Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([N:13]([CH3:21])[C:14]([NH:16][CH2:17][CH2:18][S:19][CH3:20])=[O:15])=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].I[CH3:25]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([N:13]([CH3:21])[C:14]([N:16]([CH3:25])[CH2:17][CH2:18][S:19][CH3:20])=[O:15])=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CSCCNC(=O)N(C)c1nnc(-c2cncc(F)c2)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCN(C)C(=O)N(C)c1nnc(-c2cncc(F)c2)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.8 %

Procedure:
An ice-cold solution of 1-[5-(5-fluoro-pyridin-3-yl)-[1,3,4]thiadiazol-2-yl]-1-methyl-3-(2-methylsulfanyl-ethyl)-urea (0.132 g, 0.4 mmol) in N,N-dimethylformamide (0.6 mL) was treated with sodium hydride (60% in mineral oil, 0.018 g, 0.4 mmol) and stirred for 5 minutes before addition of a solution of iodomethane (0.063 g, 0.4 mmol) in N,N-dimethylformamide (0.1 mL). The ice bath was removed after 5 minutes. The reaction mixture was stirred at room temperature for 14 hours, diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, purified by normal and reversed phase chromatography to give the title compound as a colorless gum (0.027 g, 20%): IR (KBr thin film) 1658 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.53 (d, J=3.2 Hz, 1H), 8.02 (ddd, J=9.1, 4.5, 1.7 Hz, 1H), 3.66 (s, 3H), 3.59 (t, J=6.8 Hz, 2H), 3.06 (s, 3H), 2.78 (t, J=7.1 Hz, 2H), 2.14 (s, 3H); ESIMS m/z 342 ([M+H]+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:17][C@H:16]([N:18]=[N+]=[N-])[CH2:15][NH:14]1)=[O:12])[CH3:9].COC([C@@H]1C[C@H](N)CN1[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=O>>[CH2:8]([O:10][C:11]([C@@H:13]1[CH2:17][C@H:16]([NH2:18])[CH2:15][N:14]1[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1

Procedure:
(2S,4S)-4-Amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid ethyl ester was prepared from (2S,4S)-4-azido-pyrrolidine-2-carboxylic acid ethyl ester trifluoroacetate salt in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C14H27N2O2 [(M+H)+] 255, obsd. 255.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2.[C:30](O)(=[O:33])[CH2:31][OH:32].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:31](=[O:32])[CH2:30][OH:33])[CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2
Reactant: O=C(O)CO
Reactant: Clc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CO)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
The compound (85 mg, 0.20 mmol) prepared in Example 96 was dissolved in N,N-dimethylformamide (1 ml). Glycolic acid (22 mg, 0.30 mmol), EDC (64 mg, 0.33 mmol) and HOBT (53 mg, 0.39 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and concentrated. The residue was purified by column chromatography to give the title compound (41 mg, Yield 44%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:23][CH2:22][C@H:21](OS(C)(=O)=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.[CH3:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1>>[CH3:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH:21]1[CH2:20][CH2:19][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([N:3]3[CH2:4][CH2:5][C:6]4([CH2:7][CH2:8][O:9][CH2:10][CH2:11]4)[C:2]3=[O:1])=[CH:17][CH:16]=2)[CH2:23][CH2:22]1
Reactant: CS(=O)(=O)O[C@H]1CC[C@@H](c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1
Reactant: C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCOCC4)C3=O)cc2)CC1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 9 by condensing cis-methanesulfonic acid 4-[4-(1-oxo-8-oxa-2-aza-spiro[4.5]dec-2-yl)-phenyl]-cyclohexyl ester (Intermediate 21) (30 mg, 0.07 mmol, 1 equiv.) and (R)-2-methylpyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1Cl
Reactant: COC(=O)c1sccc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1cc(F)c(F)cc1Cl
Yield: 33.5 %

Procedure:
Synthesized as described for 3 using 2-chloro-4,5,-difluorobenzenesulfonyl chloride (500 mg; 2.02 mmol), methyl 3-aminothiophene-2-carboxylate (382 mg; 2.43 mmol), 4-dimethylaminopyridine (62 mg; 0.51 mmol), pyridine (10 mL), and anhydrous dichloromethane (10 mL). The crude product was purified by automated silica gel chromatography (Biotage®) using ethyl acetate/hexanes as eluant system (0 to 20% v/v over 7 column volume gradient elution) to yield the title product as a white solid (249 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@@H:8]([O:15]C(=O)C1C=CC=CC=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:29])[C@H:7]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCCCC[C@H](OC(=O)c1ccccc1)[C@@H](CCCCC)C(=O)OC(C)(C)C
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCCCC[C@H](O)[C@@H](CCCCC)C(=O)OC(C)(C)C
Yield: 54.5 %

Procedure:
The (2R,3S)-3-benzoyloxy-2-pentylnonanoic acid t-butyl ester (1.24 g, 3.06 mmol) obtained in Production Example C-7-1 was dissolved in anhydrous toluene (4 ml), and then tributyltin oxide (2.34 g, 3.92 mmol) was added thereto to be refluxed with heating. Then, 39 hours later, distilled water was added to the reaction mixture, and extracted 3 times with diethyl ether. The resulting organic layer was dried with anhydrous magnesium sulfate, filtered, and condensed. The obtained residue was purified by column chromatography (silica gel: 30 g, n-hexane/ethyl acetate=20/1), and the target compound (501 mg, 54%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[C:26]([CH3:43])[CH:25]=2)[N:14]=1>CCO.CN(C=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[C:26]([CH3:43])[CH:25]=2)[N:14]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate (A41) (0.248 g, 0.407 mmol) in EtOH (10 mL) was added to a solution of 10% Pd/C (53% water; 0.680 g) in DMF (6 mL). The resulting mixture was stirred at room temperature for 16 hours under an atmosphere of hydrogen then filtered through a pad of Celite, washing with EtOAc (80 mL). The volatiles were removed in vacuo to afford a yellow oil which was purified by silica gel column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to yield the title compound A42 as a clear oil (0.196 g, 79%); 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.61 (s, 1H), 7.51 (dd, J=7.9, 1.5 Hz, 1H), 7.39 (d, J=2.2 Hz, 1H), 7.29-7.19 (m, obscured by solvent), 7.17 (d, J=8.4 Hz, 1H), 4.42-4.18 (m, 2H), 3.75 (s, 2H), 3.67 (s, 3H), 3.19-3.03 (m, 4H), 2.90-2.73 (m, 3H), 2.37 (s, 3H), 1.75 (d, J=12.6 Hz, 2H), 1.62 (m, 2H), 1.50 (s, 9H). LCMS-A: rt 7.094 min; m/z 613.2 [M+H]+.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH:15]([OH:27])[CH2:16][N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][CH2:26][N:17]1[CH2:16][CH:15]([OH:27])[CH2:14][NH:13][C:9](=[O:11])[CH2:8][O:7][C:4]1[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Cc1ccc(OCC(=O)O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.1 %

Procedure:
A mixture of compound 2-(p-tolyloxy)acetic acid (100 mg, 0.60 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (124 mg, 0.60 mmol), BOP-Cl (183 mg, 0.72 mmol) and DIPEA (1 mL) in DCM (10 mL) was stirred at room temperature for 4 h. The solvent was removed by concentration and the crude product was purified by pre-HPLC to give the title compound (27.8 mg, yield 13.1%). 1H NMR (500 MHz, MeOD): δ 7.32-7.25 (m, 3H), 7.20 (d, J=7.2 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.65-4.52 (br.s, 1H), 4.52 (s, 2H), 4.46-4.30 (br.s, 1H), 4.30-4.24 (m, 1H), 3.85-3.70 (br.s, 1H), 3.43 (d, J=5.6 Hz, 1H), 3.26-3.17 (m, 4H), 2.26 (s, 3H) ppm; ESI-MS (m/z): 355.2 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[C:10]([C:22]#[N:23])=[CH:11][C:12]2[CH:17]=[C:16]([O:18]C)[C:15]([OH:20])=[C:14]([Cl:21])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:24])[C:10]([C:22]#[N:23])=[CH:11][C:12]2[CH:17]=[C:16]([OH:18])[C:15]([OH:20])=[C:14]([Cl:21])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=C(C#N)C(=O)Nc2cccc(Cl)c2)cc(Cl)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: N#CC(=Cc1cc(O)c(O)c(Cl)c1)C(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
Demethylation was effected in the same manner as in Example 2 by using N-(3-chlorophenyl)-2-cyano-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propenamide (587 mg, 1.62 mmol) and 1M solution of boron tribromide in methylene chloride. The resulting solid was suspended in ethanol, refluxed for 10 minutes, allowed to cool to room temperature and filtered to give the objective N-(3-chlorophenyl)-2-cyano-3-(3-chloro-4, 5-dihydroxyphenyl)propenamide (250 mg, 44% in yield).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[N:16]=[C:15]([NH2:17])[CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:17][C:15]1[N:16]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(C=Cc2cccc(N)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cccc(C=Cc2ccc(O)cc2)n1
Reaction time: 72 h
Yield: 24.8 %

Procedure:
A suspension of 6-[2-(4-methoxy-phenyl)-vinyl]-pyridin-2-yl-amine (1.0 g, 3.8 mmol) (example 3) in CH2Cl2 (60 ml) was treated with boron tribromide (2.4 ml, 25 mmol) and stirred for 72 hr. The precipitate was filtered, dissolved in AcOEt and washed with aqueous NaHCO3 solution. The organic phase was dried (Na2SO4), concentrated and the residue was chromatographed (SiO2 with CH2Cl2/MeOH/NH4OH=140/10/1) and crystallized to provide 0.20 g (25%) of the light yellow title compound. Mp. 224–225° C. (iPr2O), MS: m/e=213 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([F:12])[CH:6]=1)=[O:4].[BH4-].[Na+].C[O-].[Na+].O>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]2[CH2:2][O:4]2)=[CH:6][C:7]=1[F:12]
Reactant: O=C(CCl)c1ccc(Br)c(F)c1
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1cc(C2CO2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of 2-chloro-1-(4-bromo-3-fluoro-phenyl)-ethanone (6.16 g) in ethanol (100 ml) at 5° C. was added portionwise over 5 min NaBH4 (788 mg). The reaction mixture was then stirred at room temperature for 1 hour to afford a light yellow solution. TLC analysis showed the reaction was complete. Sodium methoxide (562 mg) was then added and the reaction mixture was stirred at room temperature overnight. TLC analysis showed a small amount of starting material remaining and so the reaction mixture was stirred at 40° C. for 1 h. The reaction mixture was then poured into water and extracted twice with EtOAc. The combined organic layers were washed with saturated brine, then dried over Na2SO4 and concentrated in vacuo to afford (RS)-2-(4-bromo-3-fluoro-phenyl)-oxirane (4.69 g) as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:45]=[CH:44][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:19]=3[N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:32][CH:31]=3)[C:17](=[O:43])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[NH:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]([N:46]4[CH2:50][CH2:49][CH2:48][CH2:47]4)=[O:27])=[CH:25][C:19]=3[N:18]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)=[CH:32][CH:31]=3)[C:17](=[O:43])[CH2:16]2)=[O:14])=[CH:44][CH:45]=1
Reactant: O=C(O)c1ccc2c(c1)N(Cc1ccc(OC3CCNCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reactant: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)N(Cc1ccc(OC3CCNCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2)N1CCCC1
Reaction time: 8 h

Procedure:
5 mg (0.008 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(4-piperidyloxy)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylic acid trifluoroacetate was dissolved in 5 ml of dichloromethane. 1 mg (0.018 mmol) of pyrrolidine, 3 mg (0.018 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.005 ml (0.036 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: CON(C)[C:4](=[O:11])[CH:5]([O:7][CH2:8][CH:9]=[CH2:10])[CH3:6].[CH:13]([Mg]Br)=[CH2:14].Cl>O1CCCC1>[CH2:8]([O:7][CH:5]([CH3:6])[C:4](=[O:11])[CH:13]=[CH2:14])[CH:9]=[CH2:10]
Reactant: C=C[Mg]Br
Reactant: C=CCOC(C)C(=O)N(C)OC
Agent: Cl
Solvent: C1CCOC1
Product: C=CCOC(C)C(=O)C=C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
(±)-N-Methoxy-N-methyl-2-(prop-2-en-1-yloxy)propanamide (1.26 g, 7.27 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Vinylmagnesium bromide (11.4 mL, 0.7 M solution in tetrahydrofuran, 8.00 mmol, 1.1 equiv) was added and the mixture was stirred at −78° C. for 10 minutes. Hydrochloric acid (5 mL, 4 M aqueous) was added, the mixture was warmed to ambient temperature and extracted with chloroform (2×30 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 30:70; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[C:28]([S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[C:28]([S:33]([CH:36]([CH3:38])[CH3:37])(=[O:34])=[O:35])=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC(C)S(=O)(=O)c1ncccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Product: CC(C)S(=O)(=O)c1ncccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1

Procedure:
The title compound was prepared as described in step D of Example 803 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and 3-bromo-2-(isopropylsulfonyl)pyridine. MS (ESI): mass calcd. for C21H18FN4O2S, 395.11; m/z found, 396.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 8.70 (dd, J=4.6, 1.6, 2H), 8.25-8.17 (m, 1H), 7.84 (dd, J=7.8, 1.7, 1H), 7.64-7.54 (m, 2H), 7.46-7.32 (m, 3H), 6.61 (s, 1H), 4.26 (hept, J=6.8, 1H), 1.34 (d, J=6.9, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])=[O:5].[CH3:21][S:22](Cl)(=[O:24])=[O:23].Cl>N1C=CC=CC=1>[F:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[C:4]([C:3]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:2]=1[NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[O:5]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-5-nitro-2',4'-difluorobenzophenone (5.1 g) and methanesulfonyl chloride (14 ml) in pyridine (40 ml) was stirred at room temperature overnight. The mixture was poured into cold 3N hydrochloric acid (200 ml). The insoluble was filtered and dissolved in a mixture of pyridine (20 ml), ethanol (5 ml) and 5% sodium hydroxide (50 ml). The solution was stirred overnight and washed with toluene. The aqueous layer was acidified with hydrochloric acid and the precipitates were filtered to give brown crystals of 2'-(2,4-difluorobenzoyl)-4'-nitromethanesulfonanilide (5.7 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2Cl)(=[O:3])[CH3:2].[S-:23][CH2:24][CH3:25].[Na+].C(S)C.[H-].[Na+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2[S:23][CH2:24][CH3:25])(=[O:3])[CH3:2]
Reactant: CC[S-]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCS
Product: CCCc1c(O)c(C(C)=O)cc2c(SCC)cc(C(=O)OC)nc12
Reaction time: 2 h

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propylquinoline-2-carboxylate (1.0 g) in dry dimethylformamide (50 mls) was added dropwise to a stirred solution of sodium thioethoxide [made by the addition of ethanethiol (0.773 g) to 50% sodium hydride in oil (0.6 g) in dry dimethylformamide (30 mls) under nitrogen]. The purple solution was stirred for 2 hours, poured into ethyl acetate and acidified with dilute hydrochloric acid. The organic layer was separated, washed with water, sodium bicarbonate solution and then dried. Evaporation of the solvent gave 0.8 g of the desired product which was recrystallised from cyclohexane to give 0.52 g of yellow needles mp 193°-195°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[C:8]2[C:16]1[N:24]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1.[Si:35]([O:42][CH2:43][CH2:44]Br)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C)C=O.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH2:44][CH2:43][O:42][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:9]=[C:8]2[C:16]1[N:24]([S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[CH:17]=1
Reactant: COc1cc2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(CCO[Si](C)(C)C(C)(C)C)c2cc1OC
Reaction time: 16 h

Procedure:
0.049 g of sodium hydride (at 60%) is added to a solution of 0.5 g of 2-(5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 12.5 ml of anhydrous dimethylformamide, under an inert argon atmosphere at a temperature in the region of 20° C. Agitation is maintained at this temperature for 30 minutes. 0.264 ml of 2-tert-butyldimethylsilyloxyethyl bromide is added. The reaction medium is agitated at the same temperature for 16 hours. 25 ml of water and 20 ml of ethyl acetate are added. After separation by settling out, the organic phase is dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (silica, 98/02 by volume dichloromethane/methanol as eluents, argon). The fractions containing the product are concentrated under reduced pressure. 0.47 g of 2-[5,6-dimethoxy-1-(2-tert-butyldimethylsilyloxyethyl)indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8]Cl.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=1
Reactant: CN1CCCCC1CCl
Reactant: CC(=O)Cc1ccc(O)cc1
Product: CC(=O)Cc1ccc(OCC2CCCCN2C)cc1

Procedure:
Prepared from 1-methyl-2-chloromethylpiperidine and 4-hydroxyphenylacetone by the method of Example 1 to give a mixture (50:50) of the above product and 4-([1-methyl-piperidin-2-yl]methoxy)phenyl acetone.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6](=O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[CH3:16][NH:17]N>C(O)(=O)C>[CH3:16][N:17]1[C:6](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][CH:4]=[N:2]1
Reactant: CN(C)C=NC(=O)C=Cc1ccccc1
Reactant: CNN
Solvent: CC(=O)O
Product: Cn1ncnc1/C=C/c1ccccc1
Temperature: 90 °C
Yield: 48.6 %

Procedure:
N-[(Dimethylamino)methylene]-cinnamamide (2.0 g, 10 mmol) was added to a mixture of acetic acid (20 mL) and methylhydrazine (0.6 mL, 11 mmol). The mixture was heated to 90° C. for 2 h. The cooled mixture was concentrated in vacuo, and made basic (pH 9) with solid K2CO3. The aqueous residue was partitioned between ethyl acetate and water, the organics were dried over Na2SO4, and concentrated in vacuo. The resultant powder was recrystallized from a minimum of boiling Ethyl acetate. The collected solids were triturated and washed with ethyl acetate to afford 1-methyl-5-[(E)-2-phenylethenyl]-1H-1,2,4-triazole (0.9 g, 49% yield) as a pale yellow powder. M.p. 67–70° C. from Ethyl acetate. 1H NMR (CDCl3, 300 MHz) δ 7.88 (s, 1H), 7.73 (d, J=16 Hz, 1H), 7.57 (m, 2H), 7.39 (m, 3H), 6.92 (d, J=16 Hz, 1H), 3.96 (s, 3H).