Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)[CH:8]=2)[C:3](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:2]1.Cl.CN(C)[CH2:23][CH2:24][CH2:25][N:26]=[C:27]=NCC.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[O:19]=[C:17]([N:26]1[CH2:25][CH2:24][CH2:23][CH2:27]1)/[CH:16]=[CH:15]/[C:3]1[C:4]2[C:9](=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:14])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: C1CCNC1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)/C=C/c1ccc2c(/C=C/C(=O)O)c[nH]c2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc2c(/C=C/C(=O)N3CCCC3)c[nH]c2c1)N1CCCC1
Yield: 69.4 %

Procedure:
A mixture of E,E-indole-3,6-diacrylic acid (1 g), 4-dimethylaminopyridine (1.19 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.86 g) and pyrrolidine (0.69 g) was dissolved in N,N-dimethylformamide (35 ml), and stirred under an atmosphere of nitrogen. Additional portions (10% by weight) of each of the reagents were added at the end of each 24 hour period (five times) until TLC monitoring indicated completion of the reaction after 6 days. The mixture was added slowly to vigorously-stirred 2M hydrochloric acid (100 ml); the precipitate was isolated by filtration, washed with water and dried under vacuum to give E,E-3,6-di(3-oxo-3-pyrrolidino-1-propenyl)indole (0.98 g, 69%) as a yellow powder; mp 268°-270° C.; partial NMR (250 MHz, DMSO-d6): 1.70°-2.02 (m, 8H, pyrrolidino H), 3.41(m, 4H, pyrrolidino H), 3.66(m, 4H, pyrrolidino H); 6.75(d, J=15.6 Hz, 1H, olefinic H); 6.94(d, J=15.5 Hz, 1H, olefinic H); 11.76(br s, 1H, NH-indole).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:6][CH2:5]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C.[Pd]>[CH2:14]([NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([O:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COCOC1CCN(CCN)CC1
Reactant: O=Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCOC1CCN(CCNCc2ccccc2)CC1
Reaction time: 24 h
Yield: 64.8 %

Procedure:
27 g of 1-(2-aminoethyl)-4-methoxymethoxypiperidine was dropwise added to a solution of 15 g of benzaldehyde in 300 ml of ethanol, at room temperature. The mixture was stirred at the same temperature for 1 day. To the reaction mixture was added 5 g of 10% Pd-C, and the resulting mixture was allowed to absorb hydrogen at room temperature at atmospheric pressure. After a reaction was over, the catalyst was removed by filtration. The filtrate was diluted with ethyl acetate. The dilution was subjected to extraction with 10% hydrochloric acid. The aqueous layer was made alkaline with an aqueous potassium hydroxide solution and then subjected to extraction with ethyl acetate. The extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: 10% methanol-chloroform) to obtain 25.50 g of 1-(2-benzylaminoethyl)-4-methoxymethoxypiperidine.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]1([CH2:29][CH2:28][N:5]2[CH2:6][CH2:7][N:2]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[N:9]=3)[CH2:3][CH2:4]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-n2nc(N3CCN(CCc4ccccc4)CC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A stirred mixture of 4.0 g of 3-(1-piperazinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazole hydrochloride, 2.4 g of (2-bromoethyl)benzene, 1.8 g of potassium carbonate and 60 ml of dimethylformamide was heated, under nitrogen, at 70°-75° for 8 hours, and then stirred at ambient temperature for 8 hours. The reaction mixture was poured into water, and the aqueous mixture extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was chromatographed on a Water's Model High Pressure Liquid Chromatograph utilizing silica columns and eluting with hexane/ethyl acetate (30%). Concentration of the appropriate fractions gave 4.3 g of 3-[4-(2-phenylethyl)-1-piperazinyl]-1-[4-(trifluoromethyl)phenyl]-1H-indazole. The free base was dissolved in diethyl ether and treated with hydrogen chloride to precipitate the corresponding hydrochloride salt. Recrystallization from ethanol/diethyl ether gave 3.1 g of 3-[4-(2-phenylethyl)-1-piperazinyl]-1-[ 4-(trifluoromethyl) phenyl]-1H-indazole hydrochloride, mp 255°-257°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](B2OC(C)(C)C(C)(C)O2)=[N:22]1>>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH2:13][CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[N:3]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: Cn1ncc2c(NCCN3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: Cn1ncc2c(NCCN3CCOCC3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-morpholin-4-yl-ethyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification on silica yielded 155. NMR (CDCl3) 2.50 (m, 4H, 2×CH2), 2.70 (t, 2H, CH2, J=5.95 Hz), 3.71 (m, 4H, 2×CH2), 3.80 (m, 2H, CH2), 4.08 (s, 3H, CH3), 3.05 (sbr, H, NH), 7.44 (t, H, ArH, J=7.32 Hz), 7.54 (d, H, ArH, J=XXHz), 7.87 (s, H, ArH), 8.35 (m, H, ArH), 9.08 (s, H, NH). MS: (ESI+) MH+=379.17
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:21][C:22]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[CH:23][CH:24]=3)[CH:17]=[C:16]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:15]=2)=[C:9]([F:36])[CH:8]=1)(=O)[CH3:2].C(N(CC)CC)C>C(#N)C>[F:36][C:9]1[CH:8]=[C:7]([C:6]2[O:37][C:1]([CH3:2])=[N:4][N:5]=2)[CH:12]=[CH:11][C:10]=1[O:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[CH:23][CH:24]=2)[CH:17]=[C:16]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)NNC(C)=O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
N′-Acetyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzohydrazide (45 mg, 0.086 mmol) synthesized in Example (49a) was dissolved in acetonitrile (3.0 mL), and (methoxycarbonysulfamoyl)triethylammonium hydroxide (50 mg, 0.210 mmol) and triethylamine (0.05 mL, 0.359 mmol) were added, followed by stirring at 100° C. for 1 day under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=80%-100%) to afford the desired compound (26 mg, yield 60%) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([NH2:14])=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:25][C:26](=O)[CH2:27][CH3:28]>C(OCC)(=O)C>[NH2:13][C:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:25]=[C:26]([CH2:27][CH3:28])[N:14]=1
Reactant: CCC(=O)CBr
Reactant: N=C(N)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cn(C(=O)OCc2ccccc2)c(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
A mixture of N-benzyloxycarbonyl guanidine 2.52 g (13.1 mmol), diisopropylethylamine 1.81 ml (8.7 mmol), 1-bromo-2-butanone 0.89 ml (8.7 mmol) and ethyl acetate 50 ml was stirred at room temperature overnight. The reaction solution was washed with water and aqueous sodium chloride solution and dried on magnesium sulfate. After evaporation of the solvent, the residue was purified by a column chromatography on silica gel and further recrystallized from n-hexane to give 0.71 g of the title compound (yield: 33%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:12]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13]1.Cl>ClCCl>[CH:12]1([C:16]([C:8]2[CH:9]=[CH:10][C:5]([OH:11])=[CH:6][CH:7]=2)=[O:17])[CH2:15][CH2:14][CH2:13]1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)C1CCC1
Reaction time: 0.75 h
Yield: 51.7 %

Procedure:
Aluminum chloride (1.59 g, 11.9 mmol) was added to a dichloromethane (10 mL) solution of phenol (1.03 g, 10.9 mmol) at room temperature, and the mixture was stirred at the same temperature for 45 minutes. Cyclobutanecarboxylic acid chloride (1.33 mL, 11.7 mmol) was added dropwise to the obtained reaction mixture at room temperature, and the mixture was stirred at the same temperature for 4 hours. Further, aluminum chloride (1.58 g, 11.8 mmol) was added at room temperature, and the mixture was stirred. The aluminum chloride was confirmed to be dissolved thoroughly, and then the mixture was stood still overnight. The reaction mixture was added to hydrochloric acid under ice cooling, and the mixture was subjected to extraction once with ethyl acetate. The organic layer thus obtained was washed with brine twice, and then was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10->80:20, v/v) to give the title compound (993 mg, yield: 51%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][CH2:22][N:21]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:20][C:19]2[N:40]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].[CH:41]1[C:54]2[C:53](=[O:55])[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46](=[O:56])[C:45]=2[CH:44]=[CH:43][C:42]=1C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CN1CC[O:89][CH2:88]C1>C1COCC1.CN(C=O)C>[C:44]1([C:88]([N:25]2[CH2:24][CH2:23][CH2:22][N:21]([S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:20][C:19]3[N:40]=[C:15]([CH:16]=[CH:17][CH:18]=3)[CH2:14][N:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:27][CH2:26]2)=[O:89])[C:45]2[C:46](=[O:56])[C:47]3[C:52](=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:53](=[O:55])[C:54]=2[CH:41]=[CH:42][CH:43]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCNCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)C1
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1C2=O
Reactant: CN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)c2c1cccc2C(=O)N1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Yield: 75.6 %

Procedure:
The title compound was prepared following the procedures illustrated above in Example 75 using 3,10-bis (2-nitrobenzenesulfonyl)-3,6,10,16-tetraazabicyclo-[10.3.1]hexadeca-1(16),12,14-triene (1.0 g, 1.7 mmol), anthraquinone-2-carboxylic acid (0.43 g, 1.7 mmol), DCC (0.35 g, 1.7 mmol), HOBT (0.23 g, 1.7 mmol) and 4-methylmorpholine (0.25 g, 2.5 mmol) in 10 mL of anhydrous THF and 20 mL of anhydrous DMF in 56 h. The compound was purified by flash chromatography on a silica gel column using 200:1 CH2Cl2—MeOH as an eluent to give 1.06 g (76%) of the title compound as a pale yellow foam.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([O:21][CH3:22])[CH:15]=1.ClC1C(Cl)=CN=C(OC)C=1[Li].[CH3:34][O:35][C:36]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[C:40]([CH3:48])[C:37]=1[CH:38]=[O:39]>O1CCCC1.O>[CH3:34][O:35][C:36]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[C:40]([CH3:48])[C:37]=1[CH:38]([C:15]1[C:16]([O:21][CH3:22])=[N:17][CH:18]=[C:19]([Cl:20])[C:14]=1[Cl:13])[OH:39]
Reactant: COc1cc(Cl)c(Cl)cn1
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: [Li]CCCC
Agent: [Li]c1c(OC)ncc(Cl)c1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc(C)c(C(O)c2c(OC)ncc(Cl)c2Cl)c(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
15.1 ml of n-butyllithium (1.57 mol/l hexane solution) was dropwise added at −20° C. to a solution having 2.40 g (23.7 mmol) of diisopropylamine dissolved in 30 ml of tetrahydrofuran, followed by stirring for 1 hour. The solution was cooled to −78° C., and a solution having 4.22 g (23.6 mmol) of 4,5-dichloro-2-methoxypyridine obtained in Step (e) dissolved in 20 ml of tetrahydrofuran was added, followed by stirring for 2 hours to prepare 4,5-dichloro-2-methoxy-3-pyridyllithium. Then, to this solution, a solution having 5.00 g (23.8 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 20 ml of tetrahydrofuran was added, followed by stirring for 30 minutes. 50 ml of water was added to the mixture to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. After extraction with ethyl ether, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography to obtain 4.66 g (yield: 51%) of (2,3,4-trimethoxy-6-methylphenyl)(4,5-dichloro-2-methoxy-3-pyridyl)methanol.
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].CN1[CH2:28][CH2:27][CH2:26]C1=O.BrCC1CC1>O.CCN(CC)CC>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:26]4[CH2:27][CH2:28]4)[CH2:3][CH2:4][C@:5]45[C@H:6]([C:7]([CH2:9][CH2:10][C@@:11]34[OH:22])=[O:8])[O:21][C:16]([C:15]=25)=[C:17]([OH:20])[CH:18]=1
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Reactant: CN1CCCC1=O
Agent: BrCC1CC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Naltrexone was prepared in high yield by direct N-alkylation of noroxymorphone with an alkyl halide in the presence of a protic solvent. Accordingly, 5.5 g of noroxymorphone, 16.5 mL of N-methyl-2-pyrrolidinone (NMP), and 1.65 mL of water were added to a flask (100 mL, 3 necked). The flask was flushed with nitrogen, and the reaction mixture was kept under nitrogen throughout the reaction. Next, 2.4 mL of bromomethylcyclopropane and 2.5 mL of triethylamine (NEt3) were added to the flask, which was then heated at 70° C. for 2 h. An additional 2.5 mL of NEt3 was added to the flask, and the mixture was heated at 70° C. for 7.5 h. HPLC analysis revealed that the reaction is completed with noroxymorphone at less than two percent or one percent and undesired side products such as quaternary ammonium salt and O-alkylation of phenol group were present at less than two percent or were undetectable. The mixture was cooled to room temperature, and water (82.5 g) was added to give a precipitate. The mixture was stirred for 1 h and then filtered. The solid was washed with water (2×5.5 mL) and dried under vacuum at 65° C. for 18 h to give 5.68 g of naltrexone as solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[F:10].C([O-])([O-])=O.[K+].[K+].[CH2:17]([Zn]CC)[CH3:18]>C1COCC1>[CH2:17]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[F:10])[CH3:18]
Reactant: CC[Zn]CC
Reactant: OCc1cnc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ncc(CO)cc1F
Yield: 40.3 %

Procedure:
To a solution of (6-chloro-5-fluoro-3-pyridinyl)methanol (300 mg, 1.857 mmol) (see Preparation 5(b) above), K2CO3 (770 mg, 5.57 mmol), and [1,1′-Bis(diphenylphosphino) ferrocene]dichloro-palladium(II) (136 mg, 0.186 mmol) in THF (6 ml), was added diethylzinc (3.71 ml, 3.71 mmol). The mixture was stirred under reflux for 6 h in a pressure tube. The resulting mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography using Flashmaster II, a 10 g spherical silica gel cartridge BP-SUP 20-40μ, and DCM/MeOH 98:2 mixture as eluent to give 116 mg of desired compound as a yellow solid.
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[CH2:12]([O:16][Si](C(C)(C)C)(C)C)[C@H:13]1[O:15][CH2:14]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:33]=2[Cl:43])=[CH:28][CH:27]=1.[H-].[Na+]>CN(C=O)C>[Cl:43][C:33]1[CH:34]=[C:35]([O:38][C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:37][C:32]=1[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:15][C@@H:13]2[CH2:12][O:16][C:4]3=[N:8][C:7]([N+:9]([O-:11])=[O:10])=[CH:6][N:5]3[CH2:14]2)=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Reactant: FC(F)(F)Oc1ccc(-c2ccc(CBr)cc2)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(-c3ccc(OC(F)(F)F)cc3Cl)cc1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A stirred solution of (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-01 (41) (reported in U.S. Pat. No. 5,668,127 via 4 steps, starting from 2,4-dinitroimidazole and tert-butyldimethylsilyl (S)-glycidyl ether) (342 mg, 1.85 mmol) and bromide 39 (741 mg, 2.03 mmol) in anhydrous DMF (7 mL) under N2 at 0° C. was treated with 60% NaH (111 mg, 2.78 mmol), then quickly degassed and resealed under N2. After stirring at room temperature for 3 h, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (20 mL), added to brine (80 mL) and extracted with CH2Cl2 (6×80 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel, eluting with CH2Cl2, to give 1 (694 mg, 80%) as a light yellow solid: mp (CH2Cl2/pentane) 80-82° C.; 1H NMR (CDCl3) δ 7.45-7.35 (m, 6H), 7.34 (d, J=8.5 Hz, 1H), 7.20 (m, 1H), 4.79 (d, J=12.0 Hz, 1H), 4.68 (d, J=12.1 Hz, 1H), 4.65 (ddd, J=12.1, 2.9, 2.5 Hz, 1H), 4.37 (br d, J=11.8 Hz, 1H), 4.24-4.12 (m, 3H). Anal. (C20H15ClF3N3O5) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])#[N:17].N1CCCCC1>CO>[C:16]([C:18](=[CH:10][C:9]1[CH:8]=[C:7]([O:12][CH3:13])[C:6]([O:14][CH3:15])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])[C:19]([O:21][CH3:22])=[O:20])#[N:17]
Reactant: COC(=O)CC#N
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Yield: 78.1 %

Procedure:
To a mixture of 7.00 g (33.15 mmol) of 6-nitroveratraldehyde (80%) and 3.4 mL (38.42 mmol) of methyl cyanoacetate in 70 mL of methanol is added 0.7 mL of piperidine. An additional 100 mL of methanol is added and the thick suspension is warmed slightly until the mixture stirred freely. After stirring at room temperature for 1 hour, the solids are collected by filtration washing with methanol followed by diethyl ether to give 7.57 g (78%) of methyl 2-cyano-3-(4,5-dimethoxy-2-nitrophenyl)-2-propenoate as a pale yellow solid, mp 162–164° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[N:10]([C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:9](=[O:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.BrC1N=C2N([C@@H:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:33])C(=O)NC2=NC=1.C(=O)([O-])[O-].[Cs+].[Cs+].COS(OC)(=O)=O.[CH3:53][N:54](C)C=O>>[CH3:20][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]4[C:34]=3[CH:32]=[CH:33][CH:53]=[N:54]4)[N:3]=[C:4]2[N:10]([C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:9]1=[O:19]
Reactant: CN(C)C=O
Reactant: C[C@H](c1ccccc1)n1c(=O)n(C)c2ncc(Br)nc21
Reactant: C[C@H](c1ccccc1)n1c(=O)[nH]c2ncc(Br)nc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COS(=O)(=O)OC
Product: C[C@H](c1ccccc1)n1c(=O)n(C)c2ncc(-c3cccc4ncccc34)nc21
Temperature: 55 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
(R)-5-Bromo-1-methyl-3-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. To a solution of (R)-6-bromo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.360 g, 1.13 mmol) in dimethylformamide (3 mL) was added cesium carbonate (excess) followed by dimethylsulfate (0.150 g, 1.13 mmol). The solution was heated to 55° C. in a screw capped tube. After one hour, the solution was filtered to remove cesium carbonate salts. The filtrate was condensed under reduced pressure and the crude product purified via Biotage silica gel chromatography (5-50% ethyl acetate/hexanes) to afford the title compound (0.306 g, 83% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.57 (d, 2H), 7.32 (m, 3H), 5.77 (q, 1H), 3.42 (s, 3H), 2.04 (d, 3H); 13C NMR (75 MHz, CHCl3) δ 52.6 (C═O); MS (ESI) m/z 333.3 [M+1]+, 335.3 [M+2]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[N:4]=[CH:3]1.S(=O)(=O)(O)[OH:19].[H][H]>O.[Pt]>[CH3:1][C:2]([CH3:17])([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:14]([CH3:16])[CH3:15])[NH2:4])[CH2:3][OH:19]
Reactant: O=S(=O)(O)O
Reactant: [H][H]
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Agent: [Pt]
Solvent: O
Product: CC(C)C(N)CCCCCCCCC(C)(C)CO

Procedure:
218 g (0.935 mol) of 3,3-dimethyl-12-isopropyl-1-aza-1,5,9-cyclododecatriene are added dropwise in the course of 15 minutes to a solution of 150 g (1.53 mols) of sulphuric acid in one liter of water. Aldehyde impurities are removed by a subsequent 20 minute steam distillation. The aqueous sulphuric acid solution is then hydrogenated at normal pressure and 20°-25° C. in the presence of a platinum-on-charcoal catalyst (5% by weight of platinum), with the absorption of 3 mols of hydrogen, to give 2,2-dimethyl-11-isopropyl-11-aminoundecanol. After filtering off the catalyst, the aqueous solution is neutralised with concentrated sodium hydroxide solution and the oily amino-alcohol which separates out is extracted by shaking with toluene and distilled. 196 g (0.763 mol) of 2,2-dimethyl-11-isopropyl-11-aminoundecanol are obtained, corresponding to a yield of 81.5% of theory; boiling point 110° C./0.02 mm Hg; nD20 =1.4684.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=O)[CH2:2][CH3:3].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[F:25])[CH:20]=O.[OH2:26]>N1CCCCC1.C(O)(=O)C>[F:16][C:17]1[CH:18]=[C:19]([CH:20]=[C:1]([C:2](=[O:26])[CH3:3])[CH2:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CCC(=O)CC(=O)OCc1ccccc1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=Cc1ccc(F)c(F)c1)CC(=O)OCc1ccccc1

Procedure:
A solution of benzyl propionylacetate (36.3 g, 176 mmol), 3,4-difluorobenzaldehyde (25.0 g, 176 mmol), piperidine (0.86 mL, 9.0 mmol) and acetic acid (0.49 mL, 9.0 mmol) was refluxed with removal of water using a Dean-Stark apparatus for 5 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The reaction mixture was washed with water (100 mL), followed by brine (100 mL) and dried over anhydrous Na2SO4. The solvent was evaporated, giving a pale yellow syrup (60.2 g). The product was used in the next step without further purification.