Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1C=CC=CC=1.[CH3:9][C:10]([OH:19])([CH2:12][CH2:13][CH:14]=[CH:15][C:16]([CH3:18])=[CH2:17])[CH3:11].CI>O>[CH3:3][O:19][C:10]([CH3:9])([CH2:12][CH2:13][CH:14]=[CH:15][C:16]([CH3:18])=[CH2:17])[CH3:11]
Reactant: c1ccccc1
Reactant: C=C(C)C=CCCC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: C=C(C)C=CCCC(C)(C)OC

Procedure:
4.8 g (0.11 mol) of a 50% suspension of sodium hydride in paraffin oil are mixed with 120 ml of benzene in a three-necked flask provided with a thermometer, stirrer, reflux condenser and dropping funnel. 16.9 g of 2,7-dimethyl-5,7-octadien-2-ol are slowly added dropwise thereto. The reaction is completed by heating the mixture at reflux for 2 hours. 28 g (0.2 mol) of methyl iodide are then added dropwise at 30° C. After completion of the addition, the mixture is heated at reflux for 2 hours. After cooling, 50 ml of water are cautiously added. The benzene layer is separated and washed neutral with water. The solvent is distilled off and the residue fractionally distilled. There are obtained 13.7 g of 2-methoxy-2,7-dimethyl-5,7-octadiene of boiling point 72° C/3 mm Hg; nD20 = 1.4670; IR n° 24872 (s 1085 cm-1); NMR n° 23421 (3.17 ppm, 3 H, S, --O--CH3). Odor: natural, fresh, reminiscent of lavender; suitable in combination with esters.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[Si:14]([O:21][C@@H:22]1[C@@H:27]([CH3:28])[CH2:26][NH:25][CH2:24][C@H:23]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>CCO>[Si:14]([O:21][C@@H:22]1[C@@H:27]([CH3:28])[CH2:26][N:25]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:24][C@H:23]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:16])[CH3:15]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 100 °C
Yield: 80.1 %

Procedure:
To a mixture of 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (110.4 mg, 0.3780 mmol) and tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (from Example 28, Step 7, 100.0 mg, 0.2902 mmol) was added EtOH (2.0 mL) followed by DIPEA (163.8 mg, 1.267 mmol). The reaction mixture was heated at 100° C. for 15 h, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to afford the sub-title compound as a yellow solid (118.2 mg, 80%). LCMS calc. for C24H41N4O6Si (M+H)+: m/z=509.3. found 509.3.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([N:10]1[C:15](=[O:16])[CH:14]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=[N:11]1)([CH3:9])([CH3:8])[CH3:7].CN([CH:23]=[O:24])C>>[C:6]([N:10]1[C:15](=[O:16])[C:14]([CH:23]=[O:24])=[C:13]([N:17]([CH3:19])[CH3:18])[CH:12]=[N:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CN(C)c1cnn(C(C)(C)C)c(=O)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1cnn(C(C)(C)C)c(=O)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (6.5 g) was added dropwise to DMF (15 ml) with ice-cooling and the mixture was stirred at room temperature for 30 minutes. Then, 2-t-butyl-5-dimethylamino-3(2H)-pyridazinone (3.3 g)/DMF (40 ml) was added dropwise with ice-cooling and the mixture was stirred at 70° C. for 1 hour. This reaction mixture was poured gradually into ice-NaHCO3 /water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated to dryness. The residue was washed with n-hexane and dried. Yellow powder, 3.7 g. 1H-NMR (CDCl3) δ: 1.63(9H,s), 3.10(6H,s), 7.71(1H,s), 10.27(1H,s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)O>[OH-].[Na+].O>[CH2:15]([O:14][C:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])=[O:13])[CH3:16]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Oc1cccc(C(=O)O)c1
Temperature: 25 °C

Procedure:
3-Hydroxybenzoic acid (13.8 g) was dissolved in a solution of sodium hydroxide (8 g) in water (50 ml) and stirred at 0°-5° with cooling while ethyl chloroformate was added dropwise. When addition was complete the solution was warmed to room temperature and stirred for 2 hours. The solution was acidified with 2 molar sulphuric acid. The white solid which separated was washed with water. The solid was taken up in chloroform and the solution dried (MgSO4) and evaporated to give 3-ethoxycarbonyloxybenzoic acid (14 g) with a melting point of 70°-72°.
Reaction SMILES: [SH:1][C:2](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[SH:3].[Na].[Na].Cl[C:12]1[C:17](Cl)=[N:16][C:15]([C:19]#[N:20])=[C:14]([C:21]#[N:22])[N:13]=1.O>CN(C)C=O>[C:5]([C:4]([C:7]#[N:8])=[C:2]1[S:3][C:12]2=[N:13][C:14]([C:21]#[N:22])=[C:15]([C:19]#[N:20])[N:16]=[C:17]2[S:1]1)#[N:6]
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: N#CC(C#N)=C(S)S
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)=C1Sc2nc(C#N)c(C#N)nc2S1
Temperature: 40 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a stirred solution of 9.3 g (0.05 mol) of disodium dimercaptomethylenemalononitrile in 100 ml of dimethylformamide was gradually added 10 g (0.05 mol) of 2,3-dichloro-5,6-dicyanopyrazine in 70 ml of dimethylformamide. The reaction mixture was stirred at 40° C for 8 hours and poured into 700 ml of water. The resulting solid was collected by suction filtration, washed with water, and dried. The crude product was dissolved in acetone-CHCl3, decolorized with charcoal and dried over MgSO4. Recrystallization from CHCl3 yields 5.0 g (37%) of yellow crystals. M.p. ~280° C (dec.). νCN (cm31 1): 2220.
Reaction SMILES: FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[Br:22]Br.O>C(Cl)Cl>[CH2:20]([O:19][C:13](=[O:18])[CH:14]([Br:22])[C:15](=[O:16])[CH3:17])[CH3:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrBr
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(Br)C(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
At −5° C. trimethylsilyl trifluoromethanesulfonate (36.9 mmol) is added dropwise to a solution of ethyl acetoacetate (30.7 mmol) and TEA (36.9 mmol) in DCM (50 mL). The solution is stirred for 90 min at 0° C. and treated over 30 min with a solution of bromine (30.7 mmol) in DCM (20 mL). After 60 min water (100 mL) is added, the layers are separated and the aq. layer is extracted three times with water (100 mL each). The organic layer is dried over MgSO4 and concentrated under reduced pressure to give the desired product which is used without further purification. 1H-NMR (CDCl3): δ=1.34 (t, J=7.16 Hz, 3H); 2.46 (s, 3H); 4.31 (q, J=7.20 Hz, 2H); 4.77 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:17])[C:11](=[C:14]([Cl:16])[CH:15]=1)[CH:12]=[O:13].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Cl:16][C:14]1[CH:15]=[C:8]([Cl:7])[CH:9]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]=1[CH:12]=[O:13]
Reactant: BrCc1ccccc1
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(Cl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Potassium carbonate (9.4 g, 67.8 mmole) was added to a stirred solution of 4,6-dichlorosalicylaldehyde (10.8 g, 56.5 mmole) in dimethylformamide (80 ml). The resulting mixture was stirred at 60° for 30 minutes and treated with benzyl bromide (10.6 g, 62.1 mmole). This mixture was stirred one hour at 60° C. and then poured into ice water (1000 ml) to give the title compound (15.9 g, 100%) which melted at 98°-100° C. after recrystallization from hexane. pmr (CDCl3) δ5.10 (2H, s), 7.33 (5H, s), 10.40 (H, s).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[NH2:5][C:6]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:7]([C:9]#[N:10])C>C1(C)C=CC=CC=1>[NH2:5]/[C:6](/[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:7](/[C:9]#[N:10])\[C:1]([Cl:4])=[O:2]
Reactant: CCC(CC)C(N)=C(C)C#N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCC(CC)/C(N)=C(\C#N)C(=O)Cl
Temperature: 25 °C

Procedure:
250 ml toluene were cooled to 0° C. and 40 g (0.4 mol) of phosgene were added. After warming up to 25° C., 13.8 g (0.1 mol) of 3-amino-2-cyano-4-ethyl-2-hexene in toluene were added. The reaction mixture was heated at 70° C. for 4 h, then the unreacted phosgene was removed by blowing out with dry N2. After cooling to 25° C. the product precipitated. Filtration and washing with diethyl ether gave 12 g (60% of theory) of the title compound as a yellow solid (m. p. 102° C.).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:61][C:62]1[O:66][CH:65]=[CH:64][CH:63]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:61][C:62]3[O:66][CH:65]=[CH:64][CH:63]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: N=C(OCc1ccco1)C(Cl)(Cl)Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4ccco4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (63 mg in 1.0 ml methylene chloride) furfuryl trichloroacetimidate (39 μl neat) was added and the reagents allowed to mix for 5 minutes. Camphorsulfonic acid (3.7mg) was added and the mixture stirred at room temperature. After 4.5 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (20 mg). MAS: (FAB) 878 (M+Li). Partial 1H NMR δ: 7.38(brs, 1 H); 6.30(m, 3 H); 5.32 M, 5.19 m(brd J=3 Hz, 1 H); 4.83 m, 4.21 M(brs, 1H); 4.62(dd J=15 Hz, 2 H); 4.41(brd J=14 Hz, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[OH-:18].[K+]>C(O)(C)(C)C>[N+:15]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)=[CH:7][C:2]=1[OH:18])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(OCc2ccsc2)cc1F
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1ccc(OCc2ccsc2)cc1O

Procedure:
A mixture of 2-fluoro-4-(3-thienylmethoxy)nitrobenzene (4.21 g), aqueous potassium hydroxide solution (50 mL; 50% w/v) and t-butanol (20 mL) is heated at reflux for 4 hours. It is then evaporated to dryness and the residue is partitioned between ethyl acetate (100 mL) and hydrochloric acid (100 mL; 1 N). The organic phase is washed with water (3×100 mL), dried over magnesium sulphate, filtered and evaporated, to give 2-nitro-5-(3-thienylmethoxy)phenol, in the form of a yellow solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15]([NH:17][C:18]2[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])=[O:23])=[CH:20][C:19]=2[O:50][CH3:51])=[O:16])[NH:7]1)=O)C.[NH3:52].CO>>[C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15]([NH:17][C:18]2[CH:49]=[CH:48][C:21]([C:22]([N:24]([CH3:47])[C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=3[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]3)=[O:39])=[O:23])=[CH:20][C:19]=2[O:50][CH3:51])=[O:16])[NH:7]1)(=[O:3])[NH2:52]
Reactant: N
Reactant: CCOC(=O)C1Cc2c(cccc2C(=O)Nc2ccc(C(=O)N(C)c3ccc(C)cc3OCCCCCC(=O)N3CCN(C)CC3)cc2OC)N1
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2c1CC(C(N)=O)N2

Procedure:
The solution of 4-[(2-ethoxycarbonylindolin-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (175 mg) in ammonia-methanol solution (8.0 ml) was stood overnight at ambient temperature. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent; 8-10% methanol in chloroform) to give 4-[(2-carbamoylindolin-4-yl)carbonyl]amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (160 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(=O)(=O)(O)O.O.C(=O)(O)[O-].[Na+].[CH3:23][CH2:24]O>CCOCC>[CH2:23]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([OH:11])[CH:4]=1)[CH3:24]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc(F)c(O)c1

Procedure:
A solution of 4-fluoro-3-hydroxy-benzoic acid (32.0 mmol) in EtOH (120 mL) is treated with conc. sulfuric acid (25.7 mL) and heated to reflux for 16 h. Water (600 mL), sodium bicarbonate (100 g) and ether (300 mL) are added successively, the layers are separated and the aq. layer is extracted twice with ether. The combined organic layers are washed twice with brine, dried over MgSO4 and concentrated in vacuo to give the desired product which is used without further purification. 1H-NMR (DMSO-d6): δ=7.75 (d, J=8.5 Hz, 1H); 7.58-7.63 (m, 1H); 7.12 (t, J=9.3 Hz, 1H); 6.21 (bs, 1H); 4.39 (q, J=7.0 Hz, 2H); 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6](Cl)[C:5]=1[N+:18]([O-:20])=[O:19].[CH3:22][OH:23].C[O-].[Na+].[Na+].[Cl-]>O>[CH3:1][N:2]([CH3:21])[NH:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6]([O:23][CH3:22])[C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reactant: CO
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COc1c(C(F)(F)F)cc([N+](=O)[O-])c(NN(C)C)c1[N+](=O)[O-]

Procedure:
To a stirred solution of 5.0 g. (0.015 mole) of N-(dimethylamino)-3-chloro-2,6-dinitro-4-trifluoromethylaniline and 50 ml. of anhydrous methanol was added 3.77 g. (0.015 mole) of a 21.8% methanolic sodium methoxide solution. The resultant mixture was stirred at room temperature for 6 hours and was then refluxed overnight for 16 hours. The methanol was then evapaorated under vacuum leaving a yellow-solid residue. To the residue was added 150 ml. of water and the mixture stirred for 30 minutes to dissolve the NaCl and any other water-soluble materials. The mixture was then filtered and the water-insoluble solids were washed well with water. The solids were then dissolved in 30 ml. of refluxing 95% ethanol. On cooling, the product crystallized and was isolated by filtration to give 3.83 g. (77.7%) of a yellow crystalline solid; m.p. 109° - 110.5° C. After recrystallization from 95% ethanol, the product melts at 110° - 111.5° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([NH2:11])=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[Br:40][CH2:41][C:42]1[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=1[C:44](Cl)=[O:45]>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([NH:11][C:44](=[O:45])[C:43]3[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=3[CH2:41][Br:40])=[CH:9][N:8]([C:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: O=C(Cl)c1ccccc1CBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12)c1ccccc1CBr
Reaction time: 8 h
Yield: 33.7 %

Procedure:
2-bromo-5-trityl-pyrrolo[2,3-b]pyrazin-7-amine (3 g, 6.588 mmol) dissolved in THF (30 mL) under N2 at rt. DIPEA (5.7 mL, 32.9 mmol) added followed by a solution of 2-(bromomethyl)benzoyl chloride (1.9 g, 8.137 mmol) in THF (10 mL). Reaction mixture stirred overnight then partitioned between EtOAc and water. Aqueous phase extracted with EtOAc. Combined organics washed with saturated NaHCO3 solution then brine, dried and concentrated. Residue taken up in DCM and purified by chromatography (0-40% EtOAc-petroleum ether gradient). Further purification by chromatography (isocratic DCM elution) gives the title compound as a yellow foam (1.45 g, 34%); 1H NMR (400 MHz, DMSO) δ 4.93 (2H, s), 7.21-7.38 (15H, m), 7.44-7.61 (3H, m), 7.62 (1H, d), 8.19 (1H, s), 8.59 (1H, s), 10.93 (1H, s) ppm; MS (ES+) 653.0.
Reaction SMILES: [OH:1][CH:2]([C:7]([O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+].O>O1CCOCC1>[OH:1][CH:2]([C:7]([O:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=1)[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)[C:3]([OH:5])=[O:4]
Reactant: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccc(C(OCCc2ccc(OC)c(OC)c2)(c2ccc(CC)cc2)C(O)C(=O)O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
9.2 g (19.3 mmol) of methyl 2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di(4-ethylphenyl)propionate were dissolved in 26 ml of dioxane, and 13 ml of 3 N NaOH solution were added. The mixture was stirred at 60° C. for 3 hours. Water was added to the mixture, and the aqueous phase was extracted twice with ether. The aqueous phase was acidified with 1 N aqueous HCl and extracted with ether, the organic phase was dried over magnesium sulfate, and the solvent was distilled off. 6.5 g (71%) of a yellowish oil were isolated and were immediately reacted further.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]CC.[Na+].O.[N+:12]([CH3:15])([O-:14])=[O:13]>C(O)C>[N+:12]([CH2:15][C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:14])=[O:13]
Reactant: O=C1CCCC1
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])CC1(O)CCCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of cyclopentanone (40.0 mL, 452 mmol) in nitromethane (36 mL) and ethanol (14 mL) was added a solution of sodium ethoxide in ethanol (2.67 M, 8.5 mL, 23 mmol). The solution was stirred for five days at room temperature. Water (400 mL) was added, and the mixture was extracted with ethyl acetate (2×350 mL). The combined organic extracts were washed with water (2×200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The starting materials and solvent were removed from the product by distillation under reduced pressure to yield 8.3 g of 1-(nitromethyl)cyclopentanol as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>O>[CH2:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Fc1ccc(NCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
A solution of 4-fluoroaniline (4.7 ml, 50 mmol), benzaldehyde (5.3 g, 50 mmol) and one crystal p-toluene-sulfonic acid is refluxed using a Dean-Stark® apparatus until no more water is collected and the mixture is concentrated in vacuo. The crude product is dissolved in 100 ml 96% ethanol and added sodium borohydride (4.0 g, 100 mmol) and stirred for 1 hour. Most of the ethanol is removed in vacuo and the residue is taken up in water and 15 g of potassium hydroxide in 50 ml water is added, causing the amine to crystallize. The product is recrystallized from methanol/water (in a ratio of 4 to 1) yielding the title compound as white crystals. Mp 38°-39° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[C:11](=O)(OC(Cl)(Cl)Cl)[O:12]C(Cl)(Cl)Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([F:10])[C:3]=1[N:4]=[C:11]=[O:12]
Reactant: Nc1c(F)cc(Cl)cc1Br
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C=Nc1c(F)cc(Cl)cc1Br
Temperature: 100 °C

Procedure:
2-Bromo-4-chloro-6-fluoroaniline (5 mmol, 1.125 g), bis(trichloromethyl) carbonate (1.7 mmol, 0.50 g) and 1,4-dioxane (10 ml) were mixed together and the mixture was heated to 100° C. for 15 minutes; the mixture was then cooled to room temperature and it was filtered. The filtrate was concentrated to afford a mixture of products (2.2 g) containing the title compound, M++MeO=283 (LC-MS run in methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][NH2:10].[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O>>[CH2:17]([O:16][C:11](=[O:15])[C:12](=[N:10][NH:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:14])[CH3:18]
Reactant: Cc1ccc(F)c(NN)c1
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)C(C)=NNc1cc(C)ccc1F

Procedure:
The title compoundwas prepared in accordance with the general method of example 25b) from (2-fluoro-5-methyl-phenyl)-hydrazine and ethyl pyruvate.
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[C:33]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34].C(OCC)(=O)C.Cl>CN(C=O)C>[C:33]([C:37]1[CH:38]=[CH:39][C:40]([N:41]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH:6]2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:42][CH:43]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(N2C(c3ccc([N+](=O)[O-])cc3)CCC2c2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.17 h

Procedure:
The product from Example 1C (3.67 g, 7.51 mmol) and 4-tert-butylaniline (11.86 ml, 75 mmol) in DMF (40 ml) was stirred under nitrogen at 50° C. for 4 h. The resulting mixture was diluted into ethyl acetate, treated with 1M HCl, stirred for 10 minutes and filtered to remove solids. The filtrate organic layer was washed twice with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (5% to 30%) to give a solid. The solid was triturated in a minimal volume of 1:9 ethyl acetate/hexane to give a light yellow solid as a mixture of trans and cis isomers (1.21 g, 36%).