Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])=[O:5].[Br:14][CH2:15][CH2:16]Br>CCCCCC.CN(C=O)C>[Br:14][CH2:15][CH2:16][C:7]([CH3:13])([S:4]([CH3:3])(=[O:5])=[O:6])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrCCBr
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.33 g, 58.3 mmol) was washed with hexane (2×10 mL) in a 100 mL two neck round bottom flask under nitrogen then suspended in DMF (30 mL). The suspension was treated dropwise with ethyl 2-(methylsulfonyl)propanoate (10.0 g, 55.49 mmol) in DMF (10 mL). The mixture was stirred 30 min at RT, cooled to 0° C., and treated dropwise with 1,2-dibromoethane (5.17 mL, 58.8). The mixture was allowed to warm to room temperature while stirring overnight. The mixture was quenched with saturated ammonium chloride (100 mL) and the mixture was extracted with diethyl ether (4×50 mL). Combined organics were washed with 50% saturated sodium chloride (4×50 mL), dried (MgSO4), filtered and the filtrate concentrated in vacuo. Crude material was chromatographed over silica gel (350 g, 230-400 mesh) eluting with 10-20% EtOAc/hexane to afford the title compound as a pale yellow oil (7.9 g, 50%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.05 Hz, 3H) 1.64 (s, 3H) 2.49-2.59 (m, 1H) 2.78 (ddd, J=13.89, 10.16, 6.64 Hz, 1H) 3.05 (s, 3H) 3.33-3.41 (m, 1H) 3.46-3.54 (m, 1H) 4.22-4.37 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C:12]#[N:13].[CH:14]([NH2:16])=O>O>[NH2:13][C:12]1[N:16]=[CH:14][N:1]=[C:2]2[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=12
Reactant: NC=O
Reactant: Cn1c(N)c(C#N)c(=O)n(C)c1=O
Solvent: O
Product: Cn1c(=O)c2c(N)ncnc2n(C)c1=O
Yield: 58 %

Procedure:
0.3 g (1.7 mmol) of 6-amino-5-cyano-1,3-dimethyluracil was added to 2 ml of formamide followed by refluxing for 2 hours. 10 ml of water was added to the solution and the crystalline precipitate was filtered off. The crude product was recrystallized from methanol to give 0.2 g of 5-amino-1,3-dimethylpyrimido[4,5-d]pyrimidine-2,4-dione (compound 9) in a 58% yield.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11]1(Cl)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6].O.[Cl-].[Na+]>C(O)(C)C>[C:5]([N:9]=[N:10][C:11]1([N:3]=[C:2]=[S:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Reactant: N#C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)N=NC1(N=C=S)CCCCC1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 91.5 grams (1.05 moles) of sodium thiocyanate in 450 ml of 75% aqueous isopropanol in a 2 liter jacketed reactor, cooled to 5° C., was added 203.2 grams (1.0 moles) of 1-t-butylazo-1-chlorocyclohexane holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional 90 minutes at room temperature, 900 ml of water added and the reaction stirred until the sodium chloride dissolved. The product was extracted with 300 ml pentane, the pentane extract washed successively with water, 10% NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 173 grams (75% crude yield) of a yellow liquid. The product had a broad band at approximately 2040 cm-1 in its infrared spectrum which is indicative of the isothiocyano band in these compounds. There was no band at 2170 cm-1 (thiocyano band).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCNCC
Reactant: CCCCCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCN(CC)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.7 %

Procedure:
Dissolve 50.90 ml (0.5 moles) diethylamine and 57.10 g (0.5 mole) heptaldehyde in 500 ml methanol and stir at room temperature for one hour. Slowly add 31.42 g sodium cyanoborohydride in 500 ml methanol to the stirred reaction mixture. Add glacial acetic acid to the reaction mixture until pH=6. Stir at room temperature overnight. Concentrate reaction mixture volume to 300 ml and then add 500 ml distilled water. Add concentrated hydrochloric acid until pH=1. Extract with 5×250 ml methylene chloride. Evaporate organic solvent and then dissolve the residue in 400 ml 0.1N HCl. Wash aqueous solution with 3×200 ml diethyl ether and then add 2N NaOH until solution is basic (pH=12). Extract with 3×200 ml diethyl ether. Dry over MgSO4, filter and evaporate, the distill in vacuo to obtain 46.0 g (53.7%) title compound.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[O:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]([O:16][CH3:17])=[O:15].[Si:18](Cl)([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[O:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[C:14]([O:16][CH3:17])[O:15][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)C1CCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(O[Si](C)(C)C)=C1CCCO1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a suspension of LDA (2.6 g, 24.3 mmol) in THF (30 mL) at −78° C. was slowly added methyl tetrahydrofuran-2-carboxylate (3.0 g, 23.0 mmol). The resulting mixture was stirred at −78° C. for 20 minutes, and TMS chloride (2.6 g, 24.3 mmol) was slowly added. The reaction was stirred for 1 hour at −78° C. and then warmed to room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, avoiding contact with water. Hexanes (20 mL) was then added, and the mixture was passed through a short plug of celite, eluting with hexanes (10 mL). The solution was then concentrated, affording the crude product in good purity.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:33]=[CH:34][CH:35]=2)[C:16]([NH:18][NH:19][C:20](=[O:32])[CH2:21][N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>P(Cl)(Cl)(Cl)=O>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][C:20]1[O:32][C:16]([C:15]2[CH:14]=[C:13]([NH:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)[CH:35]=[CH:34][CH:33]=2)=[N:18][N:19]=1
Reactant: Cc1cc(Nc2cccc(C(=O)NNC(=O)CN3CCc4ccccc4C3)c2)c2ccccc2n1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Nc2cccc(-c3nnc(CN4CCc5ccccc5C4)o3)c2)c2ccccc2n1
Temperature: 0 °C
Yield: 36.7 %

Procedure:
A mixture of 92 (195 mg, 0.42 mmol) in phosphorous oxychloride (0.5 mL) was heated overnight before mixing cautiously with ice water (2 mL). The mixture was extracted with 7:3 CH2Cl2/MeOH, and the organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution) to give the desired product as a pale yellow solid (69 mg, 37%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: C1CNCCNC1
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Product: Clc1ccc(OCCOc2nccnc2N2CCCNCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and homopiperazine (287 mg, 2.87 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 128 mg (69%) of the title product. HRMS m/z calcd for C17H21CIN4O2(M)+348.1353, found 348.1353. Anal. (C17H21CIN4O2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[S:28](Cl)(=[O:30])=[O:29]>CN(C)C1C=CN=CC=1.ClCCl>[Br:17][C:18]1[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][C:19]=1[S:28]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:30])=[O:29]
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 24 %

Procedure:
To a cooled (0° C.) solution of methyl 3-aminothiophene-2-carboxylate (534.0 mg; 3.4 mmol), 4-dimethylaminopyridine (94.3 mg; 0.77 mmol) and pyridine (2.5 mL; 30.9 mmol) in anhydrous dichloromethane (60 mL) was added 2-bromo-4-(trifluoromethyl)benzene-1-sulfonyl chloride (1.0 g; 3.09 mmol) portion-wise. After addition was complete the reaction mixture was stirred at 0° C. for 20 minutes, gradually allowed to war to room temperature, stirred for 16 hours, and then washed with aqueous hydrochloric acid (50 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) to give the title product as a white solid (330 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([CH:16]3[C:21](=[O:22])[C:20]([CH3:24])([CH3:23])[O:19][C:18]([CH3:26])([CH3:25])[C:17]3=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)(Cl)Cl>[CH3:39][O:38][C:36](=[O:37])[O:27][C:17]1[C:18]([CH3:26])([CH3:25])[O:19][C:20]([CH3:24])([CH3:23])[C:21](=[O:22])[C:16]=1[C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:15]
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1=C(OC(=O)OC)C(C)(C)OC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.141 g, 0.366 mmol) in dry chloroform (3 ml) is added triethylamine (0.152 ml, 1.09 mmol), and methyl chloroformate (0.084 ml, 1.09 mmol) and the mixture is stirred at room temperature for 2 hours. Solvents are removed, and the residue is purified directly by column chromatography (hexane/ethyl acetate 5:1 ratio) to afford carbonic acid 4-(4′-chloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethyl-5-oxo-5,6-dihydro-2H-pyran-3-yl ester methyl ester (0.150 g) as a white solid.
Reaction SMILES: CN(C)CCN(C)C.[C:9]([O-:12])([O-])=[O:10].[K+].[K+].[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[CH:16]>Cl[Cu]>[C:17]1([C:15]#[C:16][C:9]([OH:12])=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C([O-])[O-]
Reactant: C#Cc1ccccc1
Agent: Cl[Cu]
Agent: CN(C)CCN(C)C
Agent: [K+]
Product: O=C(O)C#Cc1ccccc1

Procedure:
An initial experiment was conducted by using 2 mol % of CuCl, 2 mol % of TMEDA (N,N,N′,N′-tetramethylethylenediamine) ligand, and K2CO3 as base for the carboxylation of 1-ethynylbenzene at ambient temperature and atmospheric pressure. Remarkably, phenylpropiolic acid was produced in excellent yield after acid workup. The isolated pure product was characterized by NMR and elemental analysis. Phenylpropiolic acid was further converted into its methylester and characterized by NMR and GC/MS.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(Cl)CCl.[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:21]([O:8][C:7](=[O:9])[CH2:6][CH:5]([S:4][C:1](=[O:3])[CH3:2])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)SC(CC(=O)O)Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)SC(CC(=O)OCc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
The product from Step B (5.4 g, 26.2 mmol) was taken up in DCM (50 mL) with stirring and cooled to 0° C. EDC (6.0 g, 31.4 mmol) and DMAP (164 mg, 1.31 mmol) were added followed by benzyl alcohol (2.4 mL, 23.6 mmol). The resulting solution was stirred at room temperature overnight with the exclusion of moisture. The reaction was diluted with DCM and washed successively with 1 M HCl, water, 5% Na2CO3 solution, brine and dried, filtered and evaporated to give a dark oil. This was purified by silica gel column chromatography eluting with hexane/ethyl acetate 1:1 to give the product as an orange oil (5.98 g, 70%). 1H-NMR δ (CDCl3) 7.38-7.17 (10H, m); 5.11 (2H, s), 4.08 (1H, m), 2.96 (2H, d, J=6.4 Hz), 2.64 (2H, d, J=6.4 Hz) and 2.27 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][N:14]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:15]3=[O:18])=[CH:11][C:10]=2[O:25][CH:26]([CH3:28])[CH3:27])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][CH3:54])=[O:51]>CN(C=O)C>[CH2:53]([O:52][C:50]([N:22]1[CH2:21][CH2:20][CH:19]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][C:9]([NH:8][C:5]4[N:4]=[C:3]([NH:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:2]([Cl:1])=[CH:7][N:6]=4)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:11]=3)[C:15]2=[O:18])[CH2:24][CH2:23]1)=[O:51])[CH3:54]
Reactant: CCOC(=O)Cl
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(N2Cc3cc(OC(C)C)c(Nc4ncc(Cl)c(Nc5ccccc5S(=O)(=O)C(C)C)n4)cc3C2=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 15 mg, 0.025 mmol) and triethylamine (37.5 uL, 0.25 mmol) in DMF (0.5 mL), is added ethyl chloroformate (5.4 mg, 0.05 mmol). The mixture is stirred at room temperature for 1 hour. The crude reaction mixture is purified by mass-trigger preparative RP LC-MS to afford the title compound 4-(6-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid ethyl ester (175) as a white solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.55 (d, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.82 (dd, 1H), 7.74 (t, 1H), 7.34 (t, 1H), 7.28 (s, 1H), 4.73 (m, 2H), 4.39 (s, 2H), 4.12 (m, 2H), 4.06 (q, 2H), 3.46 (m, 1H), 2.92 (m 2H), 1.76 (m, 2H), 1.68 (m, 2H), 1.29 (d, 6H), 1.20 (t, 3H), 1.17 (d, 6H); MS m/z 671 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:24])[CH:16](O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.Cl>N1C=CC=CC=1>[C:1]([C:9]1[CH:10]=[C:11]([C:15]([CH3:24])=[CH:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)C(C)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CC=C(C)c1cccc(C(=O)c2ccccc2)c1
Temperature: 0 °C
Yield: 91.3 %

Procedure:
A solution of 6.2 g of ethyl 4-(m-benzoyl-phenyl)-4-methyl-3-hydroxy-butyrate (by process of Step E of Example XIX) in 60 ml of pyridine was heated at 100°C for 3 hours in the presence of 5 ml of phosphorus oxychloride and was then poured into a mixture of 200 g of ice and 65 ml of concentrated hydrochloric acid. The mixture was extracted with ether and the ether phase was washed with water, then with an aqueous saturated sodium bicarbonate solution and then water until the wash water was neutral. The solution was dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 5.35 g of ethyl 4-(m-benzoyl-phenyl)-4-methyl-3-butenoate.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:16])[NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(C)(C)C.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:16].[C:20]([OH:22])([C:19]([F:24])([F:23])[F:18])=[O:21]
Reactant: CC(C)(C)NC(=O)CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)CCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2-tert-Butylcarbamoyl-ethyl)-carbamic acid tert-butyl ester (0.65 g, 2.64 mmol) is dissolved in trifluoroacetic acid (3.5 ml) and allowed to stir at room temperature under an inert atmosphere for 3 hours. The solvent is removed in vacuo to yield the titled compound as a TFA salt which is used crude in the next step:
Reaction SMILES: Cl[CH:2]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClC(c1cccnc1)c1cccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(c2cccnc2)c2cccnc2)CC1
Temperature: 80 °C
Yield: 30.6 %

Procedure:
A round bottom flask was charged with 3,3′-(chloromethylene)-dipyridine (415 mg, 2.03 mmol), tert-butyl piperazine-1-carboxylate (1.20 g, 6.45 mmol), and acetonitrile (50 mL). The reaction was heated to 80° C. for 2 hrs, concentrated under reduced pressure, and purified by silica chromatography (100% CH2Cl2 to 5% 2M NH3 in MeOH) yielding tert-butyl 4-(di(pyridin-3-yl)methyl)piperazine-1-carboxylate (220 mg, 31%). 1H NMR 400 MHz (CDCl3) δ 8.64 (d, J=2.0 Hz, 3H), 8.48 (dd, J=4.8, 1.7 Hz, 3H), 7.70 (dt, J=7.9, 1.9 Hz, 3H), 7.24 (ddd, J=7.9, 4.8, 0.7 Hz, 3H), 5.28 (s, 1H), 4.36 (s, 1H), 3.47-3.39 (m, 6H), 2.34 (s, 6H), 1.42 (s, 9H). LCMS (ESI, m/z): 355 [M+H]+.
Reaction SMILES: C(OC(=O)[N:7]([CH:17]1[CH2:19][CH:18]1[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][N:21]=1)[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:26][C:25]1[C:20]([CH:18]2[CH2:19][CH:17]2[NH:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[I:15])=[N:21][CH:22]=[C:23]([Cl:27])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)c1ccccc1I)C1CC1c1ncc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CC1c1ncc(Cl)cc1Cl)c1ccccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
0.800 g of tert-butyl[2-(3,5-dichloropyridin-2-yl)cyclopropyl](2-iodobenzoyl)carbamate (0.00075 mol) are dissolved in 7 ml of dichloromethane. 0.70 ml of trifluoroacetic acid are added to the reaction mixture which is left stirring at room temperature overnight. The reaction mixture is quenched with 15 ml of an aqueous solution of saturated sodium bicarbonate. After separation, the aqueous phase is extracted with dichloromethane (10 ml). The combined organic phases are dried over magnesium sulfate, filtered, concentrated to dryness and purified on silica to yield to 245 mg of N-[2-(3,5-dichloropyridin-2-yl)cyclopropyl]-2-iodobenzamide (65%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:11]=2)[CH:5]=1>O1CCCC1>[OH:29][CH:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][N:12]1[N:11]=[C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH3:3])[NH:8][N:7]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:20]
Reactant: Cc1cc(Nc2nn(CC(=O)c3ccccc3)c(=O)c3ccccc23)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nn(CC(O)c3ccccc3)c(=O)c3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
Sodium borohydride (6 mg, 0.15 mmol) was added in one portion to a stirred solution of 4-(5-Methyl-1H-pyrazol-3-ylamino)-2-(2-oxo-2-phenyl-ethyl)-2H-phthalazin-1-one (17 mg, 0.05 mmol) (Example E-9) in tetrahydrofuran (THF) (1 ml). The reaction mixture was stirred at room temperature for two hours. After this time LC-MS indicated complete consumption of starting material, methanol (0.5 ml) was added and the reaction mixture was concentrated under vacuum. The resulting residue was purified by flash column chromatography (elution: 97% dichloromethane (DCM), 3% methanol (MeOH)) to give the title compound (2.2 mg, 12% yield) as a white solid. MS (ESI+)=(M+H)+ 361.98.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([F:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6].[F:16][C:17]([F:23])([F:22])[S:18](Cl)(=[O:20])=[O:19]>CCCCCC.C(OCC)C>[F:15][C:4]([F:3])([F:14])[CH:5]([O:6][S:18]([C:17]([F:23])([F:22])[F:16])(=[O:20])=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: OC(c1ccc(F)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: O=S(=O)(OC(c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
NaH (640 mg, 16 mmol, 60% in mineral oil) was washed twice with hexane (20 mL) and then suspended in dried diethyl ether (20 mL). A solution of 2,2,2-trifluoro-1-(4-fluoro-phenyl)ethanol (1.94 g, 10 mmol) in diethyl ether (10 mL) was added at 0° C. After stirring for 2 h at room temperature, a solution of trifluoromethanesulfonyl chloride (1.68 g, 10 mmol) in diethyl ether (10 mL) was added. After 2 h, the reaction mixture was quenched by adding a solution of NaHCO3 and the product was extracted with diethyl ether. The extracts were washed with brine and dried, and the solvent was removed to yield trifluoromethanesulfonic acid 2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ester (3.3 g).
Reaction SMILES: [CH2:1]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:22]([O-])(=[O:24])[CH3:23].[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCOCC>[OH:21][C:17]1[CH:16]=[C:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:20]=[CH:19][C:18]=1[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCCCCCCCc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCc1ccc(C(C)=O)c(O)c1

Procedure:
A 20 g portion of 3-tetradecylphenol, acetate was heated at 110° C. and 8.4 g of aluminum chloride was added in portions over a 3 hour period. The mixture was allowed to cool, then diluted with ether, poured onto ice containing 10 ml of concentrated hydrochloric acid and extracted several times with ether. The ether extracts were combined, washed with water, brine and dried. The crude material was chromatographed on silica gel, eluting with hexane:ethyl acetate (50:1), giving 15.8 g of the desired compound, mp 45°-46° C.