Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:42]([O:44][C:45]([O:47][CH2:48][O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH2:67])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:57][CH:56]=1)=[O:46])[CH3:43]>CN(C=O)C>[CH2:42]([O:44][C:45]([O:47][CH2:48][O:49][C:50](=[O:71])[C@@:51]([CH2:69][OH:70])([CH3:68])[CH2:52][C@H:53]([NH:67][C:6]([C:4]1[NH:3][N:2]=[N:1][CH:5]=1)=[O:8])[CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:59][CH:60]=1)=[O:46])[CH3:43]
Reactant: O=C(O)c1c[nH]nn1
Reactant: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)OCOC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.2 %

Procedure:
1,2,3-Triazole-4-carboxylic acid (14 mg, 124 μmol), DIPEA (86.3 μL, 496 μmol) and HATU (47.1 mg, 124 μmol) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. This was then combined with (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid ethoxycarbonyloxymethyl ester (51 mg, 120 μmol). The resulting mixture was stirred for 15 minutes and the reaction was quenched with AcOH. The product purified by preparative HPLC and lyophilized to yield the title compound (5 mg; purity 90%). MS m/z [M+H]+ calc'd for C26H30N4O2, 511.21. found 511.6.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:3][CH:2]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19]Br.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][N:11]([C:9]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:10])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(CBr)OC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CN(CC(=O)O)C(=O)OCc1ccccc1)OC
Temperature: 100 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
A mixture of N-α-CBZ-glycine (2.0 g, 9.57 mmol), bromoacetaldehyde dimethyl acetal (2.25 mL, 19.13 mmol) and Cs2CO3 (2.78 g, 3.12 mmol) in 20 mL of anhydrous DMF was stirred at 100° C. for 24 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate (3×80 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 45-50% ethyl acetate/hexanes to give the product 37 (1.74 g, 61%). 1H NMR (400 MHz, CDCl3) δ 3.38 (s, 6H), 3.98 (d, J=5.7 Hz, 2H), 4.12 (d, J=5.3 Hz, 2H), 4.54 (t, J=5.3 Hz, 1H), 5.10 (s, 2H), 5.50 (bs, 1H), 7.32 (m, 5H).
Reaction SMILES: [CH3:1][S:2]([CH:5]=[CH2:6])(=[O:4])=[O:3].[CH3:7][NH2:8].[ClH:9]>C(O)C>[ClH:9].[CH3:7][NH:8][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: C=CS(C)(=O)=O
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CNCCS(C)(=O)=O
Reaction time: 8 h

Procedure:
Methylvinyl sulphone (2.1 g, 19.78 mmol) and methylamine (33% solution in IMS, 40 ml , excess) were mixed and heated at reflux under a nitrogen atmosphere for 6 hours. After standing overnight at room temperature, the mixture was concentrated in vacuo to give a yellow oil, which was treated with ethereal HCl to give a sticky solid. Trituration with absolute ethanol gave the title compound as a white solid which was collected by filtration and dried at 60° C. in vacuo (1.01 g, 5.82 mmol, 29%); δH [2H6]DMSO 9.27 (2H, br s), 3.59 (2H, dd), 3.31 (2H, dd), 3.12 (3H, s), 2.57 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](O)=[O:11])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1.C(N1C=CN=C1)([N:20]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH2:20])=[O:11])=[C:7]([O:13][CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:17]=1
Reactant: CC(C)Oc1c(C(=O)O)oc2ccc(Cl)cc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1c(C(N)=O)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxylic acid (200 mg, 0.79 mmol) in 5 mL of dry tetrahydrofuran is added 1,1'-carbonyldiimidazole (167 mg, 1.03 mmol). The reaction solution is heated at reflux for 1 hour then cooled to room temperature. Aqueous ammonium hydroxide (3 mL) is added and the reaction mixture is stirred at room temperature overnight. The reaction is diluted with ethyl acetate and washed with 1N HCl, saturated aqueous sodium bicarbonate, and brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 5-chloro-3-(1-methylethoxy)-2-benzofurancarboxamide in 84% yield; mp=154°-155° C.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:11]2[CH:12]([CH3:15])[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)=O.O1CCCC1.CO.[OH-].[Li+]>O>[CH3:15][CH:12]1[C:11]2=[C:6]([NH2:5])[CH:7]=[CH:8][CH:9]=[C:10]2[O:14][CH2:13]1
Reactant: CC1COc2cccc(NC(=O)C(F)(F)F)c21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1COc2cccc(N)c21
Temperature: 25 °C
Reaction time: 47 h
Yield: 92.6 %

Procedure:
To a stirred solution of Intermediate 24 (0.087 g) in 2:2:1 tetrahydrofuran:methanol:water (5 ml) was added lithium hyroxide (0.149 g) and the mixture stirred at room temperature for 47 h, then at 60° C. for 2.5 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous layer was re-extracted with dichloromethane and the combined organic layers dried over sodium sulphate and concentrated in vacuo to give the title compound as a colourless oil (0.049 g).
Reaction SMILES: C1(CCC[N:10]2[CH2:15][CH2:14][N:13]([C:16]([CH:18]3[CH2:22][S:21][CH:20]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:19]3)=[O:17])[CH2:12][CH2:11]2)C=CC=CC=1.C(O[CH:33]=[O:34])(=O)C.C(O[CH2:39][CH3:40])(=O)C>ClCCl>[CH:33]([N:19]1[CH:18]([C:16]([N:13]2[CH2:12][CH2:11][NH:10][CH2:15][CH:14]2[CH2:16][CH2:18][CH2:22][C:40]2[CH:39]=[CH:27][CH:28]=[CH:23][CH:20]=2)=[O:17])[CH2:22][S:21][CH:20]1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:34]
Reactant: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCc2ccccc2)CC1
Reactant: CCOC(C)=O
Reactant: CC(=O)OC=O
Solvent: ClCCl
Product: O=CN1C(C(=O)N2CCNCC2CCCc2ccccc2)CSC1c1cccnc1

Procedure:
To a solution of 40 mg of 1-(3-phenylpropyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine in 5 ml of dichloromethane, there was added 0.5 ml of a formic acidacetic anhydride (5:3, v/v) mixture, and the resultant mixture was stirred overnight at room temperature. Ethyl acetate (20 ml) was added to the reaction mixture, the dilution was washed with 5% aqueous sodium hydrogen carbonate and with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 30 mg of 1-[3-formyl-2-(3-pyridyl)thiazolidin-4-ylcarbonyl]-(3-phenylpropyl)piperazine as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:13]=[S:14].C(=O)([O-])O.[Na+].CC(O)C>O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][N:2]=[C:13]2[SH:14])=[CH:20][CH:19]=1
Reactant: NCC(=O)c1ccccc1
Reactant: COc1ccc(N=C=S)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc(-n2c(-c3ccccc3)cnc2S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 17.5 parts of 2-amino-1-phenylethanone hydrochloride, 16.5 parts of 1-isothiocyanato-4-methoxybenzene, 10 parts of sodium hydrogen carbonate and 200 parts of 2-propanol is stirred first for 30 minutes at room temperature and further for 2 hours at reflux temperature. The reaction mixture is poured onto 500 parts of water. The product is filtered off and stirred and refluxed for 1 hour with 240 parts of hydrochloric acid solution 10%. After cooling, the product is filtered off, washed with water and 2-propanol, and dried, yielding 25.3 parts (90%) of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol; mp. 267.4° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:5][CH:6]=1.C1C(=O)N([I:19])C(=O)C1>CN(C)C=O>[I:19][C:6]1[NH:5][N:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1n[nH]cc1C
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c(I)c1C
Temperature: 50 °C
Reaction time: 6 h
Yield: 73.4 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of ethyl 4-methyl-1H-pyrazole-3-carboxylate (600 mg, 3.89 mmol) in N,N-dimethylformamide (20 mL). NIS (2.2 g, 9.78 mmol) was added and the resulting mixture was stirred for 6 h at 50° C., then quenched with water (10 mL). The mixture was extracted with ethyl acetate (3×40 mL) and the combined organic extracts were washed with aqueous Na2S2O3 (sat., 2×30 mL) and brine (2×20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:10) as eluent to obtain the title compound as a white solid (800 mg, 73%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:56][CH2:57][CH2:58][C:59]([CH3:64])([N+:61]([O-:63])=[O:62])[CH3:60]>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:56][CH2:57][CH2:58][C:59]([CH3:64])([N+:61]([O-:63])=[O:62])[CH3:60])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CCCCl)[N+](=O)[O-]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCC(C)(C)[N+](=O)[O-])c4ccc(OC(F)F)cc34)nc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (208 mg, 0.35 mmol) in DMF (15 mL) was added K2CO3 (193 mg, 1.4 mmol) and 1-chloro-4-methyl-4-nitropentane (100 mg, 0.59 mmol), after the addition, the reaction mixture was heated to 100° C. with stirring for 4 hours. Then, the mixture was quenched with H2O (25 mL) and product extracted with EtOAc (50 mL). The organic layer was washed with H2O (100 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(4-methyl-4-nitropentyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (200 mg, 69%) as yellow solid, material used in the next step without further purification. LCMS: (M+H)+=772; (M+Na)+=794.0.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][Si](C=[N+]=[N-])(C)C.CCCCCC>CO>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)([OH:14])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(OCC2(O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
The compound (0.86 g) obtained in Step 4 was dissolved in methanol (10 mL) and to the solution was added a 2M trimethylsilyidiazomethan-hexane solution (1.3 mL). After completion of the reaction, the residue from which the solvent was removed under reduced pressure was purified by silica gel column chromatography (Chromatorex NH™) (eluent; ethyl acetate:hexane=1:19 to 1:9) to obtain the titled compound (0.8 g) as crystals.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:11]=[CH:10][NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[C:12]([O-:15])(=O)[CH3:13].[Na+].CN([CH:20]=[O:21])C>>[C:12]([O:21][CH2:20][C:1]1[CH:6]=[C:5]2[C:4](=[CH:3][CH:2]=1)[NH:11][C:10]([CH2:2][CH2:1][CH2:6][CH3:5])=[N:9][C:7]2=[O:8])(=[O:15])[CH3:13]
Reactant: CN(C)C=O
Reactant: CC(=O)[O-]
Reactant: O=c1[nH]cnc2ccccc12
Agent: [Na+]
Product: CCCCc1nc(=O)c2cc(COC(C)=O)ccc2[nH]1
Temperature: 60 °C
Yield: 68 %

Procedure:
To a solution of 2.1 g (7.0 mmol) of the quinazolinone prepared in Example 12 in 15 mL of dry DMF was added 1.74 g (20.0 mmol) of sodium acetate. The mixture was heated to 60° C. for 3 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in 100 mL of CH2Cl2. The solution was washed with water (3×20 mL), brine (1×20 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo. The residue was recrystallized from MeOH/H2O to give 1.31 g (4.8 mmol) of a colorless solid. 68% yield. 1H-NMR (CDCl3): 0.99 (t, 3H, J=7.32 Hz), 1.50 (m, 2H), 1.83 (m, 2H), 2.14 (t, 3H), 2.77 (3 line m, 2H, J=7.71 Hz), 5.23 (s, 2H), 7.69-7.78 (m, 2H), 8.25 (s, 1H), 10.90 (bs, 2H).
Reaction SMILES: [F-:1].[Cs+].[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1Cl.O>CS(C)=O>[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[F:1]
Reactant: [F-]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1F
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 94.6 %

Procedure:
Cesium fluoride (11.2 g) was added to a solution of 2-chloro-3-nitrobenzoic acid methyl ester (10.6 g, 49.0 mmol) in DMSO (49 mL), and the mixture was stirred at 140° C. for 40 minutes. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed in series with water and saturated saline, and dried over magnesium sulfate. The title compound (9.23 g, 95%) was then obtained by vacuum concentration as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:17][C:18]([OH:20])=[O:19]>C(O)(=O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH:16]([N:15]2[C:10](=[O:11])[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]3[C:7]2=[O:9])[CH2:17][C:18]([OH:20])=[O:19])=[CH:26][CH:25]=1
Reactant: COc1ccc(C(N)CC(=O)O)cc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(C(CC(=O)O)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Yield: 79 %

Procedure:
A mixture of 3-nitrophthalic anhydride (1.54, 8.0 mmol) and 3-amino-3-(4-methoxyphenyl)propionic acid (1.56 g, 8.0 mmol) in 15 mL of acetic acid was refluxed for 3.5 h under nitrogen. The reaction was cooled and removed some of the solvent. The slurry was filtered and the solid was dried to afford 2.34 g (79%) of 3-(4-methoxyphenyl)-3-(3-nitrophthalimido)propionic acid as a white powder: mp 178°-180° C.; 1H NMR (DMSO-6, 250 MHz) δ8.07-8.02 (m, 3H), 7.38 (d, 2H, J=8.7), 6.90 (d, 2H, J=8.7, 5.68-5.07 (m, 1H), 3.72 (s, 3H), 3.48-3.22 (m, 2H); 13C NMR (DMSO-d6) δ171.6, 165.7, 163.0, 158.8, 144.4, 136.4, 133.0, 130.2, 128.6, 128.5, 127.0, 122.4, 113.9, 55.1, 50.0, 35.8. Anal. Calcd for C18H14N2O7. Theoretical: C, 58.38; H,3.81; N, 7.56. Found: C, 58.18; H, 3.79; N, 7.36.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH2:2][CH3:3].[CH2:11]([Li])CCC.[C:16]1(C)[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=1>>[CH2:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:22](=[NH:23])[C:17]1[CH:16]=[CH:21][C:20]([CH3:11])=[CH:19][CH:18]=1)[CH2:2][CH3:3]
Reactant: Cc1ccccc1C#N
Reactant: CCCc1ccccc1N
Reactant: [Li]CCCC
Product: CCCc1ccccc1NC(=N)c1ccc(C)cc1

Procedure:
Procedure as described for Amidine X using the following amounts: 6.00 mL of 2-n-propylaniline (42.6 mmol); 21.3 mL of 2.0 M butyllithium (42.6 mmol); 5.00 g of toluonitrile (42.6 mmol). Filtration of the final pentane solution yielded 9.53 g (89%) of light yellow solid. 1H NMR (400 MHz, CDCl3): 7.76 (d, 2H), 7.22 (m, 3H), 7.15 (t, 1H), 6.99 (t, 1 H), 6.84 (d, 1 H), 4.69 (s, 2H), 2.51 (t, 2H), 2.39 (s, 3H), 1.58 (m, 2H), 0.90 (t, 3H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22].[OH-].[K+]>O1CCCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:3][C:1]#[N:2])=[CH:15][C:14]=1[C:21]([F:22])([F:23])[F:24]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#CC=Cc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 87.1 %

Procedure:
A solution of 10.6 g (0.06 mol) of diethyl cyanomethylphosphonate and 12.5 g (0.06 mol) of 4-chloro-3trifluoromethyl-benzaldehyde in 65 ml of tetrahydrofuran is added dropwise to a suspension of 6.7 g (0.12 mol) of pulverulent potassium hydroxide in 185 ml of tetrahydrofuran. During this process the temperature of the reaction mixture rises slightly. Stirring is subsequently continued at room temperature for 20 minutes, and the solid which separates out in this process is filtered off and washed with tetrahydrofuran. The filtrate is concentrated in vacuo and the residue which remains is dried. 12.1 g (87.0% of theory) of 4-chloro-3-trifluoromethyl-cinnamonitrile are obtained in the form of an E/Z isomer mixture.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][N:17]=3)[NH:12][C:11]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][CH2:28][Cl:29].O>O1CCCC1>[Cl:29][CH2:28][CH2:27][CH2:26][N:17]1[CH2:16][CH:15]=[N:14][C:13]2[NH:12][C:11]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[C:18]1=2
Reactant: ClCCCBr
Reactant: Fc1ccc(-c2c(-c3ccncc3)[nH]c3nccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2c(-c3ccncc3)[nH]c3c2N(CCCCl)CC=N3)cc1
Temperature: 65 °C
Yield: 39.4 %

Procedure:
To a suspension of sodium hydride (1.03 g, 25.8 mmol, 60% in mineral oil) in dry tetrahydrofuran (20 ml) was slowly added 7-(4-fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine (0.75 g, 2.58 mmol) followed by 1-bromo-3-chloropropane (4.05 g, 25.8 mmol). The reaction mixture was heated at 65° C. for 72 h. Water was added slowly to quench the excess sodium hydride and the organics were removed in vacuo. Water was added to the residue and the aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, elating with ethyl acetate, to give 1-(3-chloropropyl)-7-(4-fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazineas a solid (0.375 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][OH:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].O1CCO[CH2:25][CH2:24]1>O>[CH2:24]([CH:21]([CH3:22])[O:20][C:18](=[O:19])[N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[OH:11])[CH3:25]
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1cccc(NO)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCC(C)OC(=O)N(O)c1cccc([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(m-nitrophenyl) hydroxylamine (19.0 g.) in dioxane (100 ml.), water (25 ml.) and sodium bicarbonate (11.0 g.) was cooled to 5° C. Ethyl chloroformate (13.3 g; 11.8 ml.) was added to the solution and the mixture stirred at 5° C. for about 1/2 hour. The reaction mixture was poured into ice water (300 ml.) and the precipitate therefrom was removed by filtering and was dried by standing. The solid product was recrystallized from benzene-hexane mixture and dried under vacuum to yield ethyl (3-nitrophenyl)-N-hydroxyurethane as yellow crystals melting 103°-105° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=O.Cl.CN.O[N:21]1[C:25]2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:25][NH:21][C:14]([C:2]1[CH:1]=[C:10]2[C:5](=[CH:4][CH:3]=1)[CH:6]=[C:7]([C:11]([OH:13])=[O:12])[CH:8]=[CH:9]2)=[O:16]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc2cc(C(=O)O)ccc2c1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a mixture of naphthalene-2,6-dicarboxylic acid (5 g), methylamine hydrochloride (1.64 g) and 1-hydroxybenzotriazole (3.75 g) in dimethylformamide (50 ml) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (3.79 g) under ice-cooling. The mixture was stirred for 1 hour at the same temperature and then at ambient temperature overnight. The mixture was diluted with water, and the precipitates were collected by filtration to give 6-(methylcarbamoyl)naphthalene-2-carboxylic acid (4.07 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:14].C([O:19][C:20](=[O:33])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=1[C:31]#[CH:32])(C)(C)C>>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][C:20]([OH:33])=[O:19])=[C:24]([C:31]#[C:32][C:2]2[CH:7]=[C:6]([S:8]([CH2:11][CH2:12][CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=2[CH3:14])[CH:25]=1)#[N:30]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCS(=O)(=O)c1ccc(C)c(Br)c1
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(C#N)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from 2-bromo-1-methyl-4-(propylsulfonyl)benzene (Intermediate 37) and tert-butyl(4-cyano-2-ethynylphenoxy)acetate (Intermediate 46), the title compound was obtained as a white solid after purification by preparative HPLC.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[CH3:27][NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([N:28]([CH3:27])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
Under nitrogen atmosphere, oxalyl chloride (2.21 g, 0.0174 mole) was added slowly dropwise to a stirred and chilled (~10° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in 75 ml of dimethylformamide. After the addition was complete, the reaction was heated at 60° C. for 5 hrs. This acylchloride solution was added dropwise to a stirred and cooled (~10° C.) solution of N-methylaniline (2.02 g, 0.019 mole), triethylamine (1.88 g, 0.019 mole), and 74 ml of dimethylformamide. The reaction was stirred at room temperature overnight. The reaction mixture was poured into 200 ml of water and diluted with water until the cloud point. The mixture was seeded and refrigerated overnight. The solid was collected by filtration and dried under high vacuum. The solid was suspended in dilute sodium bicarbonate, collected by filtration, washed with water, and dried under high vacuum at 50° C. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum first at 56° C., then at 98° C. for 2 days to give 3.0 g (45.7%) of crystals, mp 170°-171° C.