Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[OH-].[Na+].C(=O)(O)[O-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>O.C(O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: NCCCCCC(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCNc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 97 %

Procedure:
5 g (38.11 mmol) of 6-aminocaproic acid are dissolved in 50 ml of water in the presence of 1.5 g (1 eq) of sodium hydroxide and 4.2 g (1.3 eq) of sodium bicarbonate in a 250 ml three-necked flask equipped with a reflux condenser and a thermometer. A solution of 4.9 ml (1.2 eq) of 4-fluoronitrobenzene in 50 ml of ethanol is run into the mixture, which mixture is subsequently brought to reflux (85°-90° C.) for 48 hours. The mixture is cooled and then extracted 3 times with dichloromethane. The aqueous phase is acidified to pH˜3 with 5N hydrochloric acid. A yellow precipitate is formed; the mixture is left overnight in a refrigerator. The precipitate is pulled dry and washed with water and with acetone. After drying, 9.3 g of a yellow product are obtained, i.e. a final yield of 97%.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[OH-].[K+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Br)[CH:15]=1>CC(C)=O>[N:1]1([CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH2:20][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: BrCc1cccc(CBr)c1
Reactant: c1ccc2[nH]cnc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: c1cc(Cn2cnc3ccccc32)cc(Cn2cnc3ccccc32)c1
Yield: 18.8 %

Procedure:
To a 1L round bottom flask equipped with a stirbar was added 26.8 g benzimidazole (227 mmol) and 12.7 g (227 mmol) finely pulverized potassium hydroxide. These were stirred in 500 mL acetone for 20 minutes at reflux. 20.0 g (78.5 mmol) α,α′-dibromo-m-xylene was then added, and the solution was stirred at reflux for 6 hours followed by room temperature stirring for 72 hours. The cloudy solution was filtered, and the white solids rinsed with acetone. The resulting filtrate was dried on silica and partitioned on a silica gel column using a gradient of 100% acetonitrile→90% acetronitrile/10% MeOH as eluent. The product fractions were evaporated of solvent to give 5 g 1-[3-(1H-benzimidazole-1yl-methyl)benzyl]-1H-benzimidazole as a white solid.
Reaction SMILES: C([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[N:13][C:14]([CH3:20])=[N:15][C:16]=32)[CH2:9]1)C1C=CC=CC=1.C(N)(=N)C1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:20]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]4[CH2:19][CH:17]([CH2:18][NH:8][CH2:9]4)[C:16]=3[N:15]=2)=[CH:23][CH:24]=1
Reactant: Cc1ncc2c(n1)C1CC2CN(Cc2ccccc2)C1
Reactant: N=C(N)c1ccncc1
Product: c1cc(-c2ncc3c(n2)C2CNCC3C2)ccn1

Procedure:
Following the method described in Example 13, 10-benzyl-4-methyl-3,5,10-triaza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene and isonicotinamidine were converted to the title compound in 7.5% overall yield. APCl MS m/z 239.1 (M+H)+.
Reaction SMILES: C[N+]([O-:5])(C)C.Br[CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[CH:18]=1>CS(C)=O.O.[Cl-].[Na+].O>[CH:7]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]#[N:17])=[CH:13][C:12]=2[CH:18]=1)=[O:5]
Reactant: C[N+](C)(C)[O-]
Reactant: N#Cc1cc2cc(CBr)ccc2o1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc2cc(C=O)ccc2o1
Temperature: 70 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
Trimethlamine-N-oxide (6.75 g, 90 mmol) was added to a solution of 5-(bromomethyl)benzofuran-2-carbonitrile (4.46 g, 18.89 mmol) in 57 mL of DMSO and 6 mL of H2O. The mixture was stirred at 70° C. for 3 hr. After the reaction was cooled to room temperature, the mixture was diluted with 72 mL of brine, and extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (2×20 mL), brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography, 100% Heptane-30% Ethyl Acetate/70% Heptane, to give 5-formylbenzofuran-2-carbonitrile (1.5 g). 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J=8.7 Hz, 1H), 8.12 (dd, J=8.7, 1.7 Hz, 1H), 8.30 (d, J=0.9 Hz, 1H), 8.46 (dd, J=1.6, 0.6 Hz, 1H), 10.11 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:14]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:14]3[CH:15]=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=3[CH3:12])[CH2:22][CH2:23]2)=[O:8])=[C:9]([CH3:11])[CH:10]=1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: Cc1cc(C)c(N2CCNCC2)cc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3cnc(F)cc3C)CC2)cc1C
Yield: 86.9 %

Procedure:
Using 6-fluoro-4-methylnicotinic acid (162 mg) and 1-(2,4,5-trimethylphenyl)piperazine (230 mg) and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (310 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(Cn1ccc2ncnc(Cl)c21)OCC
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (1 g) was dissolved in N,N-dimethylformamide (13 mL), cesium carbonate (6.37 g) and 2-bromo-1,1-diethoxyethane (2.94 mL) were sequentially added and the mixture was stirred at 80° C. for 4.5 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100) to give the title compound (1.26 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([C:16]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17]1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][N:18]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:17]1)=[O:15])[CH3:12]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCNC1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(F)cc3)cc2)CCN(C(=O)Nc2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation using 4-chloro phenyl isocyanate and 3-(4′-fluoro-biphenyl-4-yloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 65) to afford the racemate as a white solid (220 mg, 76%)
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].ClC[C:9]#[N:10].[C:11]1(C)C=CC=CC=1>>[CH3:5][CH2:4][CH:3]([C:2]1([O:6][CH2:1]1)[C:9]#[N:10])[CH3:11]
Reactant: Cc1ccccc1
Reactant: N#CCCl
Reactant: CCCCC=O
Product: CCC(C)C1(C#N)CO1

Procedure:
A solution of 17.2 g. of valeraldehyde and 16.5 g. of chloroacetonitrile in 20 ml. of toluene is treated with sodium t-amylate and worked up in the manner described in Example 3, above, to give a toluene solution of 3-butylglycidonitrile (I).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Clc1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Product: c1ncn(-c2nc(NCCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)n1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][SH:11])=[CH:7][C:6]=1[CH3:12])[CH3:3].C[O-].[Na+].CO.Cl[CH2:19][CH2:20][NH:21][C:22]([NH:27][CH2:28][CH:29]([OH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:23][N+:24]([O-:26])=[O:25]>CO>[CH3:3][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][S:11][CH2:19][CH2:20][NH:21][C:22]([NH:27][CH2:28][CH:29]([OH:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:23][N+:24]([O-:26])=[O:25])=[CH:7][C:6]=1[CH3:12])[CH3:1]
Reactant: O=[N+]([O-])C=C(NCCCl)NCC(O)c1ccccc1
Reactant: Cc1cc(CS)sc1CN(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CSCCNC(=C[N+](=O)[O-])NCC(O)c2ccccc2)sc1CN(C)C
Reaction time: 24 h
Yield: 10.5 %

Procedure:
In 5 ml of methanol was dissolved 0.14 g of 5-(dimethylamino)methyl-2-mercaptomethyl-4-methylthiophene, and 0.2 ml of a 3.57N sodium methoxide-methanol solution was added at room temperature in a nitrogen atomsphere, after which 0.2 g of N-(2-chloroethyl)-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediamine was added at one time, after which the reaction mixture was allowed to stand at room temperature for 24 hours, and the deposited substance was removed by filtration, after which the solvent was removed by distillation under reduced pressure. Chloroform was added to the resulting residue, and the insolubles were removed by filtration, after which the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography (basic alumina, eluent; chloroform:methanol=10:1 by volume) to obtain 0.033 g (yield 11%) of N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediamine having a melting point of 114°-115° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C@H:18]4[O:22]C(C)(C)[N:20](C(OC(C)(C)C)=O)[C@@H:19]4[CH2:32][F:33])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3]1.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[C:37]([OH:39])([C:36]([F:41])([F:40])[F:35])=[O:38].[NH2:20][C@H:19]([CH2:32][F:33])[C@@H:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]3[CH2:5][S:2](=[O:1])(=[O:34])[CH:3]=3)=[N:11][CH:10]=2)=[CH:17][CH:16]=1)[OH:22]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(C4=CS(=O)(=O)C4)nc3)cc2)OC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CF)[C@H](O)c1ccc(-c2ccc(C3=CS(=O)(=O)C3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the product of step 4, Example 18 (0.15 g, 0.233 mmol, 1 eq) in methylene chloride (5 mL) is added trifluoroacetic acid (0.4 mL) at 0° C. Resulting reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo and stripped with methylene chloride (3×10 mL) to afford crude TFA salt of title compound (0.185 g), which is used as such in next step. LCMS (m/z): [M+H] 349.1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=O.Cl>C(O)C>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]=[CH2:13])=[CH:6][CH:5]=1)=[O:3]
Reactant: C=CCOc1ccc(C(C)=O)cc1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Solvent: CCO
Product: C=CCOc1ccc(C(=O)C=Cc2ccc(OC)cc2OC)cc1
Product: COc1ccc(C(C)=O)cc1
Reaction time: 0.5 h

Procedure:
0.88 g of 4-allyloxyacetophenone and 0.42 g of 2,4-dimethoxybenzaldehyde were dissolved in 3.5 ml of ethanol, and to the solution was added ethanol saturated with 3.5 ml of hydrogen chloride. The mixture was left at room temperature for 30 min during which time it turned heavily red. The solution was concentrated in vacuo and the residue chromatographed (column chromatography over silica gel 60 (Merck 0.063-0.200 mm, 100 g), eluent toluene and toluene to which increasing amounts of ethyl acetate were added) to give 500 mg of 4-methoxyacetophenone and 471 mg of 2,4-di-methoxy-4′-prop-2-enyloxychalcone. The chalcone was recrystallized from petroleum ether-ethyl acetate to give 370 mg of slightly yellow crystals. For data, see Example 2.24.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.Br[CH2:42][CH2:43][CH2:44][OH:45]>>[OH:45][CH2:44][CH2:43][CH2:42][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCO)cc3)cc21

Procedure:
Analogously to Method I, 0.200 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 259b) and 0.045 ml of 3-bromopropanol is used to obtain the title compound as a colourless oil. Rf=0.19 (1:3 EtOAc-heptane); Rt=4.90.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:24])(=[O:23])[NH:11][CH:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Cl)[CH:34]=1.CCOC(C)=O.CCCCCC>CN(C)C=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:24])(=[O:23])[N:11]([CH:12]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:13]([CH3:15])[CH3:14])[CH2:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2cccnc2)C(C(=O)OC(C)(C)C)C(C)C)cc1

Procedure:
To a stirring solution of 4-(1-tert-Butoxycarbonyl-2-methyl-propylsulfamoyl)-benzoic acid methyl ester (Compound 1*—884 mg, 2.38 mmol) in dimethylformamide (30 ml) at ambient temperature was added cesium carbonate (10.86 g, 33.34 mmol). Then 3-picolyl chloride hydrochloride (546 mg, 3.33 mmol) was added to the suspension and the reaction mixture was stirred at room temperature for 24 hours by which time TLC (EtOAc/Hexane 1:1) monitoring showed the reaction to be completed. The mixture was evaporated to dryness and the residue was stirred in ethyl acetate (50 ml). The ethyl acetate phase was extracted with water (1×50 ml), dried (MgSO4), filtered and evaporated to afford the crude product as a brown oil. This oil was purified by flash chromatography to furnish the pure product as colourless oil.
Reaction SMILES: [CH:1]1([N:4]([CH:15]2[CH2:20][CH2:19][CH:18]([CH2:21]C(OC)=O)[CH2:17][CH2:16]2)[C:5](=[O:14])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[F:13])[CH2:3][CH2:2]1.[CH3:26][Mg]Br.C([O:31][CH2:32][CH3:33])C>C1COCC1>[CH:1]1([N:4]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][C:32]([OH:31])([CH3:33])[CH3:26])[CH2:17][CH2:16]2)[C:5](=[O:14])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[F:13])[CH2:3][CH2:2]1
Reactant: COC(=O)CC1CCC(N(C(=O)c2ccc(C)cc2F)C2CC2)CC1
Reactant: CCOCC
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N(C2CC2)[C@H]2CC[C@H](CC(C)(C)O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(4-(N-cyclopropyl-2-fluoro-4-methylbenzamido)cyclohexyl)acetate (0.075 g, 0.22 mmol) in THF (2 mL) was added methylmagnesium bromide, (3.0 M solution in diethyl ether, 0.43 ml, 1.3 mmol) at room temperature. After being stirred for 2 hours at room temperature, the reaction mixture was quenched with saturated NH4Cl (10 ml) and then extracted with EtOAc three times. The organic phase was dried over Na2SO4 and then concentrated in vacuo. The crude product was purified through silica gel chromatography eluting with 5% MeOH—CH2Cl2 and then 50% EtOAc-hexane. The desired product was obtained as a white solid (0.038 g). MS: 348 (M+1), C21H30FNO2.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[N:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29]([O:31]CC)=[O:30])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:34]=[CH:35][N:36]=[CH:37][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[N:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:34]=[CH:35][N:36]=[CH:37][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CN1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nn2)CC1
Agent: Cl
Product: O=C(O)CN1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nn2)CC1
Temperature: 90 °C
Reaction time: 17 h

Procedure:
A mixture of compound 344 and hydrochloric acid (1 N aqueous solution) (7 mL) was stirred at 90° C. for 17 h. After concentration, the residue was subjected to reverse phase preparative HPLC (acetonitrile/H2O containing 0.1% TFA each, 40 min from 10 to 30%). Lyophilization provided compound 346 (50 mg) as a yellow solid (TFA salt). 1H NMR (500 MHz, DMSO-d6) δ ppm 10.94 (1 H, br. s.), 9.55 (1 H, s), 9.33 (1 H, s), 8.65 (1 H, d, J=6.1 Hz), 8.53 (1 H, d, J=5.9 Hz), 8.23 (1 H, d, J=9.5 Hz), 7.60 (1 H, d, J=9.8 Hz), 5.34 (1 H, dq, J=8.9, 8.8 Hz), 4.16 (2 H, br. s.), 3.40 (8 H, br. s.), 2.33-2.44 (2 H, m), 1.92-2.18 (4 H, m), 1.62-1.81 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 474.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[CH2:10](O)[CH:11]=C>>[CH2:1]([O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7])[CH:10]=[CH2:11]
Reactant: C=CCO
Reactant: CCC(=O)CC(=O)OC
Product: C=CCOC(=O)CC(=O)CC
Reaction time: 24 h
Yield: 90 %

Procedure:
A mixture of 35 g of methyl-3-ketopentanoate and 36 mL of allyl alcohol are distilled to about 120° to 125° C., removing both methyl alcohol and allyl alcohol. Allyl alcohol (36 mL) is added to the reaction mixture, which is again distilled at 120°-125° C. This process is repeated for a total of four 36 mL portions of allyl alcohol over a 24 hour period. The remaining mixture is then vacuum distilled to yield 38.03 g of allyl-3-ketopentanoate (90% yield), bp 90°-95° C. under 10-14 mm Hg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][N:9]2[C:14]3=[N:15][C:16]([Sn](C)(C)C)=[CH:17][N:18]=[C:13]3[NH:12][CH2:11][C:10]2=[O:23])[CH2:3][CH2:2]1.Br[C:25]1[N:30]=[C:29]2[N:31]([CH2:36][CH2:37][CH:38]3[CH2:43][CH2:42]OCC3)C(=O)CNC2=NC=1.C[Sn](C)C.C[Sn](C)C>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.O1CCOCC1>[NH:31]1[C:29]2=[N:30][CH:25]=[C:42]([C:16]3[N:15]=[C:14]4[N:9]([CH2:8][CH2:7][CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[C:10](=[O:23])[CH2:11][NH:12][C:13]4=[N:18][CH:17]=3)[CH:43]=[C:38]2[CH:37]=[CH:36]1
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(CCC1CCOCC1)C(=O)CN2
Reactant: O=C1CNc2ncc(Br)nc2N1CCC1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: C1COCCO1
Product: O=C1CNc2ncc(-c3cnc4[nH]ccc4c3)nc2N1CCC1CCOCC1
Temperature: 110 °C
Yield: 54.6 %

Procedure:
1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.4 g, 1.29 mmol), hexamethylditin (0.57 g, 1.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.176 mmol) were placed in a sealed tube with 1,4-dioxane (5 mL). The flask was evacuated, flushed with nitrogen, sealed and heated at 110° C. for 1 h. The reaction mixture was cooled to room temperature and filtered through Celite, washing with ethyl acetate. The filtrate was concentrated and sonicated with a small volume of solvent mixture (50% hexane in ethyl acetate) and isolated by filtration to yield the title compound (0.34 g, 0.8 mmol, 54.6% yield). MS (ESI) m/z 427 [M+2]+.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:8][C:9]1[C:16]([Cl:17])=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=O.[OH2:28]>>[Cl:8][C:9]1[C:16]([Cl:17])=[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[CH:5][C:4]([O:3][CH2:7][CH3:6])=[O:28]
Reactant: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Reactant: O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a slurry of 4.8 g. (0.1 mole of a 50% mineral oil suspension) of NaH in 370 ml. of tetrahydrofuran was added 22.4 g. (0.1 mole) of triethylphosphonoacetate dropwise over a period of 15 minutes. This mixture was stirred for 15 minutes and then 30 g. (0.096 mole) of 2,3-dichloro-4-(p-nitrophenoxy)benzaldehyde was added portionwise in 15 minutes. After stirring for one hour, the reaction mixture was poured into water and the resulting product filtered and washed with EtOH to give 29.8 g. (81%) of the title compound, m.p. 145°-145.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3O)[N:4]=1.P(Cl)(Cl)([Cl:25])=O>O>[Cl:25][CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3Cl)n1
Temperature: 90 °C

Procedure:
2.3 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy-3-hydroxy-phthalide (see Example 84) are suspended in approximately 40 ml of phosphorus oxychloride, and the suspension is heated at 90° C. for 2 hours. The reaction mixture is then introduced at from 35° to 45° C. into 250 ml of water. It is then diluted with a further 500 ml of water and the crystals which separate are filtered off and washed neutral with water to yield pure 3-chloro-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide in the form of slightly yellowish crystals, m.p. 143°-144° C.