Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:17]([O-:19])[CH3:18].[Na+].[Na].Cl>C(O)C>[CH2:17]([O:19][CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH3:18]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cc2cccc(CBr)c2o1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOCc1cccc2cc(C(=O)OCC)oc12
Temperature: 25 °C
Yield: 69 %

Procedure:
4.67 g (16.5 mmol) of ethyl 7-bromomethyl-benzofuran-2-carboxylate were added to a solution of sodium ethanolate in anhydrous ethanol (freshly prepared from 400 mg (17.4 mmol) of sodium in 40 ml of anhydrous ethanol) and the mixture was heated at reflux for one hour. After cooling to room temperature the mixture was poured into 100 ml of 1N HCl and extracted twice with 150 ml of dichloromethane. After drying over magnesium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane). There were obtained 2.8 g (69%) of ethyl 7-ethoxymethyl-benzofuran-2-carboxylate as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27](Cl)=[O:28])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:27](=[O:28])[CH:26]=[CH:25][C:22]1[CH:23]=[CH:24][C:19]([S:16](=[O:18])(=[O:17])[NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:20][CH:21]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.21 g, 3.01 mmol) in tetrahydrofuran (4.0 ml) a saturated NaHCO3 solution (2.6 ml) was added and the resultant mixture was stirred at ambient temperature for 25 min. To the reaction mixture a 3-(4-phenylsulfamoyl-phenyl)-acryloyl chloride (44a) (0.19 g, 0.59 mmol) solution in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, and the solvent was removed. The residue was washed with diethyl ether to give the title compound (0.074 g, 39%) as white crystals, m.p. 176-177.5° C. 1H NMR (DMSO-d6, HMDSO), δ: 6.54 (1H, d, J=16.0 Hz); 6.96-7.32 (5H, m); 7.47 (1H, d, J=16.0 Hz); 7.76 (4H, s); 9.14 (1H, br s); 10.29 (1H, br s); 10.86 (1H, s). Anal. Calcd for C15H14N2O4S, %: C, 56.59; H, 4.43; N, 8.80. Found, %: 55.82; H, 4.38; N, 9.01.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:43]=[C:42]([N:44]2[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]2)[CH:41]=[CH:40][C:38]=1[NH2:39])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([N:44]4[CH2:49][CH2:48][N:47]([CH2:50][CH2:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH2:46][CH2:45]4)=[CH:43][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 67 %

Procedure:
3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(ethyloxy)-4-{4-[2-(methylsulfonyl)-ethyl]-1-piperazinyl}aniline (Example 143, step C) (64 mg, 0.194 mmol), and p-toluenesulfonic acid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 10 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (98 mg, 0.13 mmol, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 9.36 (s, 1H), 8.34 (d, J=13.00 Hz, 2H), 8.21 (d, J=4.94 Hz, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.72 (d, J=8.97 Hz, 1H), 7.59 (s, 1H), 7.36-7.48 (m, 3H), 7.19 (t, J=7.97 Hz, 2H), 6.96 (s, 1H), 6.66 (s, 1H), 6.41-6.52 (m, 2H), 4.05 (q, J=6.59 Hz, 2H), 3.30-3.37 (m, 2H), 3.07-3.14 (m, 4H), 3.02 (s, 3H), 2.74 (t, J=6.32 Hz, 2H), 2.54-2.61 (m, 4H), 1.22 (t, J=6.68 Hz, 3H). MS (ESI): 753 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][C:13](=O)[CH3:14].N1CCCC1.CCOC(C)=O>CO>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:13]([CH3:14])([CH3:12])[CH2:9][C:8]2=[O:10]
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(F)ccc1O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2cc(F)ccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.2 %

Procedure:
In a 500 mL round-bottomed flask was added 1-(5-fluoro-2-hydroxyphenyl)ethanone (20.0 g, 130 mmol, Aldrich Chemical), propan-2-one (19.0 mL, 260 mmol), and pyrrolidine (21.5 mL, 260 mmol) in methanol (150 mL) to give a orange solution. The reaction mixture was stirred at ambient temperature for 48 h. The reaction mixture was poured into EtOAc (200 mL) and washed with 1N HCl (50 mL), saturated NaHCO3 (50 mL), and brine (50 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to provide an orange residue which was purified by silica gel chromatography (gradient elution, 0-20% EtOAc/hexanes) to provide the title compound (14.2 g, 73.1 mmol, 56%) as a white solid. MS (DCI/NH3) m/z 208 (M+NH4)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=[O:10])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.[CH3:13][Mg]Br>C1COCC1.CCOCC>[CH3:1][NH:2][C:3]1[C:8]([CH:9]([OH:10])[CH3:13])=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1
Reactant: C[Mg]Br
Reactant: CNc1nc(SC)ncc1C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNc1nc(SC)ncc1C(C)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.5 g 4-Methylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde were dissolved in 30 ml THF and 14 ml of a 1.4 M solution of methyl magnesium bromide in ether were added dropwise below 5° C. After stirring for 1 hr at 0° C., another 14 ml Grignard solution were added within 30 min. Stirring was continued for 30 min at 0° C. and finally at RT for 25 hrs. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:24](O)([CH3:26])[CH3:25])[C:7]([O:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[C:1]([C:4]1[N:5]=[C:6]([C:24]([CH3:26])=[CH2:25])[C:7]([O:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:8][C:9]=1[NH:45][C:44]1[CH:46]=[CH:47][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)[CH2:36][CH2:37]2)=[CH:42][CH:43]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2nc(Cl)c(C(N)=O)nc2C(C)(C)O)C1
Reactant: CN1CCN(C2CCN(c3ccc(N)cc3)CC2)CC1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Yield: 65.4 %

Procedure:
A mixture of tert-butyl (3R)-3-{[5-carbamoyl-6-chloro-3-(2-hydroxypropan-2-yl)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (300 mg), 4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (680 mg), diisopropylethylamine (400 μL), and N-methylpyrrolidone (1.2 mL) was reacted in a microwave reaction device at 180° C. for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1), and then washed with diisopropyl ether to obtain tert-butyl (3R)-3-{[5-carbamoyl-6-({-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-3-(prop-1-en-2-yl)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (304 mg) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([Br:5])=[O:4].[C:6]1([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH2:12]([C:6]1[CH:11]=[CH:10][C:9]([CH2:2][C:3]([Br:5])=[O:4])=[CH:8][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Br)Cc1ccc(Cc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
A mixture of 2.7 g (0.030 mol) of bromoacetyl bromide, 54 ml of methylene chloride and 4 g (0.0238 mol) of diphenylmethane is cooled to 0-5° C. and 3.7 ml (0.0274 mol) of aluminum chloride are added. The mixture is stirred at room temperature for 4 hours. It is poured into a water/ice mixture and the two phases are separated. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is taken up with isopropyl ether, the mixture is stirred and the precipitate formed is filtered off. 4.5 g of 2-(4-benzylphenyl)acetyl bromide are isolated. The resulting product is mixed with 8 ml of trifluoroacetic acid and 4.57 ml (0.048 mol) of triethylsilane. The mixture is heated at 80° C. for 4 hours and the residue is taken up with an ethyl ether/sodium bicarbonate mixture. The two phases are separated, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 6.5 g of the title compound, which is purified by chromatography on a silica gel column using a 9/1 cyclohexane/ethyl acetate mixture as the eluent. The first eluted fraction, which corresponds to the title compound, is isolated.
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[N:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C([O-])(=O)C.[Na+].[Br:25]Br>>[NH2:15][C:14]1[C:13]2[N:12]=[C:11]([Br:25])[N:10]([C@@H:1]3[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]3[OH:3])[C:19]=2[N:18]=[N:17][N:16]=1
Reactant: BrBr
Reactant: Nc1nnnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Nc1nnnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 20 °C
Reaction time: 72 h

Procedure:
The 2-azaadenosine [for preparation see Patent WO 01/16149, 2001] (70 mg, 0.26 mmol) was added to a solution of sodium acetate 0.5M (1.4 mL). The solution was heated until the 2-azaadenosine was solubilized. A solution of bromine (100 μL of Br2 in 10 mL of water) (6.3 mL, 1.22 mmol) was added and the mixture was stirred at 20° C. for 3 days. A second portion of the bromine's solution (6.3 mL, 1.22 mmol) was added and the mixture was stirred at 20° C. for 3 hours. The reaction mixture was evaporated to dryness. The crude product was purified on silica gel reverse-phase (C18) using water/acetonitrile (9/1) as eluant to give the title compound as a yellow powder.
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]([CH2:31][CH2:32][CH3:33])[C:19](=[O:30])[N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH:21]=2)=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+].Cl>CCO>[CH3:34][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][C:17]2[N:18]([CH2:31][CH2:32][CH3:33])[C:19](=[O:30])[N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH:21]=2)=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:35])=[O:3]
Reactant: CCCn1c(CCOc2ccc(OC(C)(C)C(=O)OCC)cc2)cn(Cc2ccc(C)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCn1c(CCOc2ccc(OC(C)(C)C(=O)O)cc2)cn(Cc2ccc(C)cc2)c1=O
Yield: 70.7 %

Procedure:
The 2-methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester (0.036 g, 0.075 mmol) was combined with aqueous 5 N NaOH (0.15 mL) in EtOH (5 mL) and heated to reflux under N2 for 1 h. The reaction was cooled and the solvent removed in vacuo to give a residue that was acidified with aqueous 1 N HCl (1 mL). The mixture was extracted with Et2O and water, the organic layer dried (MgSO4), and the solvent removed in vacuo to afford 0.024 g (71%) 2-methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenoxy)-propionic acid. HRMS (ES+) m/z exact mass calcd for C26H33N2O5 [M+0.1] 453.2389, found 453.2387. 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28]Br)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:31]1([C:37]2([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:27][CH2:28][N:40]3[CH2:39][CH2:38][C:37]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41]3)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(CN2CCC(CCBr)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(CN2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare according to the method of example 57.8 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzyl)-pyrrolidin-3-yl]-ethyl-bromide (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (7.5 mmol, 1.5 eq.). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Cl)ccc1C(=O)O
Product: COc1cc(Cl)ccc1C(=O)Cl

Procedure:
A solution of 2.0 g of 4-chloro-o-anisic acid in 22 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is is concentrated from toluene three times and dried under vacuum to give 2.0 g of the desired product as a residue.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=1[CH3:25])(=[O:14])[CH:6]=[CH:7]C1C=CC=CC=1>ClC1C=CC=CC=1>[C:20]([C:19]1[CH:23]=[C:24]2[C:16](=[C:17]([CH3:25])[CH:18]=1)[NH:15][C:5](=[O:14])[CH:6]=[CH:7]2)([OH:22])=[O:21]
Reactant: Cc1cc(C(=O)O)ccc1NC(=O)C=Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Cc1cc(C(=O)O)cc2ccc(=O)[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
7.1 g of aluminum chloride was added to a solution of 2.5 g of 4-cinnamoylamino-3-methylbenzoic acid in 12.5 ml of chlorobenzene. The mixture was stirred at 90° C. for 1 hour to give rise to a reaction. The reaction mixture was poured into ice water. The resulting precipitate was collected by filtration and dispersed in 70 ml of ethanol and 70 ml of water. The dispersion was made alkaline with a 30% aqueous sodium hydroxide solution and then treated with active carbon. The resulting material was made acidic with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and then washed with hot ethanol to obtain 0.9 g of 6-carboxy-8-methylcarbostyril as a light brown powder.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].C(=O)([O-])O.[Na+].[CH3:16][C:17]([CH3:19])=O>>[CH3:16][C:17]1([CH3:19])[O:4][C@@H:3]2[C@@H:5]([C@@H:7]([CH2:9][OH:10])[O:8][CH:2]2[OH:1])[O:6]1
Reactant: CC(C)=O
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Temperature: 58 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
To 500 ml of acetone were added 20.0 g of D-ribose and 250 mg of anhydrous cupric chloride, and the mixture was stirred for 5 hours under reflux in a warm-water bath at 58° C. The refluxing solvent was continuously dried with 30 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. After the conclusion of the reaction, a small amount of aqueous sodium hydrogencarbonate is added to the reaction mixture, and the acetone was distilled off under reduced pressure. The residue was dissolved in benzene, and the solution was washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The benzene was distilled off under reduced pressure and the residue was subjected to distillation under reduced pressure, producing 13 g (51%) of 2,3-O-isopropylidene-D-ribofuranose as a fraction of 109°-112° C./0.04 mmHg.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]1=[O:7].[OH-].[Na+].Cl[CH2:11][C:12]([OH:14])=[O:13].Cl>>[O:7]=[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=c1cncc[nH]1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1ccncc1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Pyrazin-2(1H)-one (0.333 g, 3.47 mmol) was added 5 N sodium hydroxide solution (2.1 mL) followed by chloroacetic acid (0.524 g, 5.54 mmol). The reaction mixture was heated at 100° C. for 2 h. After cooled down to ambient temperature, 2 N hydrochloric acid (3.5 mL) was added and the reaction mixture was directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to yield the title compound as a yellow solid. LC/MS 155.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C-:20]#[N:21].[K+].O>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=[C:2]([C:20]#[N:21])[C:3]2=[O:19])=[CH:13][CH:14]=1
Reactant: [C-]#N
Reactant: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Temperature: 140 °C
Yield: 65.1 %

Procedure:
A mixture of 3-chloro-1-(4-chlorophenyl)-1,2-dihydroquinoxalin-2-one (10.0 g) and potassium cyanide (2.5 g) in dry dimethylformamide (100 ml) was heated at 140° C. for 24 hours. The mixture was added to water and the product was extracted into chloroform. Evaporation of the solvent and crystallisation of the residue from ethanol gave the title compound (6.3 g) mp 232°-235° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:33])[CH2:3][CH2:4][N:5](CC1C=CC=CC=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:21][CH2:22][CH:23]([NH2:25])[CH3:24])CC1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[NH2:25][CH:23]([CH3:24])[CH2:22][CH2:21][NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH:2]([NH2:1])[CH3:33]
Reactant: CC(N)CCN(CCCCCCCN(CCC(C)N)Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(N)CCNCCCCCCCNCCC(C)N
Yield: 97.4 %

Procedure:
Combine N,N'-bis[3-(amino)butyl]-N,N'-bis[(phenyl)methyl]-1,7-diaminoheptane (13.4 g, 0.029 mol), Pearlman's Catalyst (2.0 g) and ethanol (90 ml) and treat the mixture with hydrogen gas at 45 lb/in2 until gas uptake ceases. Remove the catalyst by filtration and remove the solvent in vacuo to obtain 7.7 g of N,N'-bis[3-(amino)butyl]-1,7-diaminoheptane (Rf is 0.37 for TLC on silica gel developed with 40% conc. ammonia in methanol). Dissolve the residue in dichloromethane (90 ml) and treat the mixture with di-t-butyldicarbonate (26.2 g, 0.12 mol) for 3 hours. Remove the solvent in vacuo and purify the residue by flash chromatography on silica gel eluting with 25% ethyl acetate in hexane to yield 17.1 g of the title compound as a clear oil. Rf is 0.35 for TLC on silica gel developed with 25% ethyl acetate in hexane.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[OH:23].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=2[OH:23])=[N:3][N:4]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: Oc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1nnc(Cl)c2ccccc12
Temperature: 80 °C
Reaction time: 17 h
Yield: 76.9 %

Procedure:
To a solution of 1,4-dichlorophthalazine (9.96 g, 50 mmol) in dichloroethane (180 ml) was added 2-naphthol (7.24 g, 50 mmol) and aluminum chloride (7.38 g, 55 mmol) and the mixture was stirred at 80° C. for 17 hrs. The dark red solution was poured in ice water (600 ml) and the resulting brown suspension was stirred vigorously for 1 hr. The solid was collected by filtration, washed with diethyl ether and dried to give 11.8 g of the title compound as a beige solid. (Yield: 77%)
Reaction SMILES: Cl.O.[N+:3]([C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-])=O>C(O)C>[NH2:3][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=Cc1ccccc1N
Yield: 84.1 %

Procedure:
A mixture of 2.2g of reduced iron, 0.5 ml of conc. hydrochloric acid and 2.5 ml of water was added to a solution of 2.2 g of ethyl o-nitrocinnamate in 30 ml of ethanol. After heating under reflux for 1 hour, insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. An aqueous sodium hydrogen carbonate solution was added to the residue followed by extraction with toluene. After the extract was washed with water and dried, the solvent was distilled off to obtain 1.6 g of ethyl o-aminocinnamate as yellow crystals.
Reaction SMILES: C[O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2nc(-c3ccccc3)ccc2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1ccc(-c2ccccc2)nn1Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 2-(4-methoxybenzyl)-6-phenylpyridazin-3(2H)-one (400 mg, 1368 mmol) in DCM (2.5 mL) at 0° C. under nitrogen was added boron tribromide (1294 μl, 13683 μmol) drop-wise over a 1 minute period. More DCM (10 mL) was added to the reaction to create a suspension and ice bath removed. After 3 hours, the reaction was chilled to 0° C. and quenched with methanol (5 mL). The pH was then adjusted to 14 with NaOH (1 M), then adjusted to 7 with HCl (5 M). The aqueous layer was then extracted 3× with 9:1 CHCl3/IPA (50 mL). The combined organics were then dried with sat NH4Cl and MgSO4. The organic was then concentrated onto dry silica (20 g) and purified on silica (40 g) eluting with 20>40% of EtOAc/DCM. Product was isolated as a white solid. MS (ESI pos. ion) calc'd for C17H14N2O2: 278; found 279 (MH+). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.21 (s, 2 H) 6.68-6.77 (m, 2 H) 7.06 (d, J=9.78 Hz, 1H) 7.22 (d, J=8.61 Hz, 2 H) 7.40-7.55 (m, 3 H) 7.89 (dd, J=8.22, 1.37 Hz, 2 H) 8.04 (d, J=9.78 Hz, 1 H) 9.42 (s, 1 H).