:18]3[C:19]=2[NH:24][N:25]=[CH:26]3)=[O:23])([CH:37]2[CH2:39][CH2:38]2)[CH2:36][CH2:35]1
Reactant: C#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1cc2cn[nH]c2c(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 530 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-5-ethynyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of N,N-dimethylformamide, is added 465 mg (3.48 mmol) of bicyclopropyl-1-ylamine hydrochloride and 485 μL (3.48 mmol) of triethylamine. The reaction is stirred at 50° C. for 16 hours and then concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexane/ethyl acetate 3:7) affords 200 mg (31% over two steps) of the product as white solid; LC/MS:554/556 (M+H)+, m.p.: 246-248° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH2:18])=[O:17])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[C:9](I)[CH:8]=3.CC1(C)C(C)(C)OB([C:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[Br:1][C:2]1[CH:14]=[C:13]2[C:5](=[C:4]([C:16](=[O:17])[NH2:18])[CH:3]=1)[NH:6][C:7]1[CH:8]=[C:9]([C:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH:28]=3)[CH:10]=[CH:11][C:12]2=1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(I)ccc12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)[nH]c2c(C(N)=O)cc(Br)cc23)CC1
Temperature: 105 °C

Procedure:
3-Bromo-7-iodo-9H-carbazole-1-carboxamide 481A (200 mg, 0.482 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (194 mg, 0.626 mmol), Pd(Ph3P)4 (35 mg, 0.030 mmol), and Na2CO3 (2M) (0.964 mL, 1.928 mmol) were mixed with toluene (10 mL) and MeOH (5 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 105° C. in an oil bath for 4 hrs. The mixture was used as it is. MS (ESI) m/z 468.22 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17].[Br:18]Br.C1(C)C=CC=CC=1>CC(O)=O>[Br:18][C:15]1[C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]([OH:17])=[C:2]([Br:1])[CH:16]=1
Reactant: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Reactant: BrBr
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCNC(=O)Nc1nc2c(Br)cc(Br)c(O)c2s1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 1-(6-bromo-7-hydroxy-2-benzothiazolyl)-3-ethyl-urea (50 mg, 0.158 mmol) in AcOH (2 mL) at about 20° C. was added Br2 (9 μl, 0.174 mmol). The reaction mixture was stirred at about 20° C. for about 15 minutes. Toluene (10 mL) was added and the solvents evaporated. The crude material was purified by preparative LC/MS to give 19 mg (30%) pure 18. 1H NMR (DMSO) δ 1.09 (t, 3H, J=6 Hz CH3), 3.19 (m, 2H, CH2), 6.55 (br s, 1H, NH), 7.68 (s, 1H, ArH), 10.51 (br s, 1H, NH or OH), 11.20 (br s, 1H, NH or OH). HPLC retention timer 2.90 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:22]=[CH:23][C:24]=3[C:25]#[N:26])[C:20]=2Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:22]=[CH:23][C:24]=3[C:25]#[N:26])[C:20]=2[N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cnn2c(Cl)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cnn2c(N3CCOCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Temperature: 160 °C
Yield: 90 %

Procedure:
A solution of 50 mg (0.138 mmol) of 6-(4-benzyloxy-phenyl)-7-chloro-pyrazolo[1,5-a]pyrimidine-3-carbonitrile in 2 mL of dimethylformamide in a 5 mL microwave vessel, was added 25 mg (0.18 mmol) of potassium carbonate, followed by 15 mg (0.166 mmol) of morpholine, and the mixture was heated in a microwave synthesizer (Emrys system from Personal Chemistry, 300 W) at 160° C. for 5 min. Since analysis by LC-MS indicated product formation, the reaction mixture was diluted with ethyl acetate, washed with brine (2 times), dried over sodium sulfate and concentrated to give a residue which was purified via reverse-phase chromatography using Gilson to afford (after lyophilization) desired 6-(4-benzyloxy-phenyl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile (90% purity) as indicated by 1H NMR; LC-MS—calcd for C24H21N5O2 [M++H]+: 412.17, found: 412.1.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH:21]=[CH:22][C:23](O)=O>>[CH3:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[CH3:29])/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: Cc1ccc(C=CC(=O)O)cc1C
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(C)c(C)c3)nc2n(CCC)c1=O

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 5.90 g (26.0 mmol) of 5,6-diamino-1,3-dipropyluracil and 5.5 g (31.3 mmol) of 3,4-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 7.70 g (yield of Compound 30 as a white powder.
Reaction SMILES: [CH2:1]([NH2:9])[C:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3].[CH3:10][C:11]([O:14][C:15](ON=C(C1C=CC=CC=1)C#N)=[O:16])([CH3:13])[CH3:12].CCN(CC)CC>O1CCOCC1>[NH:9]([C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])[CH2:1][C:2]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCC(=O)NCC(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Yield: 56.4 %

Procedure:
An oven-dried 20 mL vial equipped with septum and stir bar was charged with 6 mL dioxane, Gly—Gly (1.325 g, 10.0 mmol), BOC—ON (2.714 g, 11.0 mmol), and Et3N (2.10 mL, 15 mmol). The mixture was stirred for 2 hours during which time a clear yellow solution formed. The mixture was extracted with EtOAc (20 mL) and H2O (15 mL). The aqueous layer was collected, washed with EtOAc and added to 50 mL 5% citric acid. The t-BOC-GlyGlyOH was extracted with EtOAc (200 ml) and dried over anhydrous Na2SO4. The EtOAc was removed in vacuo and triturated with hot Et2O. White crystals were collected, washed with Et2O and dried to give 1.309 g of the title compound: 1H NMR (300 MHz, DMSO-d6): δ 12.3 (bs 1H, CO2H), 8.04 (t, 1, NH), 6.98 (t, 1H, NH), 3.75 (d, 2H, CH2), 3.56 (d, 2H, CH2), and 1.38 (s, 9H, C(CH3)3).
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH3:9])=[O:6])[CH3:4].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[C:19]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11])[CH3:9])=[O:6])[CH3:4])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)Nc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: Br
Solvent: O
Solvent: c1ccncc1
Product: C[C@H](NC(=O)c1ccccc1)C(=O)N[C@@H](C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
4.1 g (0.013 mol) of L-alanyl-L-alanine anilide hydrobromide were dissolved in 120 ml of dry pyridine and 3 ml (0.026 mol) of benzoyl chloride were added. The solution was stirred at room temperature for 3 hours and was then evaporated to yield a solid. 50 ml of water were added, the solid was filtered off, washed with 50 ml of water and then recrystallise from ethanol to yield 3.15 g (72%) of N-benzoyl-L-alanyl-L-alanine anilide of melting point 245°-248° C.; [α]D20 =+66.6° (c=1.086% in dimethylformamide).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CN(C)C=O>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[CH2:2][N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14]
Reactant: ClCc1cnccn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cnccn1
Temperature: 110 °C
Yield: 73 %

Procedure:
To a solution of 2-(chloromethyl)pyrazine (2.63 g, 20.5 mmol) (prepared according to Zhang, X.-A. et al., J. Am. Chem. Soc. 2008, 130, 15788-15789) in N,N-dimethylformamide (20 mL) was added potassium phthalimide (3.98 g, 21.5 mmol). The reaction mixture was heated for 16 h at 110° C., allowed to cool to ambient temperature and concentrated in vacuo. The residue was partitioned between dichloromethane (150 mL) and water (50 mL). The organic phase was washed with water (50 mL) and brine (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in a mixture of ethyl acetate and hexanes (1:1) to afford 2-(pyrazin-2-ylmethyl)isoindoline-1,3-dione as a light brown solid in 73% yield (3.56 g): 1H NMR (300 MHz, CDCl3) δ8.63 (s, 1H), 8.45 (s, 2H), 7.89-7.83 (m, 2H), 7.76-7.70 (m, 2H), 5.03 (s, 2H); MS (ES+) m/z 240.0 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3](=O)[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClC1C=CC=CC=1.CCOC(C)=O>[CH:2]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1)([CH3:13])[CH3:1]
Reactant: CC(C)C(=O)CSc1ccccc1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1csc2ccccc12
Temperature: 136 °C
Reaction time: 18 h

Procedure:
To a hot solution (136° C.) of PPA (8.2 g) in chlorobenzene (50 mL) is added a solution of compound 563-C (4.34 g; 22.4 mmol) in chlorobenzene (35 mL). The reaction was stirred at 136° C. for 18 h, cooled to ambient temperature, diluted with EtOAc, quenched with H2O, and the EtOAc layer was washed with H2O, brine, dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford compound 563-D as an oil. 1H-NMR (DMSO-d6): δ 1.31-1.33 (d, 6H), 3.26-3.31 (m, 1H), 7.33-7.43 (m, 2H), 7.83-7.85 (m, 1H), 7.95-7.97 (m, 1H); MS: m/z 328.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:19][CH3:20])[C:8](=[O:18])[CH2:9][CH2:10][S:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:5][N:4]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:3]=1.[OH:27]O>FC(F)(F)C(O)C(F)(F)F>[Cl:1][C:2]1[C:6]([N:7]([CH2:19][CH3:20])[C:8](=[O:18])[CH2:9][CH2:10][S:11]([CH2:12][CH2:13][C:14]([F:16])([F:15])[F:17])=[O:27])=[CH:5][N:4]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:3]=1
Reactant: OO
Reactant: CCN(C(=O)CCSCCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CCN(C(=O)CCS(=O)CCC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.2 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide (I) (500 mg, 1.229 mmol) in hexafluoroisopropanol (5 mL) stirring at room temperature was added 30% hydrogen peroxide (523 mg, 4.92 mmol). The solution was stirred at room temperature for 15 minutes. It was quenched with saturated sodium sulfite solution and extracted with CH2Cl2. Silica gel chromatography (0%-10% MeOH/CH2Cl2) gave the title compound as white semi-solid (495 mg, 95%): IR (thin film) 1660 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.96 (d, J=2.4 Hz, 1H), 8.64 (dd, J=4.7, 1.4 Hz, 1H), 8.07-8.00 (m, 2H), 7.46 (ddd, J=8.3, 4.8, 0.7 Hz, 1H), 3.85-3.61 (m, 2H), 3.23-3.08 (m, 1H), 3.03-2.76 (m, 3H), 2.74-2.52 (m, 4H), 1.18 (t, J=7.2 Hz, 3H); ESIMS m/z 423 ([M+H]+).