Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](OC(C)=O)=[O:3].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[NH:15]1[CH2:18][CH:17]([NH:19][C:20]2[C:21]([CH3:40])=[N:22][C:23]3[C:28]([N:29]=2)=[C:27]([C:30]2[NH:38][C:37]4[CH2:36][CH2:35][NH:34][C:33](=[O:39])[C:32]=4[CH:31]=2)[CH:26]=[CH:25][CH:24]=3)[CH2:16]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:2]([N:15]1[CH2:16][CH:17]([NH:19][C:20]2[C:21]([CH3:40])=[N:22][C:23]3[C:28]([N:29]=2)=[C:27]([C:30]2[NH:38][C:37]4[CH2:36][CH2:35][NH:34][C:33](=[O:39])[C:32]=4[CH:31]=2)[CH:26]=[CH:25][CH:24]=3)[CH2:18]1)(=[O:3])[CH3:1]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CNC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CC(Nc2nc3c(-c4cc5c([nH]4)CCNC5=O)cccc3nc2C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
Ac2O (4.49 μl, 0.048 mmol) was added to a mixture of 2-(3-(azetidin-3-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (20.0 mg, 0.043 mmol) and DIPEA (0.023 mL, 0.130 mmol) in DCM (1.0 mL), and the resulting yellow suspension was stirred at 25° C. for 10 min. The mixture was concentrated in vacuo, and the residue was taken up in in DMSO (2.0 mL) and purified by reversed-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) to provide 2-(3-((1-acetylazetidin-3-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (19.0 mg, 0.038 mmol, 87% yield) as a red solid: 1H NMR (400 MHz, MeOH-d4) δ ppm 7.86 (1H, d, J=7.4 Hz), 7.66 (1H, d, J=7.4 Hz), 7.44 (1H, t, J=7.8 Hz), 7.18 (1H, s), 4.89-4.97 (1H, m), 4.69 (1H, t, J=8.3 Hz), 4.46 (1H, dd, J=9.9, 8.1 Hz), 4.23 (1H, dd, J=9.2, 5.1 Hz), 4.05 (1H, dd, J=10.4, 5.1 Hz), 3.64 (2H, t, J=7.1 Hz), 3.04 (2H, t, J=7.0 Hz), 2.66 (3H, s), 1.91 (3H, s). 19F NMR (376 MHz, MeOH-d4) δ ppm −77.73 (3F, s). m/z (ESI, +ve) 391.1 (M+H)+.
Reaction SMILES: [Pb](Br)Br.[Al].[CH3:5][O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:8]=1[CH:9]=[O:10].Cl.[C:20](Cl)([Cl:23])([Cl:22])[Cl:21]>CN(C)C=O>[OH:10][CH:9]([C:8]1[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:7]=1[O:6][CH3:5])[C:20]([Cl:23])([Cl:22])[Cl:21]
Reactant: COc1cc(OC)c(OC)cc1C=O
Reactant: ClC(Cl)(Cl)Cl
Agent: Br[Pb]Br
Agent: Cl
Agent: [Al]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(O)C(Cl)(Cl)Cl)cc1OC
Reaction time: 1 h
Yield: 79 %

Procedure:
In 50 ml of dimethylformamide, 0.37 g of lead bromide, 0.41 g of aluminum foil and 1.96 g of 2,4,5-trimethoxybenzaldehyde were added, followed by the addition of 1.9 ml of carbon tetrachloride at room temperature. The resulting mixture was stirred for one hour. After the completion of the reaction, 2N hydrochloric acid was added to the reaction mixture under ice cooling, followed by extraction with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium bicarbonate, water and saturated saline, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the crude product so obtained was washed with methanol, whereby 2.49 g of 1-(1-hydroxy-2,2,2-trichloroethyl)-2,4,5-trimethoxybenzene were obtained (yield: 79%). The physical properties of the product were equal to those of the product obtained in Referential Example 2.
Reaction SMILES: FC(C(F)(F)F)(C(F)(F)F)C[CH:4]([CH2:12][C:13](F)([C:18](F)(F)F)[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9].[CH2:31]([CH2:33][NH2:34])[OH:32]>ClCCl>[OH:32][CH2:31][CH2:33][NH:34][S:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:12][CH:13]([C:14]([F:15])([F:16])[F:17])[CH3:18])(=[O:9])=[O:10]
Reactant: NCCO
Reactant: O=S(=O)(Cl)CCCC(CC(F)(C(F)(F)F)C(F)(F)F)CC(F)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(CCCCCS(=O)(=O)NCCO)C(F)(F)F
Temperature: 25 °C
Yield: 35.7 %

Procedure:
Referring to scheme (42) above, a solution of the 6,7,7,7-tetrafluoro-4-(2,3,3,3-tetrafluoro-2-trifluoromethyl-propyl)-6-trifluoromethyl heptane-1-sulfonyl chloride (25 grams), described above, in 125 mL dichloromethane can be added to a cooled solution (0° C.-5° C.) of ethanolamine (17.6 grams) in dichloromethane (125 mL) drop-wise to form a mixture. The mixture can be agitated, allowed to warm to room temperature, and diluted with dichloromethane (250 mL). The diluted mixture can be washed with deionized water (250 mL). 5% (wt/wt) HCl (250 mL), and saturated bicarbonate solution (250 mL). The organic layer can be separated, dried over sodium sulfate, filtered, and concentrated under vacuum to afford 6,7,7,7-tetrafluoro-4-(2,3,3,3-tetrafluoro-2-trifluoromethyl-propyl)-propyl)-6-trifluoromethyl-heptane-1-sulfonic acid (2-hydroxy-ethyl)-amide (5.0 grams) with residual dichloromethane and ethanolamine by NMR analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([C:16]([NH:18][CH:19]3[CH2:21][CH2:20]3)=[O:17])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>ClCCl>[CH:19]1([NH:18][C:16]([C:11]2[N:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:25])[CH2:23][CH3:24])=[CH:3][CH:4]=3)[C:12]=2[CH2:13][CH2:14][CH3:15])=[O:17])[CH2:20][CH2:21]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(N)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CC)cc1
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 1-(4-aminophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.29 g) obtained in Example 1d) in dichloromethane (10 ml) was added propionyl chloride (0.09 ml) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/4 to 1/1) to give the title compound as a white powder (0.11 g, 31%).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(N(C(C)C)CC)(C)C.[O:43]1[C:45]([CH3:47])([CH3:46])[CH2:44]1>CO>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:44][C:45]([CH3:47])([OH:43])[CH3:46])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: CC1(C)CO1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(C)(C)O)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
To a mixture of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (250 mg, 0.52 mmol) in MeOH (3 mL) was added diisopropylethylamine (110 μL, 0.62 mmol) followed by 1,2-epoxy-2-methylpropane (230 μL, 2.6 mmol) and the reaction mixture was stirred at RT for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (SiO2, 0-7.5% MeOH in DCM) to give a solid that was recrystallised from heptane to give 421 (87 mg, 38%). LCMS: RT=7.41 min, [M+H]+=440. 1H NMR δ (ppm) (DMSO-d6): 8.26 (1H, d, J=8.17 Hz), 8.06 (1H, d, J=0.59 Hz), 7.16 (1H, dd, J=8.23, 1.81 Hz), 7.00 (1H, d, J=1.76 Hz), 5.83-5.75 (1H, m), 4.32 (2H, t, J=5.03 Hz), 4.00 (1H, s), 3.65 (2H, t, J=6.98 Hz), 3.61-3.51 (1H, m), 3.39 (2H, t, J=5.08 Hz), 3.14 (2H, t, J=6.52 Hz), 2.32 (2H, s), 1.51 (6H, d, J=6.59 Hz), 1.03 (6H, s)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28](Cl)=[O:29].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[C:27]=1[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:29]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1cccc(C)c1C(=O)Cl
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: Cc1cccc(C)c1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 28.1 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 2,6-dimethylbenzoyl chloride (0.143 mmol), the title compound (12 mg, yield 18%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>ClCCl>[CH:1]1([NH:5][S:22]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=2)(=[O:23])=[O:24])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NC2CCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a stirred solution of cyclobutylamine (4.3 g, 59.7 mmol) and triethylamine (11.2 mL, 79.6 mmol) in dichloromethane (300 mL) was added the solution of 4-nitro-benzenesulfonyl chloride (8.8 g, 39.8 mmol) in dichloromethane (50 mL) at 0° C. The mixture solution was stirred at room temperature for 4 h and then washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford N-cyclobutyl-4-nitro-benzenesulfonamide (9.4 g, 92.5%) as a white powder: MS (ESI) M+1=257.1.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([Cl:11])=[C:9]([C:12]([N:14]3[CH2:17][CH:16]([N:18]4[CH2:23][CH2:22][N:21](C(=O)C(F)(F)F)[CH2:20][CH2:19]4)[CH2:15]3)=[O:13])[S:8][C:7]=2[CH:30]=1>CCN(CC)CC.CO>[Cl:11][C:10]1[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:30][C:7]=2[S:8][C:9]=1[C:12]([N:14]1[CH2:17][CH:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:15]1)=[O:13]
Reactant: O=C(c1sc2cc(C(F)(F)F)ccc2c1Cl)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(c1sc2cc(C(F)(F)F)ccc2c1Cl)N1CC(N2CCNCC2)C1

Procedure:
A solution of compound 1c (0.30 g, 0.60 mmol) in Et3N (1 mL) and MeOH (9 mL) was stirred at room temperature for 3 days. It was then concentrated to give compound 1d, which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[CH3:21][C:22]1[C:23]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=3)[CH:2]2[CH3:1])=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]
Reactant: COc1ccc2c(c1)CCNC2C
Reactant: Cc1nc(Cl)nc(Cl)c1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(c1nc(Cl)nc(C)c1C)C2C
Temperature: 85 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
After 1-methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline(1.3 g, 7.3 mmol) and triethylamine(1.0 ml, 7.3 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine(1.2 g, 6.64 mmol) in dimethylformamide, the reaction mixture was stirred for 3 hours at 85° C. The reaction mixture was cooled to a room temperature and diluted with ethyl acetate. The organic layer was washed with water and aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, concentrated under a reduced pressure, and then purified by a silica gel column chromatography to give 1.7 g of the titled compound. (Yield: 78.5%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[C:18](Cl)(=O)[CH3:19]>C1(C)C=CC=CC=1>[CH3:18][C:19]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1cc(C(=O)O)ccc1Nc1ccccc1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1nc2cc(C(=O)O)ccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.7 %

Procedure:
A 2-neck flask was charged with 3-amino-4-phenylaminobenzoic acid (see Synthesis Example 1-2) (1.40 g, 6.35 mmol) and anhydrous toluene (15 mL) and this was refluxed. To this was added dropwise over approx. 15 minutes acetyl chloride (1.00 g, 12.70 mmol) in toluene solution (approx. 2.5 mL), and this was stirred under these conditions for 2.5 hours. This was allowed to cool to room temperature, and was extracted with dilute aqueous sodium hydroxide solution (10%, 200 mL). After separating the dark orange aqueous layer, it was cooled in ice (5 to 10° C.), and concentrated hydrochloric acid (12 M) was added to the liquid to give approx. pH 4. The precipitated crystals were filtered off, washed with distilled water, and dried under reduced pressure with heating to yield the title compound (1.34 g, 83.5% yield) as a light purple solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCCC1
Product: O=C(O)C1(c2ccc(Cl)c([N+](=O)[O-])c2)CCCCC1

Procedure:
Prepared analogously to Example 1b from 1-(4-chlorophenyl)-cyclohexanecarboxylic acid and fuming nitric acid at −25° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]3[N:21]=[N:22][NH:23][N:24]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[CH:10]1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]3[N:21]=[N:22][N:23]([CH3:27])[N:24]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[CH:10]1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccccc1Cn1cnc(-c2cc(-c3nn[nH]n3)ccn2)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nnc(-c2ccnc(-c3cn(Cc4ccccc4Cl)cn3)c2)n1
Yield: 95 %

Procedure:
The title compound was prepared in 95% yield from 2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (Example 129), MeI and potassium carbonate in DMF. 1H NMR (400 MHz, DMSO): δ 4.49 (3H, s), 5.41 (2H, s), 7.27-7.30 (1H, m), 7.38-7.40 (2H, m), 7.52-7.55 (1H, m), 7.79 (1H, d, J=5.2 Hz), 7.84 (1H, s), 7.96 (1H, s), 8.50 (1H, s), 8.67 (1H, d, J=5.1 Hz). [M+H] Calc'd for C17H14ClN7, 352. Found, 352.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[CH2:18]([O:20][C:21](=[O:30])[C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[C:23](O)=[O:24])[CH3:19].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH2:18]([O:20][C:21](=[O:30])[C:22]([OH:29])([C:23](=[O:24])[NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)[CH2:26][CH2:27][CH3:28])[CH3:19]
Reactant: CCCC(O)(C(=O)O)C(=O)OCC
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCCC(O)(C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21)C(=O)OCC
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A solution of 500 mg (2 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one and 466 mg (2 mmol) (RS)-2-hydroxy-2-propyl-malonic acid monoethyl ester in 40 ml tetrahydrofuran were cooled to 0° C. and 331 mg (2 mmol) 1-hydroxy-benzotriazole hydrate, 830 μl (5 mmol) diisopropylethylamine and 470 mg (2 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 90/10 to 50/50) yielded 630 mg (71%) (R/S)-2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid ethyl ester as a colorless foam, MS (m/e): 397.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCOCC.[H-].C([Al+]CC(C)C)C(C)C>O>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH:17]=2)=[C:12]([OH:23])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1ccc(C2=CC(=O)CCC2)c(O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc(C2=CC(O)CCC2)c(O)c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a -30° C. solution of 1.00 g. (3.18 mmole) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-cyclohexenone in 60 ml. of ether was added dropwise 6.3 ml. of a 1 M (in toluene) diisobutylaluminum hydride solution. The reaction was stirred 30 min. longer at -30° C. and then added to 1.5 1. water. The quenched solution was extracted with three 400 ml. portions of ether and the combined extracts washed twice with 125 ml. of saturated sodium chloride and dried over magnesium sulfate. After evaporation the crude product was purified via column chromatography on 50 g. of florial eluted with ether to yield an oil. Crystallization of the oil from pentane gave 256 mg. (25%) of the title product.
Reaction SMILES: C[C:2]1[S:6][C:5]([C:7](O)=O)=[CH:4][CH:3]=1.I[CH2:11][CH3:12].[C:13](=O)([O-:15])[O-:14].[K+].[K+].O>CN(C)C=O>[CH2:11]([O:15][C:13]([C:4]1[CH:3]=[CH:2][S:6][C:5]=1[CH3:7])=[O:14])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CCI
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccsc1C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-Methyl-2-thiophenecarboxylic acid (2.84 g) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (1.68 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3-thiophenecarboxylic acid ethyl ester (1.84 g). 5-Methyl-2-thiophenecarboxylic acid ethyl ester (1.84 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.31 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred for 1.5 hour over a water bath, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g). 4-Chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g) was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (16 ml) was added. The mixture was stirred at 60° C. for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid (0.98 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[N:7]=1.Cl.[NH2:10][C:11]([CH3:21])([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[O:13].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl.O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([NH:10][C:11]([CH3:21])([CH3:20])[C:12]([NH:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[O:13])[N:7]=1
Reactant: CC(C)(N)C(=O)NCC(F)(F)F
Reactant: Clc1cnnc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Nc1cnnc(Cl)n1)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a Dioxane (12.0 ml) solution of 3,5-dichloro-1,2,4-triazine I-15a (846 mg, 5.64 mmol) was added 2-amino-2-methyl-N-(2,2,2-trifluoroethyl) propanamide hydrochloride (1,242 mg, 5.64 mmol) followed by diisopropylethylamine (2.96 ml, 16.92 mmol). Dichloromethane (2 mL) was added and the reaction stirred for 2 hours at room temp. The reaction was diluted with dichloromethane and poured into saturated sodium bicarbonate. A precipitate formed. The solid was filtered washed with dichloromethane and then dried under reduced pressure to afford the product I-15 (1.02 g, 60.3%). LRMS (ESI) m/z 297.9 [(M+H)+; calcd for: C9H11ClF3N5O: 298.1].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(F)c(N)cc23)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A mixture of N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine (310 mg, 1 mmol) and SnCl2.2H2O (171 mg, 4.5 mmol) in ethyl acetate (35 mL) was refluxed for 2 h. After cooled to room temperature, the mixture was treated with 5% aqueous NaHCO3 to adjust its pH to 9-10, and then subjected to extraction with EtOAc. The organic layers were washed with saturated brine and H2O and dried. The solvent was removed under reduced pressure to give 225 mg (81%) N4-(3-ethynylphenyl)-7-fluoroquinazoline-4,6-diamine as a yellow solid.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)[C@H:10]1[CH2:27][CH3:28])(C(C)(C)C)(C)C.C(O)C.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:27]([C@H:10]1[C@H:9]([OH:8])[CH2:13][C:12](=[O:14])[N:11]1[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:24])[F:25])[CH:16]=1)[CH3:28]
Reactant: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.2 %

Procedure:
To a solution of 4-[(2S,3R)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (1.32 g) in tetrahydrofuran (30 mL)-ethanol (15 mL) was added 6 mol/L hydrochloric acid (15 ML), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=6/1→1/9) to give the title compound as a colorless solid (yield: 507.3 mg, 53%).