Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].Cl.[Cl:8][C:9]1[CH:10]=[C:11]([N:26]([C:31]2[C:50]([CH:51]3[CH2:53][CH2:52]3)=[CH:49][C:34]3[C:35]([C:45]([NH:47][CH3:48])=[O:46])=[C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[O:37][C:33]=3[CH:32]=2)[S:27]([CH3:30])(=[O:29])=[O:28])[CH:12]=[CH:13][C:14]=1[CH2:15][CH2:16][B:17]1[O:21]C(C)(C)C(C)(C)[O:18]1>C1COCC1.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([N:26]([C:31]2[C:50]([CH:51]3[CH2:53][CH2:52]3)=[CH:49][C:34]3[C:35]([C:45](=[O:46])[NH:47][CH3:48])=[C:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)[O:37][C:33]=3[CH:32]=2)[S:27]([CH3:30])(=[O:28])=[O:29])[CH:12]=[CH:13][C:14]=1[CH2:15][CH2:16][B:17]([OH:18])[OH:21]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(CCB4OC(C)(C)C(C)(C)O4)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(CCB(O)O)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
Sodium periodate (722 mg, 3.37 mmol) and 1N aqueous HCl (2.70 mL, 2.70 mmol) were added to a cold (0° C.) solution of 6-(N-(3-chloro-4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (150 mg, 0.225 mmol) in THF (3 mL). The mixture was stirred at 0° C. for 10 min and then warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate. The organic layer was separated, washed with 5% aqueous sodium thiosulfate and brine and dried over sodium sulfate. The solvent was evaporated and the residue was subjected to reverse phase HPLC (C18, acetonitrile:water with 0.1% formic acid) to give 33 mg (25%) of the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.41-8.51 (m, 1H) 8.14 (s, 1H) 7.92-8.02 (m, 2H) 7.59 (s, 2H) 7.46-7.51 (m, 1H) 7.35-7.44 (m, 3H) 7.29-7.35 (m, 1H) 7.17 (s, 1H) 3.37 (s, 3H) 2.79-2.87 (m, 3H) 2.62-2.74 (m, 2H) 2.11-2.24 (m, 1H) 0.93-1.09 (m, 1H) 0.75-0.93 (m, 4H) 0.46 (m, 1H). LCMS (m/z, ES+)=585 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17]CC=C)=[CH:9][CH:8]=1)[CH3:2].C(O[C:28](=O)[CH:29](OCC)[CH2:30]C1C2C(=CC=CC=2)C(O)=CC=1)C.C(Br)C=C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([CH2:30][CH:29]=[CH2:28])[CH:8]=1)[CH3:2]
Reactant: C=CCOc1ccc(CC(OCC)C(=O)OCC)c2ccccc12
Reactant: CCOC(=O)C(Cc1ccc(O)c2ccccc12)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)=O
Product: C=CCc1cc(CC(OCC)C(=O)OCC)c2ccccc2c1O
Temperature: 160 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
0.87 g (2.65 mmol) [rac]-3-(4-allyloxy-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester [prepared from [rac]-2-ethoxy-3-(4-hydroxy-naphthalen-1-yl)-propionic acid ethyl ester (example 150 a] and allylbromide, potassium carbonate in acetone at 60° C.] was stirred for 2 hours at 160° C. without any solvent. The dark residue was purified by flash chromatography (silica gel, hexane/AcOEt=4:1) to yield 0.82 g (94%) of [rac]-3-(3-allyl-4-hydroxy-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester as yellow oil.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26](C(OC(C)(C)C)=O)[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([O:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:28]=3)=[N:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([O:34][CH2:35][CH2:36][N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:28]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CCOc1ccc2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(OCc5ccccc5)cc34)n(C(=O)OC(C)(C)C)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCOc1ccc2cc(-c3n[nH]c4ccc(OCc5ccccc5)cc34)[nH]c2c1

Procedure:
The compound {2-[2-(5-benzyloxy-1H-indazol-3-yl)-1H-indol-6-yloxy]ethyl}diethylamine is prepared in the following way: 390 mg of 5-benzyloxy-3-[1-tert-butoxycarbonyl-6-(2-diethylaminoethoxy)-1H-indol-2-yl]-indazole-1-carboxylic acid tert-butyl ester in solution in 5 ml of dichloromethane and 2 ml of trifluoroacetic acid are stirred at ambient temperature for 20 hours. The solvent is evaporated off under vacuum in a rotary evaporator to obtain 480 mg of {2-[2-(5-benzyloxy-1H-indazol-3-yl)-1-indol-6-yloxy]ethyl}diethylamine in the form of a trifluoroacetate salt.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=[CH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].[BH3-]C#N.[Na+]>CO.CC(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=CCCC(=O)O
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1CCCC(=O)O
Reaction time: 0.33 h
Yield: 30.1 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-yl)cyclopropanecarboxamide (350 mg, 0.93 mmol, 1 eq) in anhydrous methanol (6.5 mL) and AcOH (65 μL) was added 4-oxobutanoic acid (15% in water, 710 mg, 1.0 mmol) at room temperature. After 20 min of stirring, NaBH3CN (130 mg, 2.0 mmol) was added in one portion and the reaction mixture was stirred for another 4 h at room temperature. The reaction mixture was quenched by addition of AcOH (0.5 mL) at 0° C. and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (5-75% ethyl acetate/hexanes) to give 4-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butylindolin-1-yl)butanoic acid (130 mg, 30%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=CCCCC1CC(c2ccc(F)cc2)=NO1
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(CCCCC2CC(c3ccc(F)cc3)=NO2)CC1
Yield: 63.7 %

Procedure:
4-[3-(4-Fluorophenyl)-4,5-dihydroisoxazol-5-yl]butanal (22.6 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 μL, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 22.8 mg (70.4%) of the target compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].F[B-](F)(F)F.[O:15]=[N+:16]=[O:17].O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:16]([O-:17])=[O:15])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=[N+]=O
Reactant: COc1ccccc1C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1C
Reaction time: 48 h

Procedure:
2-Methylanisole (20 g) in 500 ml dichloromethane chilled in an ice bath is treated with 27.2 g of nitronium tetrafluoroborate and stirred two days. The mixture is poured into water, the layers are separated, and the aqueous phase is washed with dicloromethane. The combined organic layers are dried, filtered, stripped, and chromatographed on silica gel with 9:1 to 8:2 hexane:ethyl acetate to give 2-methyl-4-nitroanisole. NMR (CDC3): δ 2.3 ⃝H,s), 3.9 (3H,s), 6.91H,d), 8.0 (1H,d), 8.1 (1H,d of d).
Reaction SMILES: O[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>P(Cl)(Cl)(Cl)=O>[N:3]1([C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:4][CH2:9][NH:10][CH2:11][CH2:2]1
Reactant: Oc1cnc2ccccc2n1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2nc(N3CCNCC3)cnc2c1
Temperature: 0 °C

Procedure:
2-Hydroxyquinoxaline (1.5 g) is heated in phosphorus oxychloride (10 mL) for 12 h, after which the reaction is concentrated and the residue partitioned between methylene chloride and 1 N NaOH. The resulting crude chloride is taken up in toluene (10 mL) and this solution is then added dropwise to a refluxing solution of piperazine (5 g) in toluene (40 mL). The resulting solution is refluxed for an additional 24 h, cooled to 0° C. for 0.5 h, filtered and concentrated. The filtrate is extracted with 10% acetic acid and the aqueous extracts washed with ether, basified and extracted with toluene. The toluene layer is washed with water, dried and concentrated. The concentrated material, which may alternatively be named quinoxalin-2-ylpiperazine, is placed under vacuum overnight (1.2 g, 77%, m.p. 74-76° C.). 1H NMR (CDCl3) 8.6 (s, 1H), 7.87 (dd, J=8, 1 Hz, 1H), 7.68 (dd, J=8, 1 Hz, 1H), 7.57 (ddd, J=8, 7, 1 Hz, 1H), 7.39 (ddd, J=8, 7, 1 Hz, 1H), 3.76 (t, J=5 Hz, 4H), 3.02 (t, J=5 Hz, 4H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCCBr)CC3)noc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (12 g, 55 mmol), K2CO3 (13 g) and 1,4-dibromobutane (20 g, 9.3 mmol, 1.7 eq) in acetonitrile (300 ml) was stirred at room temperature overnight. The inorganic material was filtered. The solution was concentrated to ˜80 ml, when crystals crashed out. The product was filtered to yield 14.16 g (73%), m.p.=243°-245° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1>>[O:19]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and [(4-phenoxy)benzene]sulfonyl chloride as described in the synthetic METHOD B to give a white solid (33.5 mg) with purity >90%. MS (pos) m/z 419.3.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>CO>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNCCc1ccccc1
Reaction time: 4 h
Yield: 76.2 %

Procedure:
Phenethylamine (121 g) is dissolved in methanol (500 ml) and thereto is added dropwise methyl acrylate (86 g) at room temperature. The mixture is stirred for 4 hours and then distilled to remove the solvent to give N-phenethyl-β-alanine methyl ester (157.8 g, 76%), b.p. 124°-127° C. (1.2 mmHg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])([F:14])[F:13])[CH:8]=[C:7]([CH2:23]P(=O)(OCC)OCC)[CH:6]=[CH:5]2.[CH:32]([C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38])=O.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15]([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])=[O:16])([F:14])[F:13])[CH:8]=[C:7](/[CH:23]=[CH:32]/[C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38])[CH:6]=[CH:5]2
Reactant: CCOP(=O)(Cc1ccc2cc(Br)c(C(F)(F)P(=O)(OCC)OCC)cc2c1)OCC
Reactant: COC(=O)c1cccc(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)c1cc2cc(/C=C/c3cccc(C(=O)OC)c3)ccc2cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl {6-bromo-7-[(diethoxyphosphoryl)(difluoro)methyl]-2-naphthyl}methylphosphonate (190 mg), and methyl 3-formylbenzoate (60 rag) in degassed THF (5 mL) at −78° C. was added potassium tert-butoxide (0.35 mL of a 1M solution in THF) and the reaction mixture was stirred for 1 h at 0° C. The mixture was quenched with a saturated solution of NH4Cl, extracted with EtOAc, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography eluting with 25% EtOAc/hexanes to afford the titled product.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[O:33][C:34](=[O:38])[O:35][C:36]=1[CH3:37].CCOC(C)=O>CN(C=O)C>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:31][C:32]2[O:33][C:34](=[O:38])[O:35][C:36]=2[CH3:37])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cc1oc(=O)oc1CBr
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCc2oc(=O)oc2C)o1
Reaction time: 14 h

Procedure:
To a stirred, room temperature solution of 5-(tetradecyloxy)furan-2-carboxylic acid (0.228 g, 0.70 mmol) in DMF (4 mL) was added potassium carbonate (0.146 g, 1.05 mmol) and 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (0.160 g, 0.84 mmol). The reaction vessel was capped and stirring was continued for 14 hrs at which time TLC ((20% EtOAc in Hexanes Rf=0.10 (SM) and 0.40 (Prod)) indicated complete consumption of the starting material. The reaction was quenched by the addition of water (5 mL), brine (5 mL) and EtOAc (30 mL). The biphasic mixture was transferred to a separatory funnel and the organic phase was extracted 3 times with brine (3×10 mL). The organic phase was dried and concentrated to give a colourless oil. The resulting crude material was purified by flash chromatography eluting with 5-20% EtOAc in hexanes to yield a colourless syrup that solidified on standing. 1H NMR (400 MHz, DMSO-d6) δ: 7.2 (d, 1H), 5.6 (d, 1H), 5.1 (s, 2H), 4.1 (t, 2H), 2.18 (s, 3H), 1.6-1.8 (m, 2H), 1.3-1.4 (m, 2H), 1.23 (d, 6H), 1.2 (s, 20H), 0.85 (t, 3H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:15])[C@@H:7]([OH:14])[C@@H:8]([NH2:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH3:4].[N:16]1([C:22]([NH:24][C:25]2([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[OH:14][C@@H:7]([C@@H:8]([NH:13][C:31]([C:25]1([NH:24][C:22]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)=[O:32])[CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:15]
Reactant: CCCCNC(=O)[C@@H](O)[C@@H](N)CCCC
Reactant: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCNC(=O)[C@@H](O)[C@H](CCCC)NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1
Reaction time: 8 h
Yield: 88.9 %

Procedure:
In anhydrous dichloromethane were dissolved 254 mg (1.21 mmol) of (2S,3S)-N-butyl-3-amino-2-hydroxyheptanamide, 310 mg (1.21 mmol) of 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid and 230 mg (1.45 mmol) of 1-hydroxybenzotriazole, subsequently, under nitrogen stream, 278 mg (1.45 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added to the solution at 0° C. Thereafter, the temperature of the reaction mixture was returned to room temperature and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 80 ml of ethyl acetate, and the resulting mixture was washed successively with water, a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated NaCl solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 489 mg (Yield: 89%) of the desired compound.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[N:3]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+]>O>[CH3:18][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cccc2[nH]c(S)nc12
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cccc2[nH]c(SC)nc12
Reaction time: 20 h
Yield: 58.3 %

Procedure:
To a solution of ethyl 2-mercapto-1H-benzimidazole-4-carboxylate (500 mg) were added iodomethane (351 mg) and potassium carbonate (622 mg) at ambient temperature and the mixture was stirred for 20 hours at same temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diisopropyl ether to give ethyl 2-methylthio-1H-benzimidazole-4-carboxylate (310 mg).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=O)(C)(C)C.[CH2:16]([O:23][C:24]([NH:26][C:27](=[NH:30])SC)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]([NH:26][C:27]([N:13]1[CH2:14][CH2:15][CH:11]([CH2:10][CH2:9][NH2:8])[CH2:12]1)=[NH:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CCN)C1
Temperature: 65 °C
Reaction time: 24 h
Yield: 67529.2 %

Procedure:
2.18 g (0.0102 mmole) (3RS)-3-(N-tert-butyloxycarbonylaminoethyl) pyrrolidine and 2.81 g (0.0125 mole) N-benzyloxycarbonyl-S-methylisothiourea was dissolved in 30 ml toluene and heated to 60-70° C. for eight hours followed by stirring at room temperature for one day. 0.3 M KHSO4-solution was added and the water layer was washed with a mixture of the toluene and ethyl acetate and left for 2 days under which time the Boc group was removed. The acidic water phase was made alkaline and extracted four times with CH2Cl2 The combined organic layer was dried (Na2SO4), filtered and evaporated to yield 2.0 g (51%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:14]=2)=[CH:8][C:7]=1[CH3:34].[OH-].[Na+].Cl>CO.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]([CH3:34])[CH:8]=2)=[C:21]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3)c2)ccc1CCC(=O)O
Yield: 107.1 %

Procedure:
A solution of 3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (0.221, 0.452 mmol) in methanol (7 mL) is treated with 5 N NaOH (2 mL) and heated to reflux until saponification is completed. The mixture is cooled, and the solvent is removed in vacuo to afford a residue that is acidified with 1 N HCl. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (Na2SO4), and the solvent removed in vacuo to afford 0.230 g (100%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C28H23O5Cl 474, found 475 and 477 (M+1 and M+3, 100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])[CH:17]=2)[N:12]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:11]=1.[CH3:37][OH:38]>CCOCC>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22](=[NH:23])[O:38][CH3:37])[CH:17]=2)[N:12]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[CH:11]=1
Reactant: CO
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C#N)c3)cc12
Agent: Cl
Solvent: CCOCC
Product: COC(=N)c1cccc(-c2cnc3c(c2)c(-c2ccccc2OC)cn3S(=O)(=O)c2ccc(C)cc2)c1

Procedure:
HCl gas was bubbled through a suspension of 3-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzonitrile (287.8 mg, 0.60 mmol) in, 3.5 mL of anhydrous MeOH. The mixture was then stirred for 5 hours at room temperature before ether (20 mL) was added. The precipitate was then collected by filtration and dried to afford methyl 3-(3-(2-methoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzimidate without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]([CH3:16])=[CH:12][C:13](O)=O>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][C:11]([CH3:16])([CH3:10])[CH2:12][CH2:13]2
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: CC(C)=CC(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1(C)CCc2cc(Cl)c(O)cc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The desired 6-chloro-2,2-dimethylchroman-7-ol was synthesized from 4-chlororesorcinol as follows. A mixture of 3,3-dimethylacrylic acid (7.0 g) and 4-chlororesorcinol (10 g) in Eaton's reagent (50 mL) was stirred at ambient temperature for 16 h. At the end, the mixture was poured over ice and the precipitate was filtered, dried and crystallized from aqueous methanol to provide 6-chloro-7-hydroxy-2,2-dimethyl-2,3-dihydro-4H-chomen-4-one (8.7 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C>[OH-].[Na+]>[O:16]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2ccccc2c1=O
Reaction time: 2 h
Yield: 80.4 %

Procedure:
4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h at reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a pale white solid (10.5 g, 92%). 1H NMR (DMSO-d6) δ 15.34 (s, 1H), 13.42 (s, 1H), 8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H).