Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9](C)[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:13][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[CH3:21][OH:22]>CC(C)=O>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[O:20])[CH2:13][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:22][CH3:21])=[CH:10][C:4]=2[N:3]=1)[CH3:19]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CO
Reactant: Cc1ccc2nc(S)[nH]c2c1
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CSc1nc2cc(OC)ccc2[nH]1
Yield: 88 %

Procedure:
A solution of 2-mercapto-5-methylbenzimidazole (200 mg, 1.22 mmol) and ethyl 3-bromopyruvate (0.20 mL, 1.43 mmol) in methanol (2 mL) and acetone (3 mL) was shaken at room temperature for 4 hours. The solvents were removed under the reduced pressure on a rotary evaporator. The residue was triturated with ethyl acetate. Solvent was decanted and the residue was dissolved in methylene chloride. The solution was washed with diluted aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. Removal of the solvent gave the expected product, 3-(5-methoxy-1H-benzoimidazol-2-ylsulfanyl)-2-oxo-propionic acid ethyl ester (300 mg, 88%). 1H-NMR (D3COD, 300 MHz) δ (ppm): 7.19 (br. s, 1H), 7.10 and 7.04 (br. 2 s, 1H), 6.94 (d, J=8.2 Hz, 1H), 4.34 (q, J=7.1 Hz, 2H), 4.31 (br. s, 1H), 3.91 (br. s, 1H), 2.37 (br. s, 3H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH:10]=[O:11])=[CH:8][CH:9]=1)=[O:4].C[Mg]Br.[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH2:10][OH:11])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C=O)o1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(CO)o1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
A solution of 5-formyl-2-furancarboxylic acid methyl ester in 65 ml of tetrahydrofuran was treated with 14 ml of a 3M solution of methyl magnesium bromide in ether at 0°-5° C. The reaction mixture was stirred at the same temperature for 1 hour, poured into a saturated solution of ammonium chloride and extracted with ether. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated giving 6.3 g (87.8%) of 5-(1-hydroxymethyl)-2-furan carboxylic acid methyl ester as a pale yellow oil after chromatographic purification. The oxidation of this secondary alcohol was carried out by using the Swern oxidation conditions. Thus, 6.3 g of 5-(1-hydroxy- methyl) -2-furancarboxylic acid methyl ester in 60 ml of methylene chloride was added to a stirred solution of 5 g of oxalyl chloride, 7.1 g of dimethyl sulfoxide in 80 ml of methylene chloride at -60° C. The reaction mixture was stirred 15 minutes at the same temperature, then 17.5 ml of triethylamine was added. The cooling bath was removed allowing the temperature to rise to 25° C. The reaction mixture was then treated with 25 ml of water, stirred for 10 minutes and extracted with methylene chloride. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 6.7 g of a brown oil. Chromatographic purification of this material on a silica gel column followed by crystallization from ethyl acetate-hexane gave 3.5 g (56.2%) of 5-acetyl-2-furancarboxylic acid methyl ester as a white solid, mp 101°-102° C.
Reaction SMILES: [B:1]([O:18]CC1C=CC=CC=1)([O:10]CC1C=CC=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)([CH3:35])[CH3:34])=[CH:29][CH:28]=1>>[CH2:3]([C:32]1[CH:31]=[C:30]([C:33]([C:36]2[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=2)([CH3:35])[CH3:34])[CH:29]=[CH:28][C:27]=1[OH:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[B:1]([O-:18])([O-:10])[O-:2]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: c1ccc(COB(OCc2ccccc2)OCc2ccccc2)cc1
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)c(Cc2ccccc2)c1
Product: [O-]B([O-])[O-]

Procedure:
The synthesis was carried out in the same manner as for the product having a low Tg. 100g of tribenzyl borate and 68g of bisphenol-A were used. The residue is poured out after distillation at a temperature of 300° C. After cooling the resulting solid was pulverised. In representative cases the Tg is above 100° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10](O)=[C:9]([CH3:14])C=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:22][CH2:23][CH2:24][OH:25].[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[CH2:61]([Cl:63])[Cl:62]>>[NH3:1].[CH2:61]([Cl:63])[Cl:62].[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][N:17]1[CH2:22][CH2:23][CH2:24][O:25][C:9]1[CH:10]=[CH:11][C:12]([CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:26][CH:14]=1
Reactant: Cc1cc(N2CCCCC2)ccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC1CCCCN1CCCO
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC1CCCCN1CCCOc1ccc(CN2CCCCC2)cc1
Product: N
Reaction time: 2 h

Procedure:
A suspension of the product of Example 17 (176 mg), 3-(2-methyl-piperidin-1-yl)-propan-1-ol (145 mg), and polymer supported triphenylphosphine (613 mg; loading: 3 mmol/g) in DCM (5 mL) was treated with di-tert-butylazodicarboxylate (316 mg). After 2 h, the resulting mixture was filtered, and the filtrate was evaporated. Chromatography of the residue (2.5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (60 mg). 1H NMR (400 MHz, CDCl3): 7.20 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 4.01–3.92 (m, 2H), 3.40 (s, 2H), 2.90–2.81 (m, 2H), 2.56–2.47 (m, 1H), 2.40–2.25 (m, 5H), 2.21–2.14 (m, 1H), 1.97–1.88 (m, 2H), 1.70–1.51 (m, 8H), 1.45–1.25 (m, 4H), 1.07 (d, J=6.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19](OC)=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.O.[NH2:26][NH2:27]>C(O)C>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:26][NH2:27])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: NN
Reactant: COC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1

Procedure:
A solution of methyl 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carboxylate (6.80 g, 20.2 mmol) and hydrazine monohydrate (9.92 mL, 202.2 mmol) in ethanol (70 mL) was heated under reflux overnight. After cooling, the precipitate was collected by filtration to give 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.CN1CCOCC1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:2][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: CCCC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCC(=O)Nc1ccc(N)cc1
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of 1,4-phenylenediamine (0.5 g, 4.62 mmol) in anhydrous CH2Cl2 (15 mL) was added NMM (0.51 mL, 4.62 mmol). To the resulting mixture was added dropwise butyryl chloride (0.45 mL, 4.62 mmol) in anhydrous CH2Cl2 (5 mL) at 0° C., and stirred for 0.5 h. The reaction mixture was extracted with CH2Cl2 (20 mL) and washed with H2O (20 mL). The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography over silica gel (EtOAc:hexane=1:3) to give N-(4-aminophenyl)butyramide (KYJ3-006-2, 0.31 g, 36%) as a colorless oil.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[C:14]2[O:15][C:16]3[C:21]([C:22]4([CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:13]=2[CH:12]=[CH:11][CH:10]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([C:4]([N:25]2[CH2:26][CH2:27][C:22]3([C:13]4[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[C:14]=4[O:15][C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cccc2c1Oc1ccccc1C21CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1Oc1ccccc1C21CCN(C(=O)C2CC2)CC1
Reaction time: 8 h

Procedure:
A solution of cyclopropane carboxylic acid chloride (1.2 ml.) in methylene chloride (10 ml.) is added dropwise with stirring to a mixture of 4-methoxyxanthene-9-spiro-4'-piperidine (2.0 g.) and triethylamine (1.6 ml.) in methylene chloride (40 ml.) at 5° C. The mixture is allowed to reach room temperature and stirred overnight. The mixture is washed with 3N hydrochloric acid, 3N sodium hydroxide solution and water, dried MgSO4 and the methylene chloride evaporated to dryness, to give 1'-cyclopropylcarbonyl-4-methoxyxanthene-9-spiro-4'-piperidine (I.R. amide band 1620 cm.-1 ; t.l.c. -- single spot) which is used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][O:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[N:10][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([S:12][CH2:13][CH2:14][O:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[N:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(SCCOC(=O)c2cccc(Cl)c2)nc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(SCCOC(=O)c2cccc(Cl)c2)nc1
Reaction time: 16 h

Procedure:
A mixture of 2-[(5-nitro-2-pyridinyl)thio]ethyl 3-chlorobenzoate (5) (0.24 g, 0.71 mmol) and 10% Pd/C (0.10 g) in toluene or methanol was agitated under a hydrogen atmosphere (40 PSI) for 1 h. The reaction mixture was filtered through Celite® and concentrated to give 2-[(5-amino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (51), LCMS: purity: 99%; MS (m/e): 309 (MH+), which was used without further purification. Acetyl chloride (4.6 μL, 0.064 mmol) was added to a room temperature solution of 2-[(5-amino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (51) (18.9 mg, 0.061 mmol) and triethylamine (18 μL, 0.13 mmol) in anhydrous dichloromethane (1.0 mL), After 16 h, the reaction mixture was diluted with dichloromethane and washed with 1N HCl and brine and then dried over anhydrous MgSO4. Purification by silica gel chromatography provided 2-[(5-acetylamino-2-pyridinyl)thio]ethyl-3-chlorobenzoate (52), LCMS: purity: 99%; MS (m/e): 351 (MH+).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[CH3:21][C:22]1[C:23]([C:28]([OH:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1.[F:31][C:32]1[CH:41]=[CH:40][C:35]([C:36](OC)=[O:37])=[CH:34][CH:33]=1>C1COCC1.O>[F:31][C:32]1[CH:41]=[CH:40][C:35]([C:36](=[O:37])[CH2:21][C:22]2[C:23]([C:28]([OH:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: Cc1cccnc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C(Cc1cccnc1C(=O)O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To generate LDA: To a chilled (ice-acetone bath) solution of diisopropylamine (5.1 mL, 36 mmol) in dry THF (30 mL) was added n-BuLi (1.45 M solution in hexanes, 24 mL, 35 mmol) drop-wise and under an atmosphere of nitrogen. The solution was stirred for 15 minutes before being added to a suspension of 3-methylpyridine-2-carboxylic acid (1.5 g, 11 mmol) in THF (50 mL) drop-wise, at −78° C. and under an atmosphere of nitrogen. The dark purple mixture was stirred at −78° C. for 30 minutes and then at −5° C. for 30 minutes. After this time the mixture was re-cooled to −78° C. and a solution of methyl 4-fluorobenzoate (1.6 mL, 12 mmol) in THF (15 mL) was added. The dark brown mixture was stirred at −78° C. for 1.5 hours and then at 0° C. for 2.5 hours. The mixture was then poured into chilled water (50 mL) and washed with ethyl acetate (3×35 mL). The aqueous layer was acidified to pH 2 with HCl and extracted with ethyl acetate (3×75 mL). The three extracts were combined and concentrated in vacuo to yield 3-[2-(4-fluorophenyl)-2-oxoethyl]pyridine-2-carboxylic acid as a pale yellow solid (1.5 g, 53% yield). ESI-MI m/z [M+H]+ 259.95. 1H NMR (400 MHz, DMSO) δ 8.61 (dd, J=4.7, 1.6 Hz, 1H), 8.14 (dd, J=8.9, 5.5 Hz, 2H), 7.86 (dd, J=7.8, 1.6 Hz, 1H), 7.62 (dd, J=7.7, 4.7 Hz, 1H), 7.40 (t, J=8.9 Hz, 2H), 4.78 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:1][N:2]([CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CNc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: CN(CCN1CCOCC1)c1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
The title compound is prepared according to the general procedure outlined in Example 61, Step 2, utilizing methyl-(6-nitro-benzothiazol-2-yl)-amine (1.18 g, 5.64 mmol) and N-(2-chloroethyl)-morpholine hydrochloride (2.45 g, 13.17 mmol) to yield 1.43 g (79%) of the product. mass spectrum (ion-spray): (m/z)=323.2 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][NH:15][S:30]([CH3:29])(=[O:32])=[O:31])([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(C2CCCCC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CNS(C)(=O)=O)(C2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 92.8 %

Procedure:
A 15-mL, round-bottomed flask was purged with nitrogen and then charged with the amine from Step A (0.063 g, 0.213 mmol), 1.7 mL of methylene chloride, and triethylamine (0.045 mL, 0.320 mmol). The reaction mixture was cooled at 0° C. in an ice-water bath and then methanesulfonyl chloride (0.018 mL, 0.23 mmol) was added dropwise via syringe. The resulting mixture was stirred at 0° C. for 50 min, warmed to room temperature, and stirred for 16.5 h. The reaction mixture was then diluted with methylene chloride and washed with two portions of 1N HCl solution, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (1:1 methylene chloride-acetone) to give the desired product (0.074 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19]CC(F)(F)F)=[CH:15][CH:14]=3)[C:9](SCCC)=[N:8][C:7]=2[N:29]=1.[F:30][C:31]([F:35])([F:34])[CH2:32][OH:33].[H-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:32][C:31]([F:35])([F:34])[F:30])=[CH:15][CH:14]=3)[C:9]([O:33][CH2:32][C:31]([F:35])([F:34])[F:30])=[N:8][C:7]=2[N:29]=1
Reactant: OCC(F)(F)F
Reactant: CCCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(OCC(F)(F)F)nc2n1
Temperature: 25 °C

Procedure:
7-Methoxy-2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (350 mg) and 2,2,2-trifluoroethanol (592 μl) were dissolved in tetrahydrofuran (3 ml), and sodium hydride (60% in oil, 165 mg) was added thereto at room temperature. The reaction mixture was heated under reflux for 3 days, and allowed to be cooled to room temperature, and poured into 0.5M hydrochloric acid (10 ml). The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white solid was purified by silica gel column chromatography (ethyl acetate/hexane) and then (NH, ethyl acetate/hexane) to give the white title compound (63 mg).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)O1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]2[C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=[C:3]2[C:2]=1[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(Cl)ccn12
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
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: Cc1ccccc1
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccncc3)c(Cl)ccn12
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 20 %

Procedure:
To a suspension of 8-bromo-7-chloro-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (389 mg, 0.955 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (783 mg, 3.823 mmol) in toluene (7 mL) and 2.0 M aqueous sodium carbonate (2.1 mL) was added (Ph3P)4Pd (165 mg, 0.143 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon in a 100° C. oil bath for 2.5 h. HPLC/MS indicated that about 20% of the title compound had formed. Additional (Ph3P)4Pd (50 mg, 0.043 mmol) was added, and the reaction mixture was stirred at 100° C. under argon for 3.5 h more. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc phase was washed with water, then saturated aqueous NaCl, dried over Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel (12 g) column chromatography eluting with a gradient of EtOAc (0-100%) in hexanes to obtain the title compound as a yellow foam (169 mg). HPLC/MS: retention time=2.04 min, [M+H]+=406.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(OCC)C>C(O)C>[C:14]([CH2:15][CH2:16][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 5.5 h

Procedure:
Combine t-butyl 1-piperazinecarboxylate (10.47 g, 56.2 mmol), ethyl acrylate (8 mL) in ethanol (30 mL). Heat at reflux. After 5.5 hours, cool the reaction mixture and evaporate in vacuo to give a residue. Combine the residue and diethyl ether (200 mL) and extract with a 1M aqueous solution of hydrochloric acid. Adjust the pH of the aqueous layer to basic using sodium bicarbonate and then extract with ethyl acetate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give t-butyl 4-carboethoxyethyl-1-piperazinecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[Si](C)(C)C)=[C:9](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:10][CH3:11])=[CH:4][CH:3]=1.[Br:22]Br.C[O-].[Na+].CCOC(C)=O>C(Cl)Cl.CO>[Br:22]/[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[C:9](\[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)/[CH2:10][CH3:11]
Reactant: CC/C(=C(\c1ccc(F)cc1)[Si](C)(C)C)c1ccccc1
Reactant: BrBr
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC/C(=C(/Br)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 58.6 %

Procedure:
To a solution of (2) (3.93 g, 13.2 mmol) in CH2Cl2 (25 mL) at −78° C. was added bromine (2.5 g, 15.8 mmol) in 11 mL CH2Cl2 dropwise over 0.5 h. A solution of NaOMe (26.2 mmol) in methanol (36 mL) was added and the mixture was allowed to warm to rt. After stirring 3.5 h, EtOAc was added and the solution was washed with water, brine, and was dried (MgSO4) . The solvent was removed under reduced pressure and the resulting solid was recrystallized (methanol) to give the bromide (3) as a white solid (2.36 g, 59%): 1 H NMR (CDCl3) δ 7.33 (m, 7 H), 7.08 (m, 2 H), 2.33 (q, J=7.7 Hz, 2 H), 0.86 (t, J=7.7 Hz, 3 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([NH:19][C:20]([C:22]3([C:25]4[CH:35]=[CH:34][C:28]5[O:29][C:30]([F:33])([F:32])[O:31][C:27]=5[CH:26]=4)[CH2:24][CH2:23]3)=[O:21])[N:10]=2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[C:43](Cl)(=[O:45])[CH3:44]>CN(C=O)C>[C:43]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([NH:19][C:20]([C:22]3([C:25]4[CH:35]=[CH:34][C:28]5[O:29][C:30]([F:33])([F:32])[O:31][C:27]=5[CH:26]=4)[CH2:23][CH2:24]3)=[O:21])[N:10]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: NCc1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCc1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(1-(3-(aminomethyl)phenyl)isoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (47 mg, 0.1 mmol) and Et3N (28 μL, 0.2 mmol) in DMF (2 mL) was added acetyl chloride (7.1 μL, 0.1 mmol). The reaction was stirred at room temperature for 10 minutes, then filtered and purified by reverse-phase HPLC to yield the product, N-(1-(3-(acetamidomethyl)phenyl)isoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 515.2. found 516.5 (M+1)+. Retention time 1.97 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.43-8.40 (m, 2H), 7.98 (d, J=8.2 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.74-7.70 (m, 1H), 7.61 (d, J=1.1 Hz, 1H), 7.50-7.38 (m, 7H), 4.33 (d, J=6.0 Hz, 2H), 1.85 (s, 3H), 1.57-1.55 (m, 2H), 1.22-1.19 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O)#[CH:2].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16])#[CH:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C#Cc1ccccc1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#Cc1ccccc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.8 %

Procedure:
To a solution of 2-ethynylbenzyl alcohol (1.00 g), phthalimide (2.20 g) and triphenylphosphine (3.96 g) in tetrahydrofuran (30 mL), a solution of diisopropyl azodicarboxylate (1.9 mol/L) in toluene (7.9 mL) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, 96 to 66% hexane in ethyl acetate) to obtain 2-(2-ethynylbenzyl)isoindoline-1,3-dione (F8, 1.44 g) as pale orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]1(=O)[C:28]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH:18]=[CH:17][C:16]1=O>>[F:12][C:11]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:2]=1[N:1]=[C:26]1[C:27](=[N:8]2)[C:28]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]1=2
Reactant: O=C1C=Cc2c(ccc3ccccc23)C1=O
Reactant: Nc1c([N+](=O)[O-])cccc1C(F)(F)F
Product: FC(F)(F)c1cccc2nc3c4ccccc4c4ccccc4c3nc12
Yield: 76 %

Procedure:
When 0.034 mole each of 2-amino-3-nitrobenzotrifluoride and phenanthrenequinone were reacted by the method of Example 1, 9 g. (76 percent yield) of 10-(trifluoromethyl)dibenzo[a,c]phenazine, mp = 195°-196° C., were obtained.