Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])[CH2:3]1
Reactant: O=C1CCC(C(=O)O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
To a stirred solution of 3-oxocyclopentanecarboxylic acid (1.5 g, 11.71 mmol) in DMF (20 mL) was added K2CO3 (1.780 g, 12.88 mmol) followed by benzyl bromide (1.360 mL, 11.71 mmol) under nitrogen. The reaction mixture was then stirred for 18 h at RT. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 20% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 332A (2.1 g, 78% yield) as an oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.42-7.31 (m, 5H), 5.16 (s, 2H), 3.22-3.12 (m, 1H), 2.58-2.45 (m, 2H), 2.44-2.29 (m, 2H), 2.23 (s, 2H).
Reaction SMILES: [C:1]1([NH:9][C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]([O-:14])=[O:13])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>CN(C)C=O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][O:13][C:12](=[O:14])[C:11]1[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:9][C:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8]
Reactant: Cc1cccc(Nc2ccccc2C(=O)[O-])c1C
Reactant: ClCc1ccccn1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2ccccc2C(=O)OCc2ccccn2)c1C

Procedure:
A 2.36 g amount of sodium N-(2,3-xylyl)anthranilate was dissolved in 20 ml of dimethyl formamide and 1.25 g of 2-chloromethyl pyridine was then added thereto. The mixture was allowed to react at a temperature of 90° C. for 3 hours. After the reaction, the solvent was distilled off in vacuo and the residue was charged with water. The mixture was then extracted with ether. After dehydration, the ether was distilled off and the resultant residue was recrystallized from methanol. Thus, 3.00 g of the desired pale yellow 2-pyridylmethyl-N-(2,3-xylyl)anthranilate having the following physical properties was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[C:18]([CH:20]=O)[N:17]=[N:16]1.[CH3:22][N:23](CC#C)[CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCCl>[CH3:22][N:23]([CH2:20][C:18]1[N:17]=[N:16][N:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:19]=1)[CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1
Reactant: C#CCN(C)C1CCCc2cccnc21
Reactant: O=Cc1cn(CCCN2C(=O)c3ccccc3C2=O)nn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(Cc1cn(CCCN2C(=O)c3ccccc3C2=O)nn1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of 1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1H-1,2,3-triazole-4-carbaldehyde, 22, (0.24 g, 0.84 mmol), N-methyl-N-(prop-2-ynyl)-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.17 g, 1.01 mmol), sodium triacetoxyborohydride (0.27 g, 1.26 mmol) and a catalytic amount of acetic acid (2 drops) in 1,2-dichloroethane (10 mL) was warmed to 65° C. and stirred at this temperature for 24 h. The reaction mixture was cooled to room temperature. A saturated aqueous solution of sodium bicarbonate was added. The product was extracted with dichloromethane. The combined organic layers were dried over potassium carbonate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-5% methanol/CH2Cl2) to afford 0.19 g (80% yield) of the desired product, AH: 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=4.4 Hz, 1H), 7.79-7.76 (m, 2H), 7.71 (s, 1H), 7.68-7.65 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.00 (dd, J=4.8, 8.0 Hz, 1H), 4.32 (dt, J=3.2, 7.2 Hz, 2H), 3.91 (dd, J=6.0, 9.2 Hz, 1H), 3.77-3.66 (m, 4H), 2.82-2.70 (m, 1H), 2.70-2.60 (m, 1H), 2.29 (s, 3H), 2.29-2.23 (m, 2H), 2.12-2.02 (m, 1H), 2.02-1.92 (m, 1H), 1.92-1.80 (m, 1H), 1.70-1.56 (m, 1H); ESI+ MS: m/z (rel intensity) 431.2 (100, [M+H]+).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:14]=[C:13](O)[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=1)[CH3:3].C(Cl)(Cl)[Cl:19]>P(Cl)(Cl)(Cl)=O>[Cl:19][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[N:14]=1
Reactant: COc1ccc2c(O)nc(CN(C)C)nc2c1
Reactant: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(CN(C)C)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-[(dimethylamino)methyl]-7-(methyloxy)quinazolin-4-ol (6.6 g, 28.0 mmol) in a mixture of chloroform (15.0 mL) and phosphorous oxychloride (15.0 mL) was heated to reflux for 90 minutes. After cooling it to room temperature the reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate (100 mL) and ethyl acetate (400 mL) and the mixture was stirred for 30 minutes. The organic layer was separated and washed with saturated sodium bicarbonate (2×100 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography using 15% methanol containing 0.5% triethylamine in ethyl acetate provided 1-[4-chloro-7-(methyloxy)quinazolin-2-yl]-N,N-dimethylmethanamine (7.0 g, quantitative). MS (EI) for C12H14ClN3O: 252 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:6](SC2C=CC=CC=2C)[CH:5]=1)(=[O:3])[CH3:2].OO.[CH2:25]([OH:27])[CH3:26]>C(O)(=O)C>[C:1]([C:4]1[CH:14]=[CH:13][C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[C:6]([O:27][C:25]2[CH:5]=[CH:4][CH:1]=[CH:2][C:26]=2[S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccccc2C)c1
Reactant: CCO
Agent: OO
Solvent: CC(=O)O
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccccc2S(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4'-acetyl-2'-(2-methylthiophenoxy)methanesulfonanilide (1.2 g) in acetic acid (7 ml) was added dropwise 30% hydrogen peroxide (1 ml). The mixture was stirred for 2 hours at 70° C. and cooled to room temperature. Ethanol (10 ml) was added, and the precipitates were filtered and washed with ethanol to give colorless needles of 4'-acetyl-2'-(2-methylsulfonylphenoxy)methanesulfonanilide (1.1 g).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:2].[CH3:12][C:13](=[CH:15][CH2:16][CH2:17]/[C:18](=[CH:20]/[CH2:21]O)/[CH3:19])[CH3:14].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:21]/[CH:20]=[C:18](\[CH3:19])/[CH2:17][CH2:16][CH:15]=[C:13]([CH3:14])[CH3:12])=[O:6])=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/COC(=O)c1ccccc1C=O
Reaction time: 0.25 h
Yield: 17.8 %

Procedure:
A solution of 7.50 g (50.0 mmol) 2-formylbenzoic acid, 4.89 g (40.0 mmol) DMAP and 15.42 g (100.0 mmol) geraniol in 75 ml dichloromethane was cooled in an ice bath before addition of a solution of 11.37 g (55.0 mmol) DCC in 25 ml dichloromethane, for 15 min. The reaction medium was maintained under stirring at 0° for 15 min, then at 20° for 48 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) and with a saturated Na2CO3 solution (2×) and water (2×). The organic phase was dried over Na2SO4, concentrated and chromatographed (SiO2, 8:2 heptane/ether) to give 2.55 g (22%) (E)-3,7-dimethyl-2,6-octadienyl 2-formylbenzoate in the pure state in the form of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[CH3:57][N:58]1[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:61]1[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-chloroindole-2-carboxylic acid (0.234 g), HATU (0.569 g), HOAT (0.203 g) and N,N-diisopropylethylamine (0.191 mL) in DMF (0.6 mL) was treated with N-methylpiperazine (0.1 mL) stirred at ambient temperature for 48 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (3-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (0.18 g). 1H NMR (400 MHz, CDCl3): δ 9.60 (br s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.26 (d, 1.8 Hz, 1H), 6.76 (d, J=1.5 Hz, 1H), 4.0 (br m, 4H), 2.56 (t, J=5.1 Hz, 4H), 2.41 (s, 3H). Analysis: Calc'd for C14H16ClN3O; C, 60.54; H, 5.81; N, 15.13; Found: C, 59.99; H, 5.94; N, 18.87.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:21])[C:18]([OH:20])=[O:19]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:21][CH2:17][C:18]([OH:20])=[O:19]
Reactant: COc1ccccc1S
Reactant: CC(Br)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1SCCC(=O)O
Reaction time: 0.5 h
Yield: 754.3 %

Procedure:
To a solution of 2-methoxythiophenol (5.0 g, 3.56 mmol) in DMF (125 mL) is added potassium carbonate (14.76 g, 10.69 mmol, 3 Eq) at 60° C. under nitrogen. The reaction mixture is stirred for 30 minutes then bromopropionic acid (6.0 g, 3.92 mmol, 1.1 Eq) is added and the resulting mixture is stirred for 90 minutes at 60° C. under nitrogen. The solvent is removed under reduced pressure and the residue is taken up in water then washed with EtOAc. The aqueous layer is acidified with aq. solution of HCl and the product is extracted with EtOAc. The organic layer is dried over MgSO4 and concentrated in under reduced pressure to afford 5.7 g (75%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[C:9]([O:10][C:11]2[C:25]([O:26][C:27]3[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=3)=[CH:24][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:17][C:13]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.CC1[N:40]=CC(C(O)=O)=NC=1>>[F:1][CH:2]([F:37])[O:3][C:4]1[C:9]([O:10][C:11]2[C:25]([O:26][C:27]3[CH:28]=[N:29][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:31][CH:32]=3)=[CH:24][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[N:40][C:21]([CH3:22])=[CH:20][N:19]=4)=[N:17][C:13]=3[CH:12]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2OC(F)F)cn1
Product: Cc1cnc(-c2nc3cc(Oc4cccnc4OC(F)F)c(Oc4ccc(S(C)(=O)=O)nc4)cc3[nH]2)cn1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 38 or in accordance with the method or by combining it with an ordinary method but using 4-(2-difluoromethoxy-pyridin-3-yloxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 215 and 5-methyl-pyrazine-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH:15]1[CH3:17])[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23]>C(#N)C>[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[CH:14]3[CH2:16][CH:15]3[CH3:17])=[CH:3][C:2]=2[F:1])[CH2:27]1)[CH3:23]
Reactant: CC1CC1n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CCNCC1CCNC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4C)c3c2F)C1
Yield: 80.6 %

Procedure:
To 0.75 g (2.57 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-(2-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid in 15 ml of acetonitrile was added 0.38 g (2.57 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene and 0.32 g (2.57 mmol) of 3-[(ethylamino)methyl]pyrrolidine. The mixture was refluxed for two hours, cooled, filtered, and the solids washed with ether to give 0.84 g of 7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-1-(2-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid, mp 225°-228° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].O>CN(C=O)C>[CH3:28][O:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24][N:13]1[CH:14]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([CH3:2])=[CH:4][CH:5]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: Cc1ccc(-c2c[nH]c(=O)[nH]c2=O)cn1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2ccc(C)nc2)c(=O)[nH]c1=O)OC
Yield: 48 %

Procedure:
5-(6-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep57, 385 mg, 1.62 mmol), K2CO3 (224 mg, 1.62 mmol) and 3-bromo-1,1dimethoxy-propane (commercially available from Aldrich, 183 mg, 1.0 mmol) were suspended in dry DMF (8 mL). After stirring the reaction at room temperature for 24 hours, additional 3-bromo-1,1dimethoxy-propane (180 mg, 0.98 mmol) was added portionwise over a period of 96 h. Water was added and the mixture washed with diethyl ether. The aqueous layer was then extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 320 mg of the final compound that was used without further purification in the next step (48% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][NH:8][C:7]=2[CH:16]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([O:14][CH3:15])=[O:13])[CH2:9][N:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]=2[CH:16]=1)#[N:2]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C1CNc2cc(C#N)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)N1CC(C(=O)OC)Oc2ccc(C#N)cc21
Temperature: 0 °C

Procedure:
A mixture of methyl 6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (629 mg, 2.88 mmol) and K2CO3 (1195 mg, 8.65 mmol) in dichloromethane (30 mL) was cooled at 0° C. and ethyl chloroformate (0.76 mL, 7.8 mmol) was added. The mixture was heated at reflux temperature for 30 h. The reaction was cooled and extracted with dichloromethane (3×20 mL), dried over Na2SO4 and concentrated. The product 4-ethyl 2-methyl 6-cyano-2H-benzo[b][1,4]oxazine-2,4(3H)-dicarboxylate was obtained as a yellow oil (670 mg, 80% yield) after purification by silica gel column chromatography (0-25% ethyl acetate/hexanes). 1H NMR (400.0 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.53 (dd, J=2.0, 8.5 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 5.36 (t, J=3.3 Hz, 1H), 4.39 (dd, J=3.5, 14.1 Hz, 1H), 4.27-4.15 (m, 2H), 3.76 (dd, J=3.2, 14.1 Hz, 1H), 3.71-3.67 (m, 3H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1>ClCCl>[Cl:1][C:2]1[C:7]([C:8]([NH:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: NCCCN1CCOCC1
Solvent: ClCCl
Product: O=C(NCCCN1CCOCC1)c1c(Cl)ncnc1Cl
Reaction time: 0.5 h
Yield: 100 %

Procedure:
4,6-Dichloropyrimidine-5-carbonyl chloride (600 mg, 2.84 mmol, prepared according to E. V. Tarasov et al. Synlett 2000, 5, 625-626) was dissolved in dichloromethane (10 ml) and TEA (395 μl, 2.83 mmol) was added. To this solution, 3-morpholinopropan-1-amine (410 mg, 2.84 mmol) was added dropwise and the mixture was stirred for 30 min. The reaction mixture was then diluted with dichloromethane, washed with 4% sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The crude (1.13 g, 87% purity, 100% yield) was used in the next synthetic step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([CH3:33])[CH:29]=4)[N:24]([CH3:34])[C:23]3=[O:35])[CH2:18][CH2:17]2)=[N:4][N:3]=1.O>C(O)(=O)C.[Pd]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[C:5]([N:16]1[CH2:17][CH2:18][CH:19]([N:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([CH3:33])[CH:29]=4)[N:24]([CH3:34])[C:23]3=[O:35])[CH2:20][CH2:21]1)=[N:4][N:3]=[CH:2]2
Reactant: COc1cc2c(Cl)nnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2cnnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Temperature: 40 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
In 10 ml of acetic acid was dissolved 300 mg (0.61 mmol) of Compound 76 obtained in Example 58, and 40 mg of 10% palladium on carbon suspended in a small amount of water was added to the solution, followed by vigorous stirring at 40° C. for 3 hours under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered using a filter aid, and the filtrate was neutralized by addition of a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, and then dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=50/1). Ether was added to the product, and the precipitated crystals were collected by filtration, washed, and dried to give 52.9 mg (yield: 19%) of Compound 77 as white crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[NH:9][N:8]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([N:8]1[C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[N:11][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:9]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: c1cnc(-c2n[nH]c(-c3cnccn3)n2)cn1
Product: CC(=O)n1nc(-c2cnccn2)nc1-c1cnccn1

Procedure:
A suspension of 3,5-dipyrazinyl-1,2,4-triazole (0.5 grams) in 20 ml. of acetic anhydride is heated on a steam bath for 17 hours. The resulting solution is filtered and concentrated to a solid. After recrystallization from benzene-hexane, 250 mg. of 1-acetyl-3,5-dipyrazinyl-1,2,4-triazole is obtained, m.p. 128°-130° C.
Reaction SMILES: [H-].[Na+].[C:3](#[N:5])[CH3:4].C([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=O)C.Cl>O1CCOCC1>[CH:11]1([C:9](=[O:8])[CH2:4][C:3]#[N:5])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)C1CCCC1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CCC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (350 mg, 8.8 mmol, 1.2 eq) in 1,4-dioxane (10 mL) was added acetonitrile (450 μL, 8.8 mmol, 1.2 eq). The mixture was stirred at room temperature for 30 min. Then cyclopentanecarboxylic acid ethyl ester (660 μL, 7.3 mmol, 1 eq) was added. After stirring for 30 min at room temperature, the mixture was heated at 105° C. during 16 h. After cooling, the solvent was evaporated to dryness and water was added (30 mL). The mixture was extracted with dichloromethane (3×30 mL) to get rid of the starting material and the aqueous phase was acidified with a 1N solution of hydrochloric acid and extracted with dichloromethane (3×30 mL). The combined organic phases were dried over magnesium sulfate, filtered and dried in vacuo to afford 3-cyclopentyl-3-oxo-propionitrile as very volatile yellow oil (1.0 g, quant. yield)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1cc(Br)ccc1O
Product: O=C(Nc1cc(Br)ccc1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-bromophenol (752 mg, 4.0 mmol) and 2-fluoro-5-nitrobenzoyl chloride (814 g, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19].[CH:20](Br)([CH3:22])[CH3:21].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:20]([CH3:22])[CH3:21])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Yield: 99.9 %

Procedure:
N-(2-Fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (VI) (20 g), isopropyl bromide (25 g), potassium iodide (5 g) and anhydrous potassium carbonate (11 g) were dissolved in a mixture of acetonitrile (135 g) and dimethylformamide (15 g), and the resultant solution was heated under reflux for 7 hours. After cooling, the reaction mixture was extracted with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration to give 23.2 g of N-(2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (II: R=isopropyl). M.P. 62.8° C.
Reaction SMILES: C[O:2][C:3]1[CH:21]=[CH:20][C:6]2[C:7]([N:10]([CH3:19])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:8][O:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+]>Br>[N:13]1([CH2:12][CH2:11][N:10]([CH3:19])[C:7]2[C:6]3[CH:20]=[CH:21][C:3]([OH:2])=[CH:4][C:5]=3[O:9][N:8]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COc1ccc2c(N(C)CCN3CCOCC3)noc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(CCN1CCOCC1)c1noc2cc(O)ccc12
Temperature: 25 °C
Yield: 90 %

Procedure:
6-Methoxy-N-methyl-N-[2-(4-morpholinyl)ethyl]-1,2-benzisoxazol-3-amine (7.0 g) was dissolved in 48% hydrobromic acid (130 ml) and heated to reflux under nitrogen for 3 hours. The reaction was cooled to room temperature, neutralized with saturated sodium carbonate (Na2CO3) extracted with ethyl acetate, dried over MgSO4 and concentrated in vacuo. Flash chromatography (silica gel) eluting with 2:1 heptane/acetone provided the product (6.0 g), m.p. 91°-92° C.