Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:8]#[CH:9])=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2.[I:22]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>ClCCl>[S:1]1[C:5]([CH2:6][CH:7]([O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])/[CH:8]=[CH:9]/[I:22])=[CH:4][C:3]2[CH:18]=[CH:19][CH:20]=[CH:21][C:2]1=2
Reactant: C#CC(Cc1cc2ccccc2s1)O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(/C=C/I)Cc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Cp2ZrHCl (1.719 g, 6.67 mmol) was added to a solution of 9-5 (1.372 g, 4.34 mmol) in dichloromethane (30 mL). The reaction was stirred for 30 min. at room temperature and N-iodosuccinimide (1.997 g, 8.88 mmol) was added. After 1 h, the reaction was poured into 100 mL of saturated NaHCO3 solution. The resulting mixture was extracted with dichloromethane (3×75 mL) and the combined organic extracts were dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (2% ethyl acetate/hexanes) gave 9-6 (1.7484 g, 91%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([S:18]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.Cl>CO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1)(=[O:19])=[O:20])[CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: COC(=O)c1ccc(S(=O)(=O)C(Cn2ccnc2)c2ccccc2OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C(Cn1ccnc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.3 %

Procedure:
1.30 ml of a 1N aqueous solution of sodium hydroxide was added to 260 mg of methyl 4-[1-(2-methoxyphenyl)-2-(imidazol-1-yl)ethylsulfonyl]benzoate (prepared as described in Example 41) in 4 ml of methanol, and the resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, the resulting mixture was neutralized with 1.30 ml of 1N aqueous hydrochloric acid, and the reaction mixture was treated and purified by the same method as described in Example 34, to give 214 mg of the title compound as a colorless powdery substance, melting at 134°-138° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Cl)Cl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(O)(=O)C>[CH3:14][C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:3]1[CH:2]=[O:1])=[O:9])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O

Procedure:
In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(OC3CCOCC3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(OC3CCOCC3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
Cyclohexyl[3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl]methanone (7.1 g) synthesized in the above-mentioned (4) was dissolved in tetrahydrofuran (200 mL) and methanol (20 mL), and sodium borohydride (90%, 1.6 g) was added under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was ice-cooled again, water (10 mL) and 1N hydrochloric acid (100 mL) were added carefully, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (6.7 g, 98%) of the title object compound as a pale-yellow oil.
Reaction SMILES: N1CCCC1C(OC1C=CC=CC=1)=O.C(O)(C(F)(F)F)=O.[N:22]1(C(OC(C)(C)C)=O)[CH2:26][CH2:25][CH:24]([C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[CH2:23]1>>[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Oc2ccccc2)C1
Agent: O=C(Oc1ccccc1)C1CCCN1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Oc1ccccc1)C1CCNC1

Procedure:
The compound 25 was prepared according to the method described for compound 23 employing TFA (0.66 mL, 8.58 mmol) and compound 24 (500 mg, 1.71 mmol) to give white solid compound. The compound was used without further purification after solvent removal.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([Br:23])[CH:22]=1>>[Br:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH:20]=[C:21]([Br:23])[CH:22]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Reactant: OB(O)c1cc(Br)cc(Br)c1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cc(Br)cc(Br)c2)cc1

Procedure:
The colourless gum (E)-ethyl 3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) and 3,5-dibromobenzene boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[C@H:13](Br)[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:7]1[CH:8]2[CH:13]1[CH2:12][CH2:11][O:10][CH2:9]2)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCOCC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
trans-(4-Bromo-tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester (intermediate D) (1.0 g, 3.5 mmol) was dissolved in 35 mL dimethylformamide. Sodium hydride (60%, 214 mg, 5.4 mmol) was added at 0° O. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by careful addition of water. The mixture was extracted three times with diethylether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate 1:0→1:1) yielded the title compound as a colorless oil (499 mg, 70%), MS: m/e=143 [(M-buten)+].
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][N:7]([CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:6]=2)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:7]2[CH:6]=[C:5]3[C:9]([CH:10]=[CH:11][CH:12]=[C:4]3[NH2:1])=[N:8]2)[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1cccc2nn(CCN3CCCC3)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2nn(CCN3CCCC3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole (1.20 g, 4.62 mmol), iron powder (2.60 g, 46.6 mmol) and ammonium chloride (0.125 g, 2.34 mmol) was suspended in a 4:1 ethanol/H2O solution. The mixture was heated to reflux for 3 hours, cooled to room temperature and the solvent removed in vacuo. The residue was stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes and filtered through a plug of silica gel. After rinsing with triethylamine/ethyl acetate (1/4), the filtrate was concentrated to provide the title product. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.66 (m, 4H), 2.50 (m, 4H), 2.96 (t, 2H, J=6.44), 4.44 (t, 2H, J=6.44), 5.51 (s, 2H), 6.70 (m, 1H), 6.88 (d, 1H, J=8.48), 6.91 (m, 1H), 8.28 (s, 1H); MS (DCI/NH3) m/z 231 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH:8]([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:14](O)(=O)C.C(N)=N>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:9][NH:10][CH:14]=[N:11]2)=[CH:12][CH:13]=1
Reactant: CC(=O)O
Reactant: NCC(N)COc1ccc(Cl)cc1
Agent: N=CN
Solvent: CCO
Product: Clc1ccc(OCC2CNC=N2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of 3-(4-chloro-phenoxy)-propane-1,2-diamine (0.19 g, 0.95 mmol) in ethanol (5 ml) was added formamidine acetate (0.1 g, 1.0 mmol) and the mixture was stirred overnight at room temperature. The solvent was evaporated, water (5 ml) was added and the mixture was extracted 3 times with dichloromethane (10 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent:ethyl acetate/methanol=90:10) to yield a light yellow oil (0.063 g, 32%); MS (ISP): 211.2 ((M+H)+).
Reaction SMILES: Cl[CH2:2][CH:3]=[O:4].C(=O)([O-])O.[Na+].[C:10]1(=O)[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]1.S(=O)(=O)(O)O>C(OCC)(=O)C.O>[O:4]=[C:3]1[C:11]2[CH:10]=[CH:15][O:16][C:12]=2[CH2:13][CH2:14][CH2:2]1
Reactant: O=C1CCCC(=O)C1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCCc2occc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a mixture of 80 ml of water and 20 ml of 40% aqueous solution of chloroacetaldehyde was added 10.0 g (119 mmoles) of sodium hydrogencarbonate while cooling with ice. To the resulting reaction mixture was added dropwise 90 ml of aqueous solution containing 11.2 g (100 mmoles) of 1,3-cyclohexanedione while cooling with ice at a rate of 0.4 ml/minute. The reaction mixture was maintained at a pH of from 9 to 6 throughout the reaction. After completing the dropping, the reaction mixture was stirred at a room temperature overnight. To the resulting reaction mixture was added about 100 ml of ethyl acetate, and then the reaction mixture was acidified (pH<1) with sulfuric acid and stirred for about one hour. The ethyl acetate layer was separated, washed with an aqueous solution of potassium carbonate, and dried on magnesium sulfate. After distilling away the ethyl acetate, the obtained residue was distilled under a reduced pressure to give 10.3 g (yield: 76%) of 4-oxo-4,5,6,7 -tetrahydrobenzofuran being a colorless oily material (boiling point: 66° C./1 torr).
Reaction SMILES: [CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(O[C:20](=[O:22])[CH3:21])(=O)C>>[CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][N:7]([CH3:8])[C:20](=[O:22])[CH3:21])[CH2:3][CH2:2]1
Reactant: CNCCC(=O)C1CC1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)N(C)CCC(=O)C1CC1
Temperature: 25 °C

Procedure:
A crude solution of 1-cyclopropyl-3-methylamino-1-propanone was cooled to 8°-10° C. and 8.2 g. (0.06 mole) of potassium carbonate was added, followed by 50 g. (0.5 mole) of acetic anhydride. The mixture was stirred until it warmed to room temperature. The benzene layer was separated, dried over magnesium sulfate, concentrated, and the residual oil distilled at 99°-150° C./0.1 mm. The distillate weighed 65 g. It was calculated to contain 80% of 1-cyclopropyl-3-(N-methylacetamido)-1-propanone by the nuclear magnetic resonance spectrum.
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:41]=[CH:40][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:4]1[N:3]([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:41][CH:40]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: O=C(O)Cn1nccn1
Reactant: COc1cccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Agent: Cl
Product: COc1cccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)N(C(=O)Cn3nccn3)C2)c1
Yield: 93 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide, gave Compound 69, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide (180 mg, 93%). 1H-NMR (400 MHz, CDCl3): σ 9.15 (s, 1H), 7.71 (s, 2H), 7.42 (d, 2H), 7.00 (t, 2H), 6.93-6.89 (m, 4H), 6.80-6.72 (m, 4H), 5.32-5.23 (m, 1H), 4.84 (d, 1H), 4.80 (d, 1H), 3.81 (s, 3H), 3.51 (dd, 1H), 3.17 (t, 1H), 2.99-2.88 (m, 2H), 2.69-2.59 (m, 2H), 1.73-1.65 (m, 1H). MS (EI) for C29H28FN5O4. found 530.2 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[NH2:16][CH2:17][CH:18]1[CH2:20][CH2:19]1.FC1C=C(C=C(S(C)(=O)=O)C=1)OCCNCCC>C(O)C>[CH:18]1([CH2:17][NH:16][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=2)[CH2:20][CH2:19]1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: NCC1CC1
Agent: CCCNCCOc1cc(F)cc(S(C)(=O)=O)c1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(OCCNCC2CC2)c1

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.05 g, 0.16 mmol) and aminomethylcyclopropane (0.11 ml, 1.3 mmol) in ethanol (5 ml). MS m/z (relative intensity, 70 eV) 287 (M+, 2), 246 (6), 138 (2), 84 (bp), 56 (14).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14](Cl)(=[O:16])[CH3:15].[Al+3].[Cl-].[Cl-].[Cl-]>>[C:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:16])[CH3:15]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)Oc1ccc(-c2ccccc2)cc1
Yield: 94 %

Procedure:
When a mixture of 4-hydroxybiphenyl with acetyl chloride and AlCl3 in a molar ratio of 1:1:1 was reacted for 1 hr, only 4-acetoxybiphenyl ##STR66## was obtained in a yield of 94%.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:71][N:72]1[CH2:77][CH2:76][O:75][CH2:74][CH2:73]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[C:55]([CH3:58])[CH:54]=[CH:53][C:52]=2[N:59]([S:61]([C:64]1[C:65]([Cl:70])=[N:66][CH:67]=[CH:68][CH:69]=1)(=[O:63])=[O:62])[CH3:60])=O)C1C=CC=CC=1.CSC.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:70][C:65]1[C:64]([S:61]([N:59]([CH3:60])[C:52]2[CH:53]=[CH:54][C:55]([CH3:58])=[C:56]3[C:51]=2[NH:50][C:49]([C:47]2[S:43][CH:44]([CH2:71][N:72]4[CH2:77][CH2:76][O:75][CH2:74][CH2:73]4)[CH2:45][N:46]=2)=[CH:57]3)(=[O:62])=[O:63])=[CH:69][CH:68]=[CH:67][N:66]=1
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccnc2Cl)c2[nH]c(C(=O)NCC(CN3CCOCC3)SCc3ccccc3)cc12
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CSC
Solvent: CC#N
Product: Cc1ccc(N(C)S(=O)(=O)c2cccnc2Cl)c2[nH]c(C3=NCC(CN4CCOCC4)S3)cc12
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
To a mixture of triphenylphosphine oxide (1.95 g) and acetonitrile (20 mL) was slowly added trifluoromethanesulfonic anhydride (0.59 mL) at 0° C., and the mixture was stirred for 10 min. N-[2-(Benzylthio)-3-morpholinopropyl]-7-[[(2-chloropyridin-3-yl)sulfonyl](methyl)amino]-4-methyl-1H-indole-2-carboxamide (1.10 g) and dimethylsulfide (0.20 mL) were added. The reaction mixture was stirred at 0° C. for 15 min. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.69 g, yield 76%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio). melting point 151-153° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[Na].S(=O)(=O)=O>CC(N(C)C)=O.O>[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([C:17]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)=[CH:15][CH:14]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: NC(=O)c1ccccc1N
Agent: O=S(=O)=O
Agent: [Na]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)c1ccc(-c2nc(O)c3ccccc3n2)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-aminobenzamide (1.36 g, 9.99 mmol, 1.00 equiv) in dimethylacetamide (25 mL), 4-(dimethylamino)benzaldehyde (1.49 g, 9.99 mmol, 1.00 equiv) and sulfonylideneoxidane sodium (1.6 g, 15.53 mmol, 1.50 equiv). The resulting solution was stirred overnight at 150° C. in an oil bath. The reaction mixture was cooled to 25° C. The resulting solution was diluted with 100 mL of water. The solids were collected by filtration. The solid was washed with 2×20 mL of water and 1×20 mL of petroleum ether. This resulted in 2.1 g (79%) of 2-[4-(dimethylamino)phenyl]quinazolin-4-ol as a gray solid. MS (ESI) m/z 266 ([M+H]+).
Reaction SMILES: CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([OH:30])=O.Cl.[CH3:32][NH:33][O:34][CH3:35]>CN(C)C=O.C(N(CC)CC)C>[CH3:35][O:34][N:33]([CH3:32])[C:28](=[O:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: CNOC
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccn1
Reaction time: 0.25 h

Procedure:
EDCI (2.30 g, 0.012 mol) and 1-hydroxy benztriazole (1.36 g, 0.009 mol) were added o a stirred solution of pyridine-2-carboxylic acid (1.0 g, 0.008 mol) in N,N-dimethyl formamide (16 mL) at 0° C. The reaction mixture was allowed to stir for 15 min then triethyl amine was added followed by addition of N,O-dimethyl hydroxyl amine hydrochloride at 0° C. The resulting mixture was stirred at RT overnight. The reaction mixture was partitioned between water (30 mL) and ethyl acetate (2×30 mL). The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using 100-200 mesh silica gel and 0-20% EtOAc: Hexane as eluant to obtain product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:42]([O:41][C:39](=[O:40])[C:31]1[CH:32]=[C:33]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:28])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:21][C:22]=2[F:27])[CH:34]=[CH:35][C:30]=1[Cl:29])[CH3:43]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2F)ccc1Cl

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 324, step 1) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=582.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:7][CH2:8][C:9]1[O:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:14]C1OC(CBr)=CC=1.C(Br)C1OC=CC=1>CCOCC>[CH2:8]([O:7][CH2:1][C:2]1[O:6][C:5]([CH3:14])=[CH:4][CH:3]=1)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(CBr)o1
Reactant: c1coc(COCc2ccco2)c1
Agent: BrCc1ccco1
Solvent: CCOCC
Product: Cc1ccc(COCc2ccco2)o1

Procedure:
d. 5-Methyl-furfuryl furfuryl ether is prepared by the procedure described by J. E. Zanetti in J.Am.Chem.Soc. 49, 1066 (1927) for the difurfuryl ether, starting with 5-methyl-furfuryl bromide (Compt, Rend. 222, 1441 (1946) instead of furfuryl bromide of Zanetti. The product was isolated by ether extraction of the crude mixture after having diluted with water. For purification the ether extract was distilled twice -- b.p. 68°-70°C. at 0.01 mm./Hg vacuum. The product was a viscous colourless liquid, darkening rapidly on contact with air.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[C:17]=3[CH3:26])[C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)c2nc[nH]c2c1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cn2cnc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
Into a 250 mL round bottomed flask charged with 4-bromo-6-nitro-1H-benzo[d]imidazole (5 g, 20.66 mmol) in N,N-Dimethylformamide (DMF) (100 mL) was added 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (7.84 g, 31.0 mmol) and potassium carbonate (8.57 g, 62.0 mmol). The resulting reaction mixture was stirred 1 h at 60° C., cooled to room temperature and poured into water, extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 80% over 10 column volumes. The expected compound was collected and evaporated to yield 4-bromo-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (2.58 g, 6.23 mmol, 30.2% yield) as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.47 (s, 3H) 5.52 (s, 2H) 7.02 (d, J=7.58 Hz, 1H) 7.27-7.37 (m, 1H) 7.72 (d, J=8.08 Hz, 1H) 8.12 (s, 1H) 8.25 (d, J=2.02 Hz, 1H) 8.48 (d, 1H); LC/MS: MS (ES+) m/e 415 [M+H]+.