Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.C1C=CC2C=[C:25]([NH2:30])C=CC=2C=1.Cl.CN(C)CCCC(N=C=N)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10]([NH:30][CH3:25])=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc2ccccc2c1
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: CC(CCCN(C)C)N=C=N
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 16 h

Procedure:
A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid (0.25 g, 0.74 mmol) and 1-hydroxybenatriazole (0.12 g, 0.88 mmol) in dichloromethane (3 ml) was stirred for 15 minutes before addition of napthylamine (40% solution in water, 0.11 μl, 1.47 mmol) and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.17 g, 0.88 mmol). The reaction mixture was stirred for 16 hours, solvent removed under reduced pressure and the residue partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with saturated sodium hydrogen carbonate, brine, dried (MgSO4), filtered and concentrated to yield the title compound which was used in the next step without further purification. LC/MS: (PS-A2) Rt 3.20 [M+H]+ 353.95.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[NH2:12][CH2:13][CH:14]([NH2:16])[CH3:15].[BH4-].[Na+].[CH2:19](O)C>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:12][CH2:13][C:14]([CH3:19])([NH2:16])[CH3:15])[CH2:8]2
Reactant: CCO
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: CC(N)CN
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(N)CNC1C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 12 h

Procedure:
In analogy to a procedure outlined in J. Med. Chem. 32, 1989, 179-182, 2-adamantanone (500 mg) and 1,2-diaminopropane (440 mg) were dissolved in dry ethanol (12 mL) and heated to reflux for 1.5 hours. The mixture was cooled to 0° C. and sodium borohydride (164 mg) was added in portions over 5 minutes). The mixture was allowed to stir at RT for 12 hours. The mixture was evaporated and the residue was dissolved in CHCl3, washed with saturated NaHCO3 solution and brine, dried over Na2SO4 and evaporated. The residue was dried in vacuo to give a slightly yellow liquid that was used without further purification. MS (ESI): 223.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CN1CCOCC1>C(Cl)Cl.C(OCC)(=O)C>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=2)=[CH:9][C:10]=1[O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24]
Reactant: Nc1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2cnc(N)c(OCc3c(Cl)cccc3Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-amino-phenyl)-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (100 mg, 0.28 mmol) in methylene chloride (5 mL) at 0° C., was added methanesulfonyl chloride (0.021 mL, 0.28 mmol) and 4-methylmorpholine (0.16 mL). The mixture was stirred at room temperature for 2 hr, and diluted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified with a silica gel column eluting with hexane-ethyl acetate (5:1) to give N-{4-[6-amino-5-(2,6-dichloro-benzyloxy)-pyridin-3-yl]-phenyl}-methanesulfonamide.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][CH2:11][CH2:12][O:13][C:14](=[O:38])[CH2:15][C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[N:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:17]=1[CH3:37].[CH3:39][S:40](Cl)(=[O:42])=[O:41].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:39][S:40]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:38])[CH2:15][C:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[N:18]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:17]=1[CH3:37])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(CC(=O)OCCO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CC(=O)OCCOS(C)(=O)=O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
DMAP (0.03 mmol) and diisopropylethylamine (DPEA) (0.5 mmol) are added to a solution of 2-hydroxyethyl-2-[1-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl)acetate in DCM (10 ml), at 0° C., MsCl (0.6 mmol) is added and it is stirred for 3 h, at RT. Then H2O is added (5 ml) and it is stirred for 1 h, the phases are separated and the organic phase is washed with NaHCO3 and then with H2O. It is dried and concentrated. The raw product is purified by chromatography (silica; hexane/EtOAc). Oil, yield 76%. 1H NMR 200 MHz (CDCl3) δ (ppm): 2.05 (s, 3H), 2.96 (s, 6H), 3.50 (s, 2H), 4.13-4.33 (m, 4H), 6.51 (s, 1H), 7.08-7.14 (m, 4H), 7.37-7.41 (m, 3H), 7.62 (d, 2H, J=8.6). MS-ESI: m/z 515 (M+Na+).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:20][C:21]1([F:29])[CH2:25][NH:24][C@@H:23]([C:26]([NH2:28])=[O:27])[CH2:22]1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([N:24]3[CH2:25][C:21]([F:29])([F:20])[CH2:22][C@@H:23]3[C:26]([NH2:28])=[O:27])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: NC(=O)[C@H]1CC(F)(F)CN1
Agent: Cl
Product: NC(=O)[C@H]1CC(F)(F)CN1C(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and (R)-4,4-difluoropyrrolidine-2-carboxamide hydrochloride (CAN 1315304-75-6) as starting materials and isolated (20 mg, 32%); MS (ESI, m/z): 394.5 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:8][C:7]=12)#[CH:2].Br[C:23]1[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=1>>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][N:6]3[N:5]=[CH:4][C:3]([C:1]#[C:2][C:23]4[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=4)=[C:7]3[N:8]=2)=[CH:13][CH:14]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2ccc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3ccc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.33) (144 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (153 mg, 68%). MS (ISP) 449.3 [(M+H)+]; mp 224-226° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][C:10]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].O>CN(C)C=O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:13]1[C:12](=[O:15])[CH2:11][C:10]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]=2[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:14]1)[CH3:33]
Reactant: CCOC(=O)CBr
Reactant: O=C1Cc2ccc(Cl)cc2C(c2ccccc2Br)CN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CC(c2ccccc2Br)c2cc(Cl)ccc2CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1500 mg of the compound from Example 10A (4.28 mol) are dissolved in 30 ml of dimethylformamide, and 2788 mg of caesium carbonate (8.56 mol) are added. 0.95 ml of ethyl bromoacetate (1429 mg, 8.56 mol) is added drop wise, and the suspension is stirred at room temperature overnight. Water is added, and the mixture is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated in a rotary evaporator. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 450 mg (24% of theory) of the title compound are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[CH2:5]Br.[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[CH2:5][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)c1cc(Oc2c(Br)cc(CBr)cc2Br)ccc1O
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc(Br)c(Oc2ccc(O)c(C(C)C)c2)c(Br)c1)OCC
Yield: 56 %

Procedure:
A mixture of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzylbromide (Example 13a) (491 mg, 1.03 mmol), triethyl phosphite (3.98 g, 12 mmol) in 20 ml of toluene was refluxed for 48 hours. The reaction mixture was concentrated and the residue was precipitated with a mixture of petroleum ether and EtOAc (8:2) to give 308 mg (0.577 mmol, 56%) of 3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzyl phosphonic acid, diethyl ester as a white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(Cl)(=O)C.Br[CH2:10][N:11]1[CH2:18][N:17]([N+:19]([O-:21])=[O:20])[CH2:16][N:15]([N+:22]([O-:24])=[O:23])[CH2:14][N:13]([N+:25]([O-:27])=[O:26])[CH2:12]1>O.C(Cl)Cl>[N:1]([CH2:10][N:11]1[CH2:18][N:17]([N+:19]([O-:21])=[O:20])[CH2:16][N:15]([N+:22]([O-:24])=[O:23])[CH2:14][N:13]([N+:25]([O-:27])=[O:26])[CH2:12]1)=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])N1CN(CBr)CN([N+](=O)[O-])CN([N+](=O)[O-])C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NCN1CN([N+](=O)[O-])CN([N+](=O)[O-])CN([N+](=O)[O-])C1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A solution of sodium azide (345 g, 5.45 mole) in water (1200 mL) was cooled to 5° C. and with good stirring a solution of acetyl chloride (286 g, 3.64 mol) in methylene chloride (640 mL) was added in 2.5 h, maintaining the temperature at 5° C. with external cooling. The upper aqueous layer was siphoned off and Compound 4 (101 g, 0.294 mol) was added. The mixture was stirred for 3 h at 10°-15° C. and filtered. The white solid was washed with methylene chloride (2×200 mL), water (200 mL), and ether (2×200 mL), and dried in a vacuum oven overnight at 40° C. The yield of Compound 5 was 71 g (79%), m.p. 130°-131° C. IR (KBr) 2080 cm-1 (N3), 1540 cm-1 (N--NO2). HPLC analysis showed a single peak. Analysis calculated for C5H10N10O6 : C,19.61: H,3.27; N,45.75. Found: C,19.99: H,3.28; N,44.99.
Reaction SMILES: C([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][N:12]([CH:17]([CH3:19])[CH3:18])[CH2:13]2)[CH2:9]1)C1C=CC=CC=1.[OH-].[Na+]>CO.O.[Pd]>[CH:17]([N:12]1[CH2:13][CH:14]2[CH2:16][CH:10]([CH2:9][NH:8][CH2:15]2)[CH2:11]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CC2CC(CN(Cc3ccccc3)C2)C1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N1CC2CNCC(C2)C1
Temperature: 25 °C

Procedure:
A 200-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a heating mantle, a condenser with a N2 inlet, and two glass stoppers. To a stirred mixture of amine (30) (5.53 g, 21.4 mmol) and 10% Pd/C (0.64 g, 30 mg/mmol of amine) in CH3OH (80 mL) was added anhydrous HCO2NH4 (3.37 g, 53.5 mmol) in one portion. Stirring the mixture at reflux under N2 for 30 min, cooling the new mixture to RT, and filtering through a celite pad was followed by concentration of the resulting solution to give a viscous oil. The oil was then dissolved in H2O (80 mL) and the pH was adjusted to ~12 by the addition of 10% NaOH. Combined extracts (CH2Cl2, 4×40 mL) of the aqueous solution were dried, filtered, and concentrated (rotary evaporator then vacuum pump, 10 min, RT/0.2 mm Hg) to give amine (31) as a light oil (3.35 g, 93.0%) which was used without further purification. IR (film) cm-1 3315 (N--H), 2965, 2900, 2850, 2790, 2760, 2725 (C--H); 1H NMR (DCCl3) δ1.01 (d, 6H, CH3, J=6.7 Hz), 1.60-1.67 [m, 3H, H(1,5) and H(9)], 2.53-2.59 [m, 3H, ring protons and CH(CH3)2 ], 2.90-3.06 [m, 6H, ring protons], 3.56 (bs, 1H, N--H); 13C NMR (DCCl3) ppm 18.12 (CH3), 30.04 [C(1,5)], 33.62 [C(9)], 52.86 [C(6,8)], 54.59 [CH(CH3)2 ], 54.65 [C(2,4)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH3:16][S:17]SC>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[C:8]([S:17][CH3:16])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CSSC
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O

Procedure:
The title compound, white solid, MS: m/e=265.1 [(M−H)−], was prepared in accordance with the general method of intermediate E from 2-methoxy-4-(trifluoromethyl)benzoic acid and dimethyl disulfide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]([O:22]C)=O)[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[C:8]#N.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.Cl.[OH2:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:22])[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[CH:8]=[O:41]
Reactant: COC(=O)c1cc(Cl)c(C#N)c([N+](=O)[O-])c1-c1cccc(F)c1
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1c(Cl)cc(CO)c(-c2cccc(F)c2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 52.9 %

Procedure:
To a mixture of methyl 4-chloro-5-cyano-3′-fluoro-6-nitrobiphenyl-2-carboxylate (1.02 g, 3.05 mmol) in methylene chloride (20 mL) was added 1.0 M diisobutylaluminum hydride in hexane (7.6 mL, 7.6 mmol) at −78° C. The reaction was warmed to room temperature over 2 hours with stirring. 5.0 M Hydrogen chloride in water (30 mL, 100 mmol) was slowly added with stirring for 1 hour. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and then concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the desired product (0.50 g, 53%). LCMS calculated for C14H10ClFNO4 (M+H)+: m/z=310.0; Found: 310.0.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[CH:6]=2)[CH2:3][CH2:2]1.[NH:29]1[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[O:31].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:35]4\[NH:29][C:30](=[O:31])[NH:32][C:33]\4=[O:34])=[C:9]3[N:8]=[C:7]([N:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CC3)n3ncc(C=O)c3n2)CC1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NC3CC3)n3ncc(/C=C4\NC(=O)NC4=O)c3n2)CC1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
The above product tert-butyl 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (250 mg, 0.645 mmol) was dissolved in 2.0 mL ethanol, added hydantoin (129 mg, 1.288 mmol) and piperidine (127 ul). The reaction was heated to 80° C. for three hours. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol, dried to yield (Z)-tert-butyl 4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (264 mg, 87% yield). The above product was further dissolved in 1:1 mixture of DCM:TFA and stirred at room temperature for 30 minutes. Mixture was concentrated and dried to yield yellow solid of (Z)-5-((7-(cyclopropylamino)-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione. LCMS (M+1=369)
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1.[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].C(Br)C>>[CH2:16]([O:15][P:14]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:17]
Reactant: BrCc1cc(-c2ccccc2)no1
Reactant: CCOP(OCC)OCC
Solvent: CCBr
Product: CCOP(=O)(Cc1cc(-c2ccccc2)no1)OCC

Procedure:
5-Bromomethyl-3-phenylisoxazole (7.14 g, 30 mmol) and triethyl phosphite (10.4 ml, 60 mmol) were heated at 150° C. until no more ethyl bromide distilled, then the temperature maintained for a further 1 h. The mixture was then distilled under reduced pressure to give 5-diethylphosphonomethyl-3-phenylisoxazole bp 190°-192° C. at 0.5 mm Hg (8.15 g, 27.6 mmol, 92%); νmax (film) 2980, 2900, 1605, 1580, 1465, 1440, 1410, 1250, 1160, 1020, 970, 770, 690, 670 cm-1 ; δH (CDCl3) 1.30 (6H, t, J 7 Hz, OCH2CH3), 3.45 (1H, d, JH-P 22 Hz, CH2 -P), 4.10 (4H, m, OCH2CH3), 6.55 (1H, d, J 3 Hz, CH-4), 7.40 (3H, m, Ph), 7.65 (2H, m, Ph); δC (CDCl3) 16.3, 16.4 (OCH2CH3), 24.7, 26.9 (CH2 -P), 62.8, 62.9 (OCH2CH3), 101.5, 101.6 (C-4), 126.8 128.9, 130.0 (Ph), 162.8 (C-3), 164.3, 164.4 (C-2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].[CH2:18](I)[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[N:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH2:18][CH3:19]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
3-Bromo-N-tert-butoxycarbonylaniline (0.82 g, 3.0 mmol) was dissolved in anhydrous DMF (15 ml) and cooled to 0° C. Sodium hydride (0.145 g, 3.6 mmol, 1.2 eq.) was added to the solution. The reaction stirred at 0° C. for 10 minutes then was warmed to room temperature. After 30 minutes at room temperature the reaction was cooled to 0° C. and Ethyl iodide (0.27 ml, 3.3 mmol, 1.1 eq.) was added over ˜1 minute. The reaction was stirred at 0° C. for 5 minutes then was warmed to room temperature. The reaction stirred at room temperature for 22 hours and was then cooled to 0° C. and quenched with a saturated bicarbonate solution and extracted with EtOAc (2 times). The combined organic layers were washed with H2O (5 times) then brine. The organic phase was dried with MgSO4/Na2SO4, filtered and the solvent was removed in vacuo to give 0.93 g of crude product which was used as is. HPLC ret. time=11.83 min. (100%).
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][NH:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].[C:12](#[N:15])[CH:13]=[CH2:14]>>[OH:9][CH:6]([CH2:7][OH:8])[CH2:5][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:14][CH2:13][CH2:12][NH2:15]
Reactant: C=CC#N
Reactant: OCC(O)CNCC(O)CO
Product: NCCCN(CC(O)CO)CC(O)CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bis-(2,3-dihydroxypropyl)amine (16.5 g., 0.1 mole) and acrylonitrile (6.4 g., 0.12 mole) was mixed in an ice bath and then warmed to room temperature. After standing for 2 hours, the mixture was then heated at 45° C.-55° C. for 3 hours. The excess acrylonitrile was removed by gentle warming under reduced pressure. The residue was taken up in ethyl alcohol, mixed with sponge nickel catalyst and hydrogenated under 200 psi hydrogen using good agitation. After filtration of catalyst the solvent and excess acrylonitrile was removed by stripping under reduced pressure to leave the product as an oil.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na].S([O-])([O-])(=O)=O.[Zn+2:15]>O>[N+:1]1([O-:8])[C:2]([SH:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Zn:15]
Reactant: [Zn+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Agent: [O-][n+]1ccccc1S
Solvent: O
Product: [Zn]
Reaction time: 0.5 h

Procedure:
To a 514.8 gm aliquot of the above solution of sodium pyridine-2-thiol-N-oxide (30.9 gm dry basis; 0.207 mole) was added a solution of zinc sulfate (20.3 gm; 52.5% concentration as hydrate; 0.113 mole), and water (81 gm) at room temperature. After 0.5 hour agitation, insoluble zinc pyridine-2-thiol-N-oxide was filtered and washed with water. The wet cake (59.9 gm) was dried to constant weight (33.8 gm; 0.107 mole or 85.2% yield; 96.1% assay). The zinc pyridine-2-thiol-N-oxide had the following color designation: L, 93.0; a, -3.7; b, 5.2. (Hunterlab Tristimulus Colorimeter, Model D25A-2, Reston, Va. 22090).
Reaction SMILES: [C:1]1([C:7]([O:25][Si](C)(C)C)=[CH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:30]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].C(Cl)(Cl)[Cl:44]>O1CCCC1>[ClH:44].[Br:30][CH:8]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:25])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1
Reactant: ClC(Cl)Cl
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)OC(=CCCN1CCC(=Cc2ccc(F)cc2)CC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(c1ccccc1)C(Br)CCN1CCC(=Cc2ccc(F)cc2)CC1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
6.21 g of 1-(4-phenyl-4-trimethylsilyloxy-3-buten-1-yl)-4-(4-fluorobenzylidene)piperidine was dissolved in 30 ml of tetrahydrofuran, and 2.83 g of N-bromosuccinimide was added in small portions to the thus prepared solution which was cooled at -50° C. The reaction mixture was further stirred at -50° C. for 1 hour and gradually warmed to -20° C., and then thereto was added saturated aqueous sodium bicarbonate and chloroform, subsequently separating the organic layer. The aqueous layer was further extracted with chloroform, and the organic layers were combined and washed with water. After drying over anhydrous magnesium sulfate, the drying agent was removed by filtration, and 8 ml of 4 N hydrogen chloride dioxane solution was added to the resulting filtrate which was cooled in an ice bath. The solvent was evaporated under reduced pressure, and the resulting residue was crystallixed from ether to obtain 6.00 g of 1-(3-bromo-4-phenyl-4-oxobutyl)-4-(4-fluorobenzylidene)piperidine hydrochloride.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:14]([O:16][C:17](=[O:25])[CH:18](Br)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]>CN(C=O)C>[CH2:14]([O:16][C:17](=[O:25])[CH:18]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:15]
Reactant: Oc1cccc2ccccc12
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1cccc2ccccc12)C(=O)OCC
Reaction time: 0.5 h

Procedure:
A solution of 25 g of 1-naphthol in 50 ml of DMF is slowly added dropwise to a solution of 7.6 g of sodium hydride dispersion in 300 ml of DMF. The suspension is stirred for 30 minutes and subsequently 41.5 g of bromomalonic acid diethyl ester in 50 ml of DMF are added dropwise. The reaction mixture is further stirred for 16 hours at room temperature and then concentrated by evaporation in a high vacuum. The residue is dissolved in ethyl acetate and washed with 2N sodium hydroxide solution, water and brine, dried over sodium sulphate and concentrated by evaporation. The residue is distilled at 145°-170°/2.6 Pa and yields α-naphthoxymalonic acid diethyl ester in the form of an orange-coloured oil.