Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccc(F)cc2)CCN(C)C1
Temperature: 95 °C
Yield: 18.4 %

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), 4-fluorophenylboronic acid (59 mg, 0.423 mmol) and K3PO4 (149 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl2(PPh3)2 (10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield crude, which was purified by reverse phase HPLC to yield 5-(4′-fluoro-biphenyl-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (19.23 mg). 1H NMR (Oxalate salt, CD3OD) δ (ppm): 7.65-7.59 (m, 3H), 7.41 (d, 1H), 7.25 (s, 1H), 7.15 (m, 1H), 7.05-6.85 (m, 5H), 4.5-3.39 (m, 2H), 3.6-3.5 (m, 1H), 3.2-3.19 (m, 1H), 2.95 (s, 3H), 2.85-2.8 (m, 1H), 2.59-2.50 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1
Reactant: c1nc[nH]n1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cncn3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine. pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]2[CH2:20][CH2:19][C:18]([O:24][CH3:25])([C:21]([OH:23])=O)[CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:27][C:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][O:24][C:18]1([C:21](=[O:23])[NH:32][C:28]2([CH3:27])[CH2:31][CH2:30][CH2:29]2)[CH2:17][CH2:16][N:15]([CH:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH2:20][CH2:19]1
Reactant: CC1(N)CCC1
Reactant: COC1(C(=O)O)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC1(C(=O)NC2(C)CCC2)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.4 %

Procedure:
1-[1-(tert-butoxycarbonyl)azepan-4-yl]-4-methoxypiperidine-4-carboxylic acid (0.163 g, 0.44 mmol) was dissolved in DMF (5 mL) and (1-methyl)cyclobutylamine hydrochloride (0.08 g, 0.66 mmol), HATU (0.25 g, 0.66 mmol) and DIPEA (0.284 g, 0.38 mL, 2.20 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min, gradient 1% to 6% MeOH in DCM]) to give tert-butyl 4-{4-methoxy-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}azepane-1-carboxylate (0.025 g, 13.4%) as a pale yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][C:15]=2[NH2:17])[NH:10][N:9]=1.[Cl:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([N:27]2[CH2:30][CH:29]([O:31][CH3:32])[CH2:28]2)[C:22]([O:33][CH2:34][CH3:35])=[C:21]([CH:36](Cl)[CH3:37])[CH:20]=1.CN(C)C=O>CCOC(C)=O>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:36]([C:21]3[CH:20]=[C:19]([Cl:18])[C:24]([C:25]#[N:26])=[C:23]([N:27]4[CH2:30][CH:29]([O:31][CH3:32])[CH2:28]4)[C:22]=3[O:33][CH2:34][CH3:35])[CH3:37])[N:9]=[C:8]([CH3:7])[C:16]=12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1N1CC(OC)C1
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1N1CC(OC)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
Cesium carbonate (50 mg, 0.2 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (16 mg, 0.10 mmol) and 6-chloro-4-(1-chloroethyl)-3-ethoxy-2-(3-methoxyazetidin-1-yl)benzonitrile (30 mg, 0.09 mmol) in N,N-dimethylformamide (3 mL, 40 mmol) and the reaction was stirred at 80° C. overnight. The mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered and concentrated the crude product. The product was purified was purified by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the title compound as a white amorphous solid (0.007 g, 20%). The product was isolated as a racemic mixture. LCMS calculated for C21H25ClN7O2(M+H)+: m/z=442.1; found: 442.1. 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 1H), 6.80 (s, 1H), 6.18 (d, J=7.1 Hz, 1H), 4.58-4.44 (m, 2H), 4.18 (m, 1H), 4.13-4.01 (m, 2H), 3.81-3.62 (m, 2H), 3.23 (s, 3H), 2.55 (s, 3H), 1.69 (d, J=7.1 Hz, 3H), 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([C:11]1[C:18]2[S:17][C:16]3[CH:19]=[CH:20][S:21][C:15]=3[C:14]=2[S:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:22]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:22][C:12]1[S:13][C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[S:17][C:18]=2[C:11]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1csc2c1sc1ccsc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCc1c(Br)sc2c1sc1ccsc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
3-decanyldithieno[3,2-b:2′,3′-d]thiophene (91) (9.03 g, 0.027 mol) was dissolved in DMF (100 mL). To this solution, N-bromosuccinimide (NBS) (4.78 g, 0.027 mol) in DMF(50 mL) was added dropwise in the dark under argon. The resulting mixture was stirred at 0° C. for three hours. GC/MS showed a single peak at 415. This solution was poured into water (500 mL). Organic solution was extracted with hexane (3'100 mL). The combined organic solutions were washed with brine (2×50 mL) and water (50 mL). After drying over MgSO4, the hexane was evaporated. The crude product was purified by column chromatography and eluted with hexane to yield the target compound (10.1 g, 90.2%). 1H NMR: solvent, CD2Cl2. δ 7.39 (d, 1H), 7.29 (d, 1H), 2.74 (t, 2H), 1.74-1.33 (m, 16H), 0.89 (t, 3H). 13C NMR: 140.89, 140.63, 136.00, 131.55, 129.22, 126.58, 121.04, 108.89, 32.31, 29.94, 29.73 (overlap), 29.35, 28.49, 23.09, 14.27.
Reaction SMILES: C([O:3][C:4]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5])C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:42](O)[C:41]3[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=3[C:35]2=[O:44])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[C:35](=[O:44])[C:36]3[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=3[CH:42]2[CH2:6][C:4]([OH:5])=[O:3])=[CH:32][CH:33]=1
Reactant: COc1ccc(N2C(=O)C3=C(CCCC3)C2O)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)C3=C(CCCC3)C2CC(=O)O)cc1
Yield: 948 %

Procedure:
Ethoxycarbonylmethylenetriphenylphosphorane (3.0 g) was added to a solution of 2-(4-methoxyphenyl)-3-hydroxy-4,5,6,7-tetrahydroisoindolin-1-one (2.59 g) in toluene (30 ml) and the solution was refluxed gently for 48 hours. After cooling, the solvent was distilled off and the residue was dissolved in 30 ml of methanol. Potassium carbonate (3 g) and water (10 ml) were added and the mixture was refluxed for an hour. After cooling, the methanol was distilled off, 100 ml of water and 100 ml of dichloromethane were added and the mixture was stirred well. The aqueous layer was separated and acidified with 5% hydrochloric acid to give crystals, which were washed with water, dried and recrystallized from methanol-ether (1:3) to give 24.6 g of 2-(4-methoxyphenyl)-3-oxo-4,5,6,7-tetrahydroisoindoline-1-acetic acid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29].[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)CC)C>ClCCl>[CH3:41][S:42]([O:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])(=[O:44])=[O:43]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (10.7 g) in dichloromethane (100 ml) were added methanesulfonyl chloride (1.44 ml) and triethylamine (3.06 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo to give a residue The residue was chromatographed on silica gel (150 g) eluting with a mixture of dichloromethane and acetone (40:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-2-(methanesulfonyloxy)methyl-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (10.39 g).
Reaction SMILES: O[C:2]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:15][CH:14]=1)([C:4]1[N:5]([CH2:9][CH2:10][O:11][CH3:12])[CH:6]=[CH:7][CH:8]=1)[CH3:3].[CH2:30]([SiH](CC)CC)[CH3:31].B(F)(F)F.CCOCC>>[CH3:12][O:11][CH2:10][CH2:9][N:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[CH:2]([C:13]1[CH:14]=[CH:15][C:16]([N:19]([CH3:29])[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:17][CH:18]=1)[CH2:3][CH2:30][CH3:31]
Reactant: CC[SiH](CC)CC
Reactant: COCCn1cccc1C(C)(O)c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: CCCC(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)c1cccn1CCOC

Procedure:
The title compound was prepared from N-(4-{1-hydroxy-1-[1-(2-methox-yethyl)-1H-pyrrol-2-yl]-ethyl}-phenyl)-N-methyl-benzenesulfonamide (Example 1) using triethylsilane and boron trifluoride diethyl etherate as described in Example 88 of U.S. application Ser. No. 10/354,922, now U.S. Pat. No. 7,071,358, and provided below as Preparative Example B.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([CH2:30][CH2:31][CH3:32])[CH:5]=1)=[S:3].Br[CH:34]1[CH2:39][CH2:38][CH2:37][O:36][C:35]1=O>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][C:34]5[CH2:39][CH2:38][CH2:37][O:36][C:35]=5[N:1]=4)=[CH:5][C:6]=3[CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: O=C1OCCCC1Br
Reactant: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Solvent: CCO
Product: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Yield: 28.8 %

Procedure:
A solution of ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (0.5 g, 1.1 mmol) (Example 144) and 3-bromotetrahydro-2H-pyran-2-one (1.2 g, 6.6 mmol) (Example 151) in EtOH (anhydrous, 15 mL) was heated at 70° C. for 18 h. The reaction mixture was cooled to rt, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:2) gave 0.17 g (29%) of the title compound as a light yellow oil. LC-MS: RT=4.52 min, (M+H)+:536.4.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15](CN(C)C)=[C:14](CN(C)C)[N:13]=[C:12]1[S:24]CCC(OCC)=O.[O-]CC.[Na+].[Na]>C(O)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15]([N:11]([CH3:15])[CH3:2])=[C:14]([N:13]([CH3:14])[CH3:12])[NH:13][C:12]1=[S:24]
Reactant: CCOC(=O)CCSc1nc(CN(C)C)c(CN(C)C)n1C1CCc2ccccc2C1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CN(C)c1[nH]c(=S)n(C2CCc3ccccc3C2)c1N(C)C
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 116.7 %

Procedure:
A mixture of ethyl 3-[1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4,5-di(dimethylaminomethyl)imidazol-2-ylthio]propionate (0.55 g, 1.2 mmol) and sodium ethoxide (3.5 mL of a solution prepared free 450 mg sodium in 45 mL of ethanol, 1.4 mmol) in 5 mL of ethanol was stirred at approximately 25° C. for 1.75 hours. The mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried (K2CO3), filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (97:3) to give 1-(1,2,3,4-tetrahydronaphthalen-2-yl)-4,5-di(dimethylamino)-1,3-dihydroimidazole-2-thione (0.24 g, 0.7 mmol), m.p. 182°-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH3:10].[N+:11]([O-])([O-:13])=[O:12].[K+]>OS(O)(=O)=O>[Cl:8][C:5]1[CH:4]=[C:3]([CH2:9][CH3:10])[C:2]([Cl:1])=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1cc(Cl)ccc1Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCc1cc(Cl)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a stiffed solution of 2,5-dichloro-1-ethylbenzene (0.795 g, 4.68 mmol) in concd H2SO4 (4.5 mL) at 0° C., KNO3 (0.473 g, 4.68 mmol) was added in one portion. The resulting pale yellow solution was allowed to warm to room temperature and was stirred overnight at room temperature. It was then poured into ice (80 g) and extracted with ether (3×30 mL). The ether was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to obtain 0.943 g (92%) title compound as an oil; 1H NMR (CDCl3) δ 1.27 (t, 3H, J=7.5 Hz), 2.80 (q, 2H, J=7.5 Hz), 7.42 (s, 1H), 7.94 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6]2.[H-].[Na+].[F:22][C:23]([F:27])([F:26])[CH2:24]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH2:24][C:23]([F:27])([F:26])[F:22])[CH2:7][CH2:6]2
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc2C1=O
Reactant: FC(F)(F)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(OC)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.5 %

Procedure:
A solution of 1C (25 g, 95 mmol) in DMF (40 mL) was added over a period of 30 min to an ice cold solution of NaH (9.53 g, 238 mmol) in DMF (20 mL), and the mixture was stirred for 10 min. Trifluoroethyl iodide (50 g, 238 mmol) was then added, and the mixture was stirred for 3 h at room temperature. The reaction mixture was then brought to 0° C., excess NaH was quenched with ice water, and the aqueous layer with extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under vacuum to give the title compound (16.2 g, 42%) as a solid. 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=9.3 Hz, 1H), 6.85 (dd, J1=2.7 Hz, J2=9.0 Hz, 1H), 6.68 (d, J=2.7 Hz, 1H), 4.1 (q, J=6.9 Hz, 2H), 3.86 (s, 3H), 3.05-2.9 (m, 4H), 2.6-2.4 (m, 4H), 1.23 (t, J=6.9 Hz, 3H). ESI-MS m/z: 345 (M+H)+.
Reaction SMILES: [C:1](N)(N)=N.C(N)(N)=N.C(O)(O)=O.Cl.[CH2:14]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:15][NH2:16]>O>[N:18]12[CH2:19][CH2:20][CH2:21][NH:22][C:1]1=[N:16][CH2:15][CH2:14][CH2:17]2
Reactant: N=C(N)N
Reactant: NCCCNCCCN
Agent: Cl
Agent: O=C(O)O
Solvent: O
Product: C1CN=C2NCCCN2C1
Reaction time: 5 h

Procedure:
In still another specific exemplary embodiment, as shown in Scheme 3 and Example 2 below, a guanidine carbonate salt (1) is dissolved in water and reacted with hydrochloric acid, followed by addition of dipropylene triamine (2). The resulting solution is warmed to reflux and stirred for 4-6 hours to yield the chloride salt of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (4) in water, as shown below:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:14])=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:5]=1)=[O:3].C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH:40]1([C:43]([CH:45]2[CH2:47][CH2:46]2)=O)[CH2:42][CH2:41]1>C(Cl)Cl>[C:15]([C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[C:43]([CH:45]2[CH2:47][CH2:46]2)[CH:40]2[CH2:42][CH2:41]2)[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[C:7]=1[OH:14])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(C1CC1)C1CC1
Reactant: CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)C=C(C2CC2)C2CC2)cc(C(C)(C)C)c1O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 4 g of 3,5-di-tert-butyl-4-hydroxyacetophenone in 250 ml of dry methylene chloride is cooled to -78° C. and 7.3 ml di-iso-propyl ethylamine (i-Pr2EtN) is added followed by 8.1 ml of trimethylsilyl trifluoromethanesulphonate (TMSOTf). The mixture is stirred at -78° C. for 10 minutes and is allowed to warm to ambient temperature over 1 hour. The mixture is cooled again to -78° C., and 3.6 ml of dicyclopropylketone is added followed by 32 ml of 1M titanum tetrachloride solution in methylene chloride. After stirring for 1 hr, the mixture is washed with 1N aqueous hydrochloric acid and the solvents are removed under reduced pressure. The residue is dissolved in 50 ml of methanol-1N aqueous hydrochloric acid and stirred for 1 hr at room temperature. The mixture is concentrated under reduced pressure and partitioned between methylene chloride and water. The organic phase is washed with aqueous sodium bicarbonate, brine and dried over sodium sulphate. The solvents are evaporated and the residue is purified by flash chromatography (10% ethyl acetate in hexane), and the product is recrystallized from hexane to give 1-(3,5-di-tert-butyl-4-hydroxyphenyl-3,3-dicyclopropylprop-2-en-1-one as an orange solid.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(Cl)([Cl:23])=O>ClC1C=CC=CC=1>[C:1]([Cl:23])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: Clc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 25 °C

Procedure:
170.4 g (0.6 mol) of stearic acid and 890 g of monochlorobenzene are introduced into the reactor and 594 g (6 mol) of phosgene are then added over about 30 minutes, while maintaining the temperature of the reaction medium at a maximum of 25° C. The set pressure is adjusted to 10.5 bar relative. The reaction medium is heated to 120° C. and is maintained at this temperature for 1 hour 30 minutes and is then heated to 150° C. and maintained at this new temperature for 1 hour. The level of residual acid is then about 1.4 mol %, the level of residual anhydride is zero and the level of stearoyl chloride obtained 98.6 mol %. The maximum pressure reached was 9 bar relative.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[C:4]([O:25][CH3:26])[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][NH:9][C:5]2[CH:6]=[C:7]([C:32]3[CH:33]=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=3[Cl:34])[C:2]([Cl:1])=[CH:3][C:4]=2[O:25][CH3:26])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: COc1cc(Cl)c(I)cc1NCCN1CCN(C(=O)OC(C)(C)C)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: O
Solvent: C1COCCO1
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
A mixture of tert-butyl 4-(2-((4-chloro-5-iodo-2-methoxyphenyl)amino)ethyl)piperazine-1-carboxylate (180 mg, 0.36 mmol), (2,5-dichlorophenyl)boronic acid (138.9 mg, 0.72 mmol), Na2CO3 (114.5 mg, 1.08 mmol), Pd(PPh3)4 (42 mg, 0.036 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was stirred at 90° C. under argon for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to afford the desired product (135 mg, 73% yield) as a solid. ESI-MS m/z: 514.3[M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Br:1][C:2]1[C:3]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CCNCCO
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Temperature: 140 °C

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 22.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2) and 2-(ethylamino)ethanol to afford a white solid. (The RM was heated at 140° C. for 18 h). HPLC (Condition 4) tR=5.92 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=450.1 [M+H]+.