Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.[NH:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:8]([C:12]([OH:14])=O)[CH:9]([CH3:11])[CH3:10].[NH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl.C1COCC1.C(N(CC)CC)C>[NH:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:8]([C:12]([NH:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:14])[CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CN
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 89 %

Procedure:
1 liter of ethyl acetate was added to 80 g of BOC-Val.DCHA and the mixture was washed twice with 600 ml of sulfuric acid and water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the free acidin an oily form. The free acid and 28 g of H-Gly-OEt.HCl were dissolved in a solvent mixture of 150 ml of chloroform and 150 ml of THF. The solution was cooled and 28 ml of triethylamine and 41.2 g of DCC were added thereto. The resultant mixture was stirred at a temperature of 0° to -2° C. for 1 hour and at room temperature overnight. The insoluble materials were removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1 N hydrochloric acid, water, a 5% sodium bicarbonate aqueous solution and water, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was crystallized by addition of n-hexane and recrystallized from ethyl acetate-diethyl ether-n-hexane to obtain 54 g (89.2%) of the desired material with a melting point of 94°-96° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:12][C:10](=[O:11])[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CCCCCCC>CN(C)C(=O)C>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:9]1[C:7](=[O:8])[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[O:12][C:10]1=[O:11]
Reactant: OCCCCCCCCCBr
Reactant: O=c1[nH]c(=O)c2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1oc2ccccc2c(=O)n1CCCCCCCCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A mixture of 6.525 g (40 mmol) of carsalam, 10.26 g (44 mmol) of 9-bromo-1-nonanol, and 5.30 g (50 mmol) of sodium carbonate in 30 mL N,N-dimethylacetamide (DMA) was heated at 75–80° C. for 3 hours. TLC (eluent:ethyl acetate/heptane) indicated the reaction was completed. The reaction was carefully poured into a mixture of ice-water. The resulting white solid was stirred for 1 hour. It was collected on sintered glass funnel, washed with water, hexane and dried in vacuo to yield 9.80 g of 3-(9-hydroxynonyl)-2H-1,3-benzoxazine-2,4(3H)-dione(80%). To a slurry of 6.11 g (20 mmol) of 3-(9-hydroxynonyl)-2H-1,3-benzoxazine-2,4(3H)-dione in 10 mL of N,N-dimethylacetamide at room temperature was added 20.4 mL (20.4 mmol) of potassium t-butoxide in THF solution. The clear brown solution became very thick. More DMA (10 mL) was added, and the mixture was heated at reflux for 5 minutes. 0.664 g (4 mmol) of potassium iodide was added, followed by dropwise addition of 3.34( 20 mmol) of ethyl bromoacetate. The reaction was refluxed for 1 hour, cooled to about 35° C. and poured into ice-water. A gum resulted. The supernatant liquid was decanted and fresh water was added. That procedure was repeated twice. The gum was dissolved in THF. The THF solution was carefully poured into hexane. The resulting solid was collected, washed with hexane and dried in vacuo. The weight of the desired product was 2.36 g (35%). HPLC: 4.39 min.; Mp: 125–128° C. HNMR(M DSO d6): δ 1.25 (12H, m), 1.37 (2H, m), 1.53 (2H, m), 3.28 (2H, m), 3.36 (2H, t), 4.85 (2H. s), 7.07 (2H, m), 7.45 (1H, t), 7.88 (1H, d), 8.70 (1H, t). Anal. Calcd for C18H27NO5: C, 64.07; H, 8.07; N, 4.15. Found: C, 63.71; H, 8.29; N, 4.31.
Reaction SMILES: [Br:1][C:2]1[C:45]([N+:46]([O-])=O)=[CH:44][CH:43]=[CH:42][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:7]1.[CH:49]([Mg]Br)([CH3:51])[CH3:50]>>[Br:1][C:2]1[C:3]([CH2:4][O:5][CH:6]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:14][CH:13]=3)[CH2:10][CH2:9][N:8]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:7]2)=[CH:42][CH:43]=[C:44]2[C:45]=1[NH:46][C:49]([CH3:51])=[CH:50]2
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc([N+](=O)[O-])c2Br)cc1
Reactant: CC(C)[Mg]Br
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3cc(C)[nH]c3c2Br)cc1

Procedure:
Analogously to Example 21b, 0.350 g of benzyl 3-(2-bromo-3-nitrobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 21c) and 2.84 ml of isopropylmagnesium bromide (0.5M in tetrahydrofuran) are reacted. The title compound is obtained as a white foam. Rf=0.23 (1:2 EtOAc-heptane); Rt=6.13.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]=[CH:20][C:19]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:27])=[C:18]2[OH:37])=[O:10].CCN(CC)CC.CO>CN(C=O)C.C(Cl)Cl>[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]=[CH:20][C:19]([C:26]([NH:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[O:27])=[C:18]3[OH:37])=[O:10])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=C(CBr)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CN1CCOCC1)OCCCc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Yield: 68 %

Procedure:
Morpholine (0.03 mL) is added to a solution of 3-(3-{[(4-chlorobenzyl)amino]-carbonyl}-8-fluoro-4-hydroxy-6-quinolinyl)propyl 2-bromoacetate from Example No. 145 (0.10 g) and Et3N (0.040 mL) in 5 mL DMF. The reaction is stirred at room temperature after which time reaction is complete. The reaction is partitioned between CH2Cl2 (50 mL) and H2O (25 mL). The organic layer is washed twice with H2O, and once with brine. The aqueous layers are combined and back-extracted with CH2Cl2. The organics are combined, dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow liquid. The liquid is re-dissolved in CH2Cl2 and adsorbed onto silica. Chromatography on a Biotage Flash 40S column (eluent 1% MeOH:CH2Cl2 (1 L), followed by 2% MeOH:CH2Cl2 (2 L) and 5% MeOH:CH2Cl2 (1 L)) affords the desired product as a white solid (0.070 g, 68%).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[CH3:26][C:27]1[N:28]=[C:29]([CH3:56])[N:30]2[C:35]=1[C:34]([O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=1)=[N:33][C:32]([C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1)=[N:31]2>ClCCl>[CH3:26][C:27]1[N:28]=[C:29]([CH3:56])[N:30]2[C:35]=1[C:34]([O:36][C:37]1[CH:38]=[C:39]([O:47][CH3:48])[C:40]([O:45][CH3:46])=[C:41]([O:43][CH3:44])[CH:42]=1)=[N:33][C:32]([C:49]1[CH:50]=[CH:51][C:52]([NH:53][C:1](=[O:4])[CH3:2])=[CH:54][CH:55]=1)=[N:31]2
Reactant: CC(=O)O
Reactant: COc1cc(Oc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cc(Oc2nc(-c3ccc(NC(C)=O)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 10 mg (0.09 mmol) of acetic acid in dichloromethane is treated with 10 mg (0.09 mmol) of HOBt and 20 mg (0.21 mmol) of 4-methylmorpholine. The mixture is cooled to −20° C. and treated with 20 mg (0.09 mmol) of EDC. It is stirred for 30 min. Subsequently, 30 mg (0.07 mmol) of 4-[5,7-dimethyl-4-(3,4,5-tri-methoxyphenoxy)imidazo[5,1-f][1,2,4]triazin-2-yl]aniline from example 1 are added thereto at −20° C., and the mixture is stirred for 5 h at 20° C. The solution is then washed with aqueous 1 N potassium hydrogensulfate solution and saturated aqueous sodium hydrogencarbonate solution. The organic phase is dried and concentrated under reduced pressure. The residue is purified by flash chromatography (eluent:dichloromethane/methanol 100:1-80:1-60:1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][C:5]2=[N:4][N:3]=1.[Cl:16][C:17]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[N:9]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:17]=4[Cl:16])=[CH:30][CH:29]=3)=[O:27])[CH2:10][CH2:11][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2n1-c1ccccc1NCC2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nnc2n1-c1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2,4-dichlorobenzoyl)amino]benzoyl chloride and 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO3 and brine. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[CH:8]=[C:9]([CH2:11][CH2:12][NH2:13])[N:10]=1)[CH2:3][CH2:4][CH3:5].[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=O.C(O)C>C(Cl)(Cl)Cl>[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]2[CH:33]([C:32]([O:36][CH2:37][CH3:38])=[O:35])[NH:13][CH2:12][CH2:11][C:9]=2[N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc(CCN)cn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)NCC2
Yield: 44.1 %

Procedure:
A mixture of 2-n-butyl-4-(2-aminoethyl)-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole hydrochloride (0.278 g), ethyl glyoxylate (0.179 g) and ethanol (5 ml) is refluxed for three days. To the mixture is added chloroform, and the mixture is washed, dried and evaporated to remove the solvent. The solvent is purified by silica gel column chromatography (solvent; chloroform/methanol=10.1) to give ethyl 2-n-butyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.136 g) as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:50]([Cl:51])=[CH:49][C:5]2[NH:6][C:7]([CH2:9][CH2:10][CH:11]3[CH2:14][CH:13]([N:15]([CH2:17][C@@H:18]4[C@H:22]5[O:23]C(C)(C)[O:25][C@H:21]5[C@H:20]([N:28]5[C:32]6[N:33]=[CH:34][N:35]=[C:36]([NH:37]CC7C=CC(OC)=CC=7OC)[C:31]=6[CH:30]=[CH:29]5)[CH2:19]4)[CH3:16])[CH2:12]3)=[N:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>FC(F)(F)C(O)=O.O>[NH2:37][C:36]1[C:31]2[CH:30]=[CH:29][N:28]([C@@H:20]3[CH2:19][C@H:18]([CH2:17][N:15]([CH:13]4[CH2:12][CH:11]([CH2:10][CH2:9][C:7]5[NH:8][C:4]6[CH:3]=[C:2]([Cl:1])[C:50]([Cl:51])=[CH:49][C:5]=6[N:6]=5)[CH2:14]4)[CH3:16])[C@@H:22]([OH:23])[C@H:21]3[OH:25])[C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(Cl)c(Cl)cc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(Cl)c(Cl)cc3[nH]2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
7-((3aS,4R,6R,6aR)-6-(((3-(2-(5,6-Dichloro-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(methyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (377 mg, 0.513 mmol) was dissolved in a mixture of Trifluoroacetic Acid (7.1 ml) and Water (0.8 ml) which had been pre-cooled at 0° C. in an ice bath. The solution was stirred at 0° C. for 30 minutes, then warmed to and stirring was continued for 3 h at RT. The suspension was concentrated and the residue was taken up in 15 ml MeOH and concentrated. This procedure was repeated twice and the residue placed on high vacuum. The material was taken up in 10 ml MeOH (gave a slurry) and was treated with 500 mg K2CO3 and 0.2 ml of water. The mixture was allowed to stir for 1.5 hr, during which time the pH of the solution was −9. The mixture was filtered through a fine frit, the solids were washed with 20 ml MeOH and the filtrate was concentrated to yield an off white solid. The material was left on high vacuum overnight and purified by flash chromatography (SiO2, eluting with 10-12% 7N NH3 in CH3OH/CH2Cl2) to give the desired product (227 mg). 1H NMR (400 MHz, MeOD) δH ppm 8.06 (s, 1 H), 7.63 (m, 2 H), 7.21 (dd, J=3.63, 2.38 Hz, 1 H), 6.59 (d, J=3.52 Hz, 1 H), 4.32 (m, 1 H), 3.88 (m, 1 H), 3.01 (m, 0.5 H), 2.84 (m, 2 H), 2.70 (m, 0.5 H), 2.51 (m, 1 H), 2.40 (m, 2 H), 2.26 (m, 2 H), 2.17 (d J=7.05 Hz, 3 H), 2.11 (m, 2 H), 2.02 (m, 1 H), 1.90 (m, 3 H), 1.62 (m, 1 H), 1.49 (m, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Br-].[CH2:12]([Zn+])[CH:13]([CH3:15])[CH3:14]>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH2:12]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Brc1ccc2occc2c1
Reactant: CC(C)C[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc2occc2c1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
5-bromobenzofuran (500 mg, 2.56 mmol) was dissolved in THF solution of isobutylzinc(II) bromide (0.5M, 15 mL, 7.40 mmol) in a microwave reaction tube. Pd(PtBu3)2 (65 mg, 0.128 mmol, 0.05 eqv.) was added to this solution. The mixture was purged with N2 gas for 3-5 min and heated at 100° C. for 30 min under microwave irradiation. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with 1N HCl aqueous solution, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (ISCO system, 5% EtOAc in hexanes) to give 0.331 g desired product (74% yield): 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.35 (d, 1H), 7.07 (d, 1H), 6.70 (s, 1H), 2.59 (d, 2H), 1.9 (m, 1H), 0.9 (d, 6H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:32]([O-:35])([O-:34])=[O:33].[Na+:36].[Na+]>C(O)C.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:32]([O-:35])(=[O:34])=[O:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:36]
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Yield: 15.2 %

Procedure:
1,4,5-Triphenyl-2-(6-bromohexyloxy)imidazole (0.95 g) was dissolved in hot ethanol (5 ml) and a solution of sodium sulphite (0.25 g) in hot water (3 ml) was added. The white suspension was heated at reflux for 24 hours then evaporated to dryness. The residue was recrystallised from ethanol then methanol/ethanol to give sodium 6-(1,4,5-triphenylimidazol-2-yloxy)hexane-sulphonate (0.15 g, 15%) as a colourless solid, m.p. 265° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.O.O.[I:16](O)(=O)(=O)=O.II.[O-]S([O-])(=S)=O.[Na+].[Na+]>O.CC(O)=O>[I:16][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([NH2:8])=[N:4][CH:5]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Cc1cccnc1N
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(I)cnc1N
Temperature: 80 °C
Yield: 207.7 %

Procedure:
To a solution of 3-methyl-2-pyridinamine (10 g) in a mixed solution of AcOH (60 mL), water (12 mL), and sulfuric acid (4.2 mL) was added periodic acid dihydrate (4.22 g) and iodine (9.39 g), and the mixture was heated at 80° C. for 2 hours. The reaction mixture was poured into 5% Na2S2O3 aq solution and extracted with ether. The organic layer was washed with 1N NaOH aq solution and brine, and dried over Na2SO4. The solvent was removed in vacuo and obtained residual solid was recrystallized with EtOH to give 5-iodo-3-methyl-2-pyridinamine (9.00 g) as pale yellow powder.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([CH:22]=[O:23])[CH:17]=[CH:16]3.[Se](=O)=[O:26]>O1CCOCC1.O>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:24][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22]([OH:26])=[O:23])[CH:17]=[CH:16]3
Reactant: O=[Se]=O
Reactant: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21

Procedure:
A mixture of (S)-2-methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (500 mg, 1.66 mmol, described in Intermediate 6) and selenium dioxide (552 mg, 4.97 mmol) in dioxane (30 mL) and H2O (3 mL) was heated at reflux for 18 h. The reaction mixture was allowed to cool, then it was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=332 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O-:13])(=[O:12])[CH3:11].[Na+].ClCC(O)=O.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][CH2:11][C:10]([OH:13])=[O:12]
Reactant: CC(=O)[O-]
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(O)CCl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CNc1ccc(Cl)c(Cl)c1
Yield: 61.8 %

Procedure:
A solution of 32.4 g (0.2 mol) of 3,4-dichloroaniline and 28 g (0.2 mol) of sodium acetate in 200 ml of acetic acid and 40 ml of water is stirred under reflux. A solution of 28.5 g (0.3 mol) of chloroacetic acid and 15.9 g (0.15 mol) of sodium carbonate in 100 ml of water is run in over the course of half an hour. The mixture is kept under reflux for 3 hours, 30 ml of concentrated hydrochloric acid are added and the acetic acid is evaporated in vacuo. The residue is taken up in ether, the solution is washed with water and the acid is extracted with dilute sodium bicarbonate, reprecipitated with 3 N HCl, filtered off and dried. 27.2 g (62% yield) of acid, melting at 128°-130° C., are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1.CCCCCC>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:25][CH2:26][S:27](=[O:29])(=[O:28])[N:8]=2
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cnc(N)c(-c2ccc(Oc3ccccc3)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(Oc3ccccc3)cc2)=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-methyl-3-(4-phenoxyphenyl)pyrazin-2-amine (124 mg) in THF (dry) (5 mL) was added to a suspension of NaH (60%, 89.0 mg) and 2-chloroethanesulfonyl chloride (0.140 mL) in THF (dry) (5 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration and washed with water and EtOAc then recrystallized from EtOAc-EtOH to give the title compound (86.0 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)c(F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CBr)cc1F
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 53.9 %

Procedure:
To a solution of 2-fluoro-4-methylbenzoic acid (1.029 g, 6.678 mmol) in carbon tetrachloride (10 ml) were added N-bromosuccinimide (1.189 g, 6.682 mmol) and 2,2′-azobisisobutyronitrile (43.9 mg, 0.267 mmol). After stirring at 90° C. for 30 min and at 100° C. for 2.5 hr, the mixture was cooled to 0° C. The precipitate was collected by filtration and washed with hexane and water to give a crude product. The crude product was dissolved in ethyl acetate (5 ml), and hexane (10 ml) was added. The precipitated solid was collected by filtration, and dried under reduced pressure to give 4-(bromomethyl)-2-fluorobenzoic acid (838.6 mg, 3.599 mmol, yield 53.9%) as a slightly yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH:4]([OH:15])[CH2:3][CH2:2][N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)=[CH:8][CH:9]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(OCC(O)CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc(OCC(O)CCN2CCN(c3ccccc3)CC2)cc1
Yield: 27.1 %

Procedure:
This compound was prepared according to the procedure of Example 25. A mixture of 6.9 g (0.03 mole) of 4-chloro-1-(4-methoxyphenoxy)-2-butanol, 4.9 g (0.03 mole) of 1-phenylpiperazine, 16.0 g (0.15 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in a total volume of 200 ml of 1-butanol gave an oil which solidified. The collected solid was recrystallized from 2-propanol to give 2.9 g (27%) of white crystalline powder, m.p. 103°-105° C.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+].Cl>C(O)C.O>[C:19]1(/[CH:18]=[CH:2]/[C:1]([C:4]2[CH:17]=[CH:16][C:7]([CH2:8][CH:9]3[S:13][C:12](=[O:14])[NH:11][C:10]3=[O:15])=[CH:6][CH:5]=2)=[O:3])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Yield: 24.5 %

Procedure:
To a slurry of 5-(4-acetylbenzyl)thiazolidine-2,4-dione (4.0 mmol, 1.0 g), and benzaldehyde (4.0 mmol, 0.41 ml) in ethanol (10 ml) was added sodium methoxide (4.8 mmol, 260 mg). The solution was heated to reflux for 1.5 hours, then more benzaldehyde was added and the mixture was heated another 1.5 hours, then cooled, diluted with water (60 ml), acidified with 2N HCl and extracted with ethyl acetate (2×50 ml). The combined extracts were washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized from isopropanol to give title product as a pale yellow solid (0.33 g, 24%); m.p. 147°°149° C.