Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[Cl:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]4)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: O=C(O)c1cccc2cc(Oc3ccnc4cc(Cl)ccc34)ccc12
Yield: 59.1 %

Procedure:
The title compound (1.57 g, 59% yield) was prepared as a brown solid from 6-hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 4,7-dichloroquinoline (1.81 g, 9.14 mmol) by an analogous procedure to that described in example 1. LC-MS (m/z) 350 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:5]2[N:4]=1.C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:5]2[N:4]=1)=[O:30]
Reactant: CSc1ncc2ccc(-c3ccccc3O)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3ccccc3O)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Into a 8-dram vial, 2-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol (0.530 g, 2.06 mmol) and Methylene chloride (15 mL, 230 mmol)were added. m-CPBA 70-75% (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 0.533 g, 2.16 mmol) was added over 10 minutes. The reaction was stirred at room temperature for 1 hour. The reaction was partitioned with DCM and sat. NaHCO3. The organic was separated, washed with Brine, and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenol as a yellow solid (0.485 g, 86%).
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16](Cl)=[N:15][C:14]=3[S:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:26]1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)CCC.CCOC(C)=O>[C:1]12([NH:11][C:12]([C:13]3[CH:18]=[CH:17][C:16]([N:25]4[CH2:30][CH2:29][CH2:28][C@@H:27]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:26]4)=[N:15][C:14]=3[S:20][CH2:21][CH2:22][CH3:23])=[O:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)C[C@@H]1CCCNC1
Reactant: CCCSc1nc(Cl)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Solvent: CCOC(C)=O
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)ccc1C(=O)NC12CC3CC(CC(C3)C1)C2
Yield: 44 %

Procedure:
N-adamantan-1-yl-6-chloro-2-(propylthio)nicotinamide (0.365 g, 1 mmol) was added to (S)-methyl 2-(piperidin-3-yl)acetate.HCl (0.194 g, 1 mmol) and potassium carbonate (0.415 g, 3 mmol) in butyronitrile (4 mL) was heated at 150° C. for 2 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in hexane. Pure fractions were evaporated to dryness to afford methyl {(3S)-1-[5-(adamantan-1-ylcarbamoyl)-6-(propylthio)pyridin-2-yl]piperidin-3-yl}acetate (0.215 g, 44%) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][O:7]1)C.O.[NH2:13][NH2:14]>C(O)CCC>[O:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:5][C:4]([NH:13][NH2:14])=[O:3]
Reactant: NN
Reactant: CCOC(=O)CC1CCCO1
Solvent: O
Solvent: CCCCO
Product: NNC(=O)CC1CCCO1

Procedure:
A solution of (rac.)-(tetrahydro-furan-2-yl)-acetic acid ethyl ester (3.84 g, 24 mmol) in n-butanol (24 mL) was treated with hydrazine hydrate (1.4 mL, 29 mmol) and the resulting mixture was then heated under reflux for 3 h. The solvent was evaporated and residual volatile components were azeotropically removed by coevaporation with toluene. Chromatographic purification (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a viscous, colorless oil (1.1 g, 32%). 1H-NMR (300 MHz, DMSO): δ=1.45 (mc, 1H), 1.70-1.95 (m, 3H), 2.13 (dd, J=6 Hz, J=14 Hz, 1H), 2.24 (dd, J=7 Hz, J=14 Hz, 1H), 3.56 (dd, J=8 Hz, J=14 Hz, 1H), 3.72 (dd, J=7 Hz, J=14 Hz, 1H), 4.05 (mc, 1H), 4.16 (s, 2H), 8.94 (s, 1H).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]1[C:17]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:9]=1[CH2:18][C:19]1[CH:20]=[C:21]([C@@H:25]2[O:33][C@H:32]([CH2:34][OH:35])[C@@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[CH:22]=[CH:23][CH:24]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:26]([O:27][C@@H:26]1[C@@H:28]([O:29][C:28](=[O:29])[CH3:30])[C@H:30]([O:31][C:32](=[O:33])[CH3:34])[C@@H:32]([CH2:34][O:35][C:5](=[O:7])[CH3:6])[O:33][C@H:25]1[C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][C:9]2[CH:10]=[C:11]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:8]=2)[CH:20]=1)(=[O:27])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 15 h

Procedure:
Acetic anhydride (0.3 ml) was added to a solution of (1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.24 g) in pyridine (5.0 ml) at room temperature and the mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with 10% aqueous solution of hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate, and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.ClC1C=CC=C(C(OO)=O)C=1.[OH-:30].[Ca+2].[OH-:32]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:32])(=[O:30])[C:10]3[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: [OH-]
Reactant: N#Cc1ccc2c(c1)Sc1ccc(Cl)cc1C=C2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc2c(c1)S(=O)(=O)c1ccc(Cl)cc1C=C2
Reaction time: 24 h

Procedure:
400 Mg. 8-chloro-3-cyanodibenzo[b,f]thiepin is dissolved in 30 cc. chloroform and 2 g. m-chloroperbenzoic acid added, and the solution stirred for 24 hours. 5 G. calcium hydroxide is added, the mixture stirred for five minutes and filtered through celite. The organic filtrate is evaporated to dryness and the residue chromatographed on silica gel and eluted with 5% ethyl acetate/benzene mixture to yield 339 mg. (76%) pure sulfone, m.p. 228°-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][S:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:29][C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:31][CH:30]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Product: CS(=O)(=O)c1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 4-methylsulfonylaniline (66 mg, 0.39 mmol). The title compound was obtained as a yellow solid (60 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.88 (1H, m), 9.01 (2H, s), 8.87 (1H, s), 7.96 (4H, s), 3.20 (3H, s). MS m/z: 502.04, 503.99 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:55])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:51]([CH3:54])[CH2:52][CH3:53])[C@H:33]([O:49][CH3:50])[CH2:34][C:35](=[O:48])OC3C(F)=C(F)C(F)=C(F)C=3F)[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:57][O:58][C@@H:59]([C@@H:65]1[CH2:69][CH2:68][CH2:67][NH:66]1)[C@@H:60]([CH3:64])[C:61]([OH:63])=[O:62].C(N(C(C)C)CC)(C)C>ClCCl>[CH:5]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:55])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:51]([CH3:54])[CH2:52][CH3:53])[C@H:33]([O:49][CH3:50])[CH2:34][C:35]([N:66]3[CH2:67][CH2:68][CH2:69][C@H:65]3[C@H:59]([O:58][CH3:57])[C@H:60]([C:61]([OH:63])=[O:62])[CH3:64])=[O:48])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:1]=2[CH:2]=[CH:3][CH:4]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 16 h
Yield: 83 %

Procedure:
To a mixture of #104 (2.00 g, <2.58 mmol, 1 eq.) in dichloromethane (6 mL, 0.4 M) was added a solution of #103 (483 mg, 2.16 mmol, 1 eq.) in dichloromethane (2 mL) followed by diisopropylethylamine (1.35 mL, 7.73 mmol, 3 eq.). The reaction mixture was stirred for 16 hours, then adsorbed onto silica and purified by silica gel chromatography (Gradient: 0% to 20% methanol in dichloromethane) to give #105 (1.67 g, 83%) as a white foam. Fractions containing the desired product with impurities (0.571 g) were collected separately.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[N:22]([C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2)=[C:23]=S.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:25]12([NH:22][C:23]3[O:19][C:18]([C:16]4[CH:15]=[CH:14][C:12]5[N:13]=[C:9]([C:3]6[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=6[Cl:1])[NH:10][C:11]=5[CH:17]=4)=[N:20][N:21]=3)[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(NC45CC6CC(CC(C6)C4)C5)o3)cc2[nH]1
Temperature: 25 °C

Procedure:
Combine 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (100 mg, 0.310 mmol) and 1-isothiocyanato-adamantane (78 mg, 0.403 mmol) in DMF (2 mL) and heat to 70° C. for 1 hr. Add EDCI (119 mg, 0.620 mmol) and heat the reaction for 1 hr. Allow the reaction to cool to room temp and dilute with water (10 mL). Collect the resulting precipitate by filtration and purify the solid by reverse-phase HPLC (35-65% ACN/H2O+5 mM NH4OH) to afford the title compound as a white solid: 1H NMR (400 MHz, MeOD) δ ppm 1.74-1.82 (m, 6H) 2.12 (s, 6H) 2.15 (br. s., 3H) 7.55-7.63 (m, 3H) 7.76 (br. s., 1H) 7.93 (br. s., 1H) 8.18 (br. s., 1H); MS (m/z) 480.1 (M+1).
Reaction SMILES: [H-].[Na+].C1(C)C=CC=CC=1.[C:10]([NH2:16])(=[O:15])[CH2:11][C:12]([NH2:14])=[O:13].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=O>C(O)CCC>[OH:13][C:12]1[CH:11]=[C:10]([OH:15])[N:16]=[C:19]([C:18]([F:25])([F:24])[F:17])[N:14]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC(=O)CC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: Oc1cc(O)nc(C(F)(F)F)n1
Reaction time: 16 h
Yield: 44.5 %

Procedure:
Sodium hydride (900 g, 57.5% dispersion in mineral oil; 518 g active NaH; 22.5M) was stirred with 7.5 L toluene in a 22 L round-bottomed flask. Butanol was added over 5 hr. so that the pot temperature was maintained at 40°. The mixture was stirred an additional 16 hr. Malonamide (765 g; 7.5 M) was added, followed by ethyl trifluoroacetate (1065 g; 7.5 M). The ensuing reaction was exothermic; the mixture was then heated on a steam-bath for 3.5 hrs. It was then stirred at 23°-25° for an additional 16 hrs. The mixture was extracted with water (1×4 L and 1×2 L). The combined aqueous extracts were treated with activated charcoal and filtered. The filtrate was maintained at 10°-15° as it was acidified to pH 1-2 with 37% hydrochloric acid. The mixture was chilled to 5°. The solid was isolated by filtration and dried at 50° in vacuo to give 600 g (44.4% yield) VI m.p. 255°-256° (Lit. 265°).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: FC(F)(F)c1cccc(I)c1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1cccc(C(F)(F)F)c1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-iodo-3-(trifluoromethyl)benzene.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:26]=[CH:25][C:24]([F:27])=[C:18]2[C:19]([O:21][C:22](=O)[C:17]=12)=[O:20]>>[F:15][C:16]1[CH:26]=[CH:25][C:24]([F:27])=[C:18]2[C:17]=1[C:22](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]2=[O:20]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Product: CCOC(=O)C(CN1C(=O)c2c(F)ccc(F)c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(4,7-difluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.80 g, 3.94 mmol) and 3,6-difluorophthalic anhydride (0.94 g, 4.33 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:8]2)=[CH:3][CH:2]=1.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][C:32]#[CH:33])[CH3:29]>CCCCCCC.CCOC(C)=O>[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][C:32]#[C:33][C:9]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:27])=[CH:6][CH:5]=2)[N:8]=1)[CH3:29]
Reactant: C#CCN(CC)CC
Reactant: Cc1ccc(-n2nc(OS(=O)(=O)c3ccc(C)cc3)c3cccnc32)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)CC#Cc1nn(-c2ccc(C)cc2)c2ncccc12

Procedure:
This product was prepared from toluene-4-sulfonic acid 1-p-tolyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 4:6; yield (64 mg, 40%); 1H NMR δ (CDCl3): 8.64 (m, 1H), 8.19 (m, 1H), 8.11 (d, J=8.52 Hz, 2H), 7.33 (d, J=8.49 Hz, 2H), 7.21-7.28 (m, 1H), 3.86 (s, 2H), 2.73 (q, J=7.17 Hz, 4H), 2.40 (s, 3H), 1.20 (t, J=7.16 Hz, 6H); LCMS m/z: 318.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH2:36]([O:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)[CH2:37][CH3:38]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:43]3[CH:44]=[CH:45][C:40]([O:39][CH2:36][CH2:37][CH3:38])=[CH:41][CH:42]=3)=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)[CH:9]=1
Reactant: CCCOc1ccc(B(O)O)cc1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: CCCOc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 4-propoxyphenylboronic acid (36 mg, 0.2 mmol) to give 5-{4-[4-(2,4-dichloro-phenyl)-2-(4′-propoxy-biphenyl-4-ylmethyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.OO.[C:18](=O)([O-])[O-:19].[K+].[K+].S(OC)(OC)(=O)=O>CO>[CH3:18][O:19][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=2[CH3:11])[CH:4]=[C:5]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C1Cc2c(C)ccc(C)c2N1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CO
Product: COC(=O)c1cc2c(C)ccc(C)c2n1OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
A flask was charged with 1.0 g (4.9 mmol) of methyl 4,7-dimethylindoline-2-carboxylate and 64 mg (0.193 mmol) of sodium tungstate-dihydrate, and the air in the reaction system was substituted with nitrogen. After 15 ml of methanol was added and the reaction mixture was cooled to 0° C., 1.25 g of 30% aqueous hydrogen peroxide solution was added and the reaction mixture was stirred for 3 hours. Then 1.1 g of potassium carbonate and 0.68 g of dimethyl sulfate were added dropwise and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was added dropwise to ice water and extracted with 15 ml of ethyl acetate three times. The ethyl acetate layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystals thus obtained were purified by silica gel column chromatography to provide 400 mg of white crystals. Yield: 36% m.p.: 90°-91° C.; 1H-NMR (300 MHz, CDCl3 /TMS; δppm): 7.16 (s, 1H), 7.00 (d, 1H), 6.82 (d, 1H), 4.11 (s, 3H), 3.94 (s, 3H), 2.68 (s, 3H), 2.48 (s,3H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[C:21]([NH:24][C:25]1[CH:44]=[CH:43][C:28]([O:29][CH2:30][CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)=[C:27]([O:45][CH3:46])[CH:26]=1)(=[O:23])[CH3:22]>CN(C)C=O>[C:21]([NH:24][C:25]1[CH:44]=[CH:43][C:28]([O:29][CH2:30][CH2:31][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9][CH2:10]2)=[C:27]([O:45][CH3:46])[CH:26]=1)(=[O:23])[CH3:22]
Reactant: COc1cc(NC(C)=O)ccc1OCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Fc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(NC(C)=O)ccc1OCCN1CCN(c2ccccc2F)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
1.07 g of 4-(2-fluorophenyl)piperazine and 1.5 ml of triethylamine are added to a solution of 1.5 g of 2-(4-acetamido-2-methoxyphenoxy)-1-(p-toluenesulfonyloxy)ethane in 10 ml of anhydrous dimethylformamide, and the mixture is stirred at 100° C. for 6 hours. After the reaction, the mixture is poured into ice-water, and the aqueous mixture is extracted with chloroform. The extract is washed with water and an aqueous saturated sodium chloride solution, successively. Said extract is dried and then evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography (Solvent; 2% methoanol/chloroform), and then recrystallized from a mixture of ethyl acetate and n-hexane. 1.3 g of 1-[2-(4-acetamido-2-methoxyphenoxy)ethyl]-4-(2-fluorophenyl)-piperazine are thereby obtained as colorless scales. Yield: 85%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[N:30]1([C:2]2[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=2)[C:5]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:10][CH:9]=2)=[O:6])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(N2CCOCC2)c1

Procedure:
Compound is formed by reacting 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide with morpholine under conditions described in general procedure B. Mp: 90-92° C. 1H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.19 (m, 1H), 7.81 (m, 1H), 7.58 (s, 1H), 7.53 (m, 3H), 7.40 (m, 2H), 7.17 (d, 1H, J=8.4), 7.01 (d, 1H, J=8.7), 4.30 (t, 2H, J=4.8), 3.74 (m, 4H), 3.57 (m, 4H), 3.18 (m, 4H), 2.85 (t, 2H, J=5.7), 2.54 (m, 4H). MS: 462.2 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][CH:24]([C:26](O)=[O:27])[CH3:25])[CH:19]=[CH:20][C:21]=1[Cl:22]>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:26](=[O:27])[C@H:24]([CH3:25])[NH:23][C:18]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-phenylalanine methyl ester hydrochloride (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a solid (mp=122-124.5° C.). The reaction was monitored by tlc (Rf=0.47 in 1:1 EtOAc:Hexanes) and the product was purified by flash chromatography using 1:1 EtOAc:Hexanes as the eluent.
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>C(O)(=O)C>[C:18]1([C:16]2[N:6]3[CH:5]=[N:4][C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]3[N:1]=[CH:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: CCOC(=O)c1nc[nH]c1N
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 1.55 g. of ethyl 5-aminoimidazole-4-carboxylate and 1.75 g. of 3-dimethylaminoacrylophenone in 25 ml. glacial acetic acid is refluxed for 6 hours and when cooled no precipitate formed. The reaction is evaporated to dryness and dissolved in methylene chloride. After being washed with a saturated sodium bicarbonate solution and dried with anhydrous sodium sulfate, the solution was passed through a short column of hydrous magnesium silicate. Hexane addition to this solution gave the desired product, m.p. 200°-204° C.