Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([O:13][C:14]([F:17])([F:16])[F:15])[C:5]=1[OH:18])[CH:2]=[CH2:3].[CH3:19]I>>[CH2:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([O:13][C:14]([F:16])([F:17])[F:15])[C:5]=1[O:18][CH3:19])[CH:2]=[CH2:3]
Reactant: C=CCc1cc([N+](=O)[O-])cc(OC(F)(F)F)c1O
Reactant: CI
Product: C=CCc1cc([N+](=O)[O-])cc(OC(F)(F)F)c1OC
Reaction time: 17 h

Procedure:
1-Allyl-2-methoxy-5-nitro-3-trifluoromethoxybenzene was prepared from 2-allyl-4-nitro-6-trifluoromethoxyphenol and methyl iodide by following Method C. The reaction was conducted at room temperature for 17 h. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (0-5%) as an eluent to give 1-allyl-2-methoxy-5-nitro-3-trifluoromethoxybenzene in 52% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>CCO.C(Cl)(Cl)Cl>[Cl:18][C:15]1[N:16]=[CH:17][C:12]([NH:11][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:13][CH:14]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])N(C)C
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CN(C)C(=C[N+](=O)[O-])Nc1ccc(Cl)nc1
Reaction time: 1 h

Procedure:
A mixture of 1.5 g (0.0093 mole) of 1-dimethylamino-1-methylthio-2-nitroethylene and 1.1 g of 5-amino-2-chloropyridine was heated at 110°-120° C. with stirring for 1 hour. After cooling, the reaction mixture was subjected to silica gel column chromatography using EtOH-CHCl3 (1:40) as the eluent to recover 0.38 g of the title compound as pale brown crystals. The NMR spectrum of this product showed that it was a 1:1 mixture of the title compound and N2 -(6-chloro-3-pyridyl)-N'-dimethyl-2-nitroacetamidine.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:9]([S:11](Cl)(=[O:13])=[O:12])[CH3:10]>N1C=CC=CC=1.O>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:11]([CH2:9][CH3:10])(=[O:13])=[O:12]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccccc1Br
Solvent: O
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccccc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a solution of 2-bromoaniline (344 mg, 2.0 mmol) in pyridine (5 mL) was slowly added ethyl-sulfonyl chloride (257 mg, 2.0 mmol) at rt and the mixture was stirred at rt for 16 hours. The pyridine was removed under reduced pressure and resulting residue diluted with water (30 mL) and extracted with DCM (10 mL×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by FCC to give the title compound (240 mg, 45%). MS (ESI): mass calcd. for C8H10BrNO2S 262.96 m/z found 264.1 [M+H]+. 1H NMR (300 MHz, CDCl3) δ 7.71 (dd, J=4.8, 1.5, 1H), 7.59 (dd, J=4.8, 1.5, 1H), 7.32-7.28 (m, 1H), 7.08-7.05 (m, 1H), 6.77 (bs, 1H), 3.14 (q, J=7.2, 2H), 1.41 (t, J=7.5, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4]Cl.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>COCCOC>[Cl:1][CH2:2][C:3]1[N:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]2[CH:4]=1
Reactant: Nc1ccccn1
Reactant: O=C(CCl)CCl
Solvent: COCCOC
Product: ClCc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The method of Vanelle et al. Tetrahedron 1991, 47, 5173-5184 was used. To a solution of 1,3-dichloro-2-propanone (2.69 g, 21.2 mmol) in 1,2-dimethoxyethane (5 mL) was added 2-aminopyridine and the mixture was stirred at room temperature for 2 hours. During this time a thick precipitate formed, and this was collected by filtration. The precipitate was refluxed in absolute ethanol for 2 hours after which volatiles were removed by evaporation. The residue was dissolved in water (30 mL) and solid NaHCO3 was added to neutralize the mixture. A white precipitate formed, and this was collected by filtration, washed with water and vacuum dried to yield the title compound pure as a cream white solid (1.43 g, 42%). 1H NMR (500 MHz, CDCl3): δ8.08 (d, J=6.7 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 7.17-7.22 (m, 1H), 6.80 (t, J=6.8 Hz, 1H), 4.78 (s, 2H).
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]([S:17][CH3:18])=[N:13][N:12]=2)=[CH:7][CH:6]=1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:32]=[C:28]([C:29]([NH2:31])=[O:30])[C:27]([OH:33])=[CH:26][CH:25]=1.O>CS(C)=O>[C:29]([C:28]1[CH:32]=[C:24]([CH:25]=[CH:26][C:27]=1[OH:33])[O:23][CH2:22][CH2:21][NH:20][CH2:19][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[C:14]([S:17][CH3:18])=[N:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:30])[NH2:31]
Reactant: CSc1nnc(-c2ccc(OCC3CO3)cc2)n1C
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Solvent: O
Solvent: CS(C)=O
Product: CSc1nnc(-c2ccc(OCC(O)CNCCOc3ccc(O)c(C(N)=O)c3)cc2)n1C

Procedure:
Analogously to Example 12, 19.5 g of 3-[4-(2,3-epoxypropoxy)-phenyl]-4-methyl-5-methylthio-4H-1,2,4-triazole are reacted with 11.0 g of 5-(2-aminoethoxy)-salicylamide in 70 ml of dimethyl sulphoxide. The resin-like crude product that is obtained on mixing with water is extracted by boiling with dioxan, the dioxan solution is concentrated by evaporation and the residue is recrystallised from methanol. 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(4-methyl-5-methylthio-4H-1,2,4-triazol-3-yl)-phenoxy]-2-propanol having a melting point of 123°-125° is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH2:12][C:13]([CH3:42])([CH3:41])[CH2:14][CH:15]1[C:19]2([C:27]3[C:22](=[CH:23][C:24]([Cl:28])=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH:17]([C:38]([OH:40])=O)[NH:16]1)(=[O:10])[CH3:9].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:67][C:68]1[CH:75]=[CH:74][C:71]([C:72]#[N:73])=[CH:70][CH:69]=1>>[Cl:28][C:24]1[CH:23]=[C:22]2[NH:21][C:20](=[O:29])[C@:19]3([C@@H:18]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=4[F:37])[C@H:17]([C:38](=[O:40])[NH:67][C:68]4[CH:75]=[CH:74][C:71]([C:72]#[N:73])=[CH:70][CH:69]=4)[NH:16][C@H:15]3[CH2:14][C:13]([CH3:42])([CH3:41])[CH2:12][O:11][C:8](=[O:10])[CH3:9])[C:27]2=[CH:26][CH:25]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(=O)OCC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Yield: 40.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-2′-(3-acetoxy-2,2-dimethyl-propyl)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 103 (0.25 g, 0.4 mmol), was reacted with diisopropylethylamine (0.47 g, 3.6 mmol), diphenylphosphinic chloride (0.38 g, 1.6 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.19 g, 1.6 mmol) to give acetic acid rac-3-[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-5′-(4-cyano-phenylcarbamoyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidin]-2′-yl]-2,2-dimethyl-propyl ester as a light yellow foam (Yield 0.1 g, 40%).
Reaction SMILES: C(OC(=O)[N:7]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][CH:29]=1)[CH2:8][C:9]1[N:10]=[C:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=3)[O:12][CH:13]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[N:38]1([CH2:37][CH2:36][CH2:35][CH2:34][C:31]2[CH:32]=[CH:33][C:28]([NH:7][CH2:8][C:9]3[N:10]=[C:11]([C:14]4[NH:15][C:16]5[C:21]([CH:22]=4)=[CH:20][C:19]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=5)[O:12][CH:13]=3)=[CH:29][CH:30]=2)[CH:42]=[CH:41][N:40]=[N:39]1
Reactant: CC(C)(C)OC(=O)N(Cc1coc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)n1)c1ccc(CCCCn2ccnn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccc2[nH]c(-c3nc(CNc4ccc(CCCCn5ccnn5)cc4)co3)cc2c1

Procedure:
[4-(4-[1,2,3]Triazol-1-yl-butyl)-phenyl]-[2-(5-trifluoromethoxy-1H-indol-2-yl)-oxazol-4-ylmethyl]-carbamic acid tert-butyl ester (0.31 g, 0.52 mmol) was stirred in a mixture of dichloro methane and trifluoro acetic acid (1:1, 10 ml) for 3 h. After concentration the crude product was purified on silica gel (ethyl acetate) yielding [4-(4-[1,2,3]triazol-1-yl-butyl)-phenyl]-[2-(5-trifluoromethoxy-1H-indol-2-yl)-oxazol-4-ylmethyl]-amine as light yellow solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[NH:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)N>>[CH2:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:23]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)[CH3:21]
Reactant: NNc1ccncc1
Reactant: CCc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CCc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccncc3)n2)c1
Yield: 47 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-ethyl-phenyl)-1H-pyridazin-4-one (A-4) and 4-hydrazinopyridine according to the method described for Example 1 in 47% yield. MS: M=344.1 (M+H)+
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzylamine (16.0 mL, 145.2 mmol) is dissolved in chloroform (110 mL), and the solution is cooled to 0° C. To this solution is added 4-methoxybenzenesulfonyl chloride (10.0 g, 48.4 mmol). The reaction is stirred at room temperature for 1 hour, and then refluxed for 1 hour. After cooling back to room temperature, the reaction is washed three times with 4N hydrochloric acid (200 mL), twice with water (100 mL), once with brine (50 mL), then dried (Na2SO4), and the solvent is evaporated to give N-[4-methoxybenzenesulfonyl]-benzylamine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:17])=[CH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)CC>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1noc(C)c1-c1ccc2c(O)ccnc2c1
Solvent: CCC(=O)O
Product: Cc1noc(C)c1-c1ccc2c(O)c([N+](=O)[O-])cnc2c1
Temperature: 125 °C
Yield: 75 %

Procedure:
To a solution of 7-(3,5-dimethyl-4-isoxazolyl)-4-quinolinol (for a preparation see Intermediate 11, 8.5 g, 35 mmol) in propanoic acid (442 ml) was added nitric acid (7 ml) at room temperature, followed by heating the reaction mixture to 125° C. for 2 h. After cooling, the mixture was filtered, washed with isopropyl ether to give the title compound as a yellow solid (7.5 g, 75%). [APCI-MS] m/z: 283 [M−H]−, Rt 2.41 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[NH:13]1[CH2:17][CH2:16][N:15]=[CH:14]1>C(#N)C>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][C:14]2[NH:13][CH:17]=[CH:16][N:15]=2)=[CH:6][CH:7]=1)[CH3:12]
Reactant: C1=NCCN1
Reactant: CCc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: CCc1ccc(C(=O)Cc2ncc[nH]2)cc1

Procedure:
1 mmol of 2-bromo-1-(4-ethylphenyl)ethan-1-one in acetonitrile was added drop wise to 5.5 mmol imidazoline in acetonitrile at room temperature for fourteen hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate to obtain 1-(4-ethylphenyl)-2-imidazolylethan-1-one.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([NH:16][C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=1[CH:26]([CH3:28])[CH3:27])=[NH:15])([CH3:3])[CH3:2].[Br:29][CH:30](Br)[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:26]([CH3:28])[CH3:27])[C:17]=1[NH:16][C:14]([NH:13][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[CH:10]([CH3:12])[CH3:11])=[N:15][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][Br:29])=[CH:32][CH:33]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=N)Nc1c(C(C)C)cccc1C(C)C
Reactant: Cc1ccc(C(Br)Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=NCc1ccc(CBr)cc1)Nc1c(C(C)C)cccc1C(C)C
Yield: 39.1 %

Procedure:
11.4 g (0.03 mole) of N,N'-bis-(2,6-diisopropylphenyl) guanidine, 8.7 g (0.03 mole) of α,α-dibromo-p-xylene and 2.1 g (0.015 mole) of anhydrous potassium carbonate were added to 50 ml of toluene. The thus-formed mixture was then refluxed under heating for 10 hours. After the mixture had been allowed to cool, the insoluble substance was removed by filtration. The thus-obtained filtrate was washed with water and the concentrated for the purpose of recovering the solvent to obtain a slightly brown powder. The powder was then recrystallized from acetone to obtain 6.6 g of white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][C:16]1([CH3:43])[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[C@H:17]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:25]2[CH:24]=[CH:23][C:22]([N:18]3[C@@H:17]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:16]([CH3:15])([CH3:43])[O:20][C:19]3=[O:21])=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)OC(=O)N(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3ccc(N)nc3)cc2)[C@H]1c1ccccc1
Temperature: 115 °C
Reaction time: 8 h

Procedure:
2-Amino-5-bromopyridine (commercially available from Sigma-Aldrich, Milwaukee, Wis.)(0.114 mL, 5.09 mmol), sodium carbonate (5.09 mL, 10.17 mmol), (S)-5,5-dimethyl-4-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-2-one (Intermediate J)(2.0 g, 5.09 mmol), and dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (415 mg, 0.509 mmol) were combined in dioxane (10.200 mL) and stirred at 115° C. overnight. LC-MS indicated good conversion to desired product. After cooling to room temperature, the reaction mixture was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide (S)-3-(4-(6-aminopyridin-3-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (1 g, 2.78 mmol, 54.7% yield) as an off-white solid. m/z (ESI) 360.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]([CH2:23][CH3:24])[C:12]3[C:17]([C:18]=2[C:19]#[N:20])=[CH:16][CH:15]=[C:14]([O:21][CH3:22])[CH:13]=3)=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C>[C:19]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]=1[C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=1)#[N:20]
Reactant: CCn1c(C#Cc2ccc(N)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCn1c(C#Cc2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.16 mmol), prepared as described by the method of Example 1H, is dissolved in pyridine (550 μL) at room temperature. Methanesulfonyl chloride (17 μL, 0.21 mmol) is added dropwise. This is stirred overnight at room temperature. The reaction mixture is then diluted in ethyl acetate and is washed with aqueous HCl, followed by brine. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2Cl2/EtOAc) yields N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide (58 mg, 92%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:23])=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:23])=[C:13]2[C:17]=1[N:16]([CH3:26])[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccccc3)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccccc3)c2n1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 18 a) except for using 8.00 g (24.3 mmol) of ethyl 7-benzyloxy-4-chloro-2-indolecarboxylate, 0.97 g (24.3 mmol) of 60% sodium hydride, 10.3 g (72.8 mmol) of methyl iodide and 200 ml of dimethylformamide. Ethyl 7-benzyloxy-4-chloro-1-methyl-2-indolecarboxylate was thus obtained in the yield of 7.71 g (92.4%).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1.Br[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[B:22](OC)([O:25]C)[O:23]C>C1COCC1.OS(O)(=O)=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([B:22]([OH:25])[OH:23])=[CH:15][CH:16]=1
Reactant: COB(OC)OC
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1

Procedure:
Intermediate 9H-Carbazole-9-akylamines 3 and 4 (Scheme 1). Both starting biphenyl derivatives 1a and 1b were synthesized by Suzuki coupling methodology [Martin, et al, Acta Chem. Scand. 47, 221-230 (1993); and Miyaura, et al, Syn. Commun., 11, 513 (1981)]. A Grignard reagent was prepared from 4-bromoanisole which was subsequently reacted with trimethyl borate in THF. Hydrolysis of the product in aqueous H2SO4 gave 4-methoxyphenylboronic acid. This was then coupled to 1-bromo-2-nitrobenzene or 4-bromo-3-nitroanisole in a mixture of (Ph3P)4Pd, aqueous Na2CO3, EtOH, and benzene to give 1a or 1b, respectively. The biphenyls 1a and 1b were subsequently refluxed in triethyl phosphite to give the carbazoles 2a and 2b. These were then alkylated with bromoacetonitrile in NaH/DMF to afford the respective carbazole-9-acetonitriles. The reduction of the nitriles was accomplished with Raney nickel and aqueous ammonia in 2-methoxyethanol to give the 9H-carbazole-9-ethanamines 3a and 3b. The propanamine 4 was prepared by conjugate addition of 2b to acrylonitrile in NaH/DMF, followed by reduction of the resulting propionitrile with Raney nickel in Ac20 to yield the propyl acetamide. Subsequent hydrolysis in 20% NaOH and EtOH gave the 9H-carbazole-9-propanamine 4. ##STR7##
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:11])[CH:3]=1.Br[CH:13](C(OCC)=O)[C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>C(O)C.CC(CC)=O>[F:10][C:9]1[C:2]([F:1])=[CH:3][C:4]2[O:11][C:13]([C:14]([OH:16])=[O:15])=[CH:6][C:5]=2[CH:8]=1
Reactant: O=Cc1cc(F)c(F)cc1O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: CCO
Product: O=C(O)c1cc2cc(F)c(F)cc2o1
Yield: 60.8 %

Procedure:
A mixture of 6.5 g (41.1 mmol) of 4,5-difluoro-2-hydroxybenzaldehyde, 10.4 ml (61.7 mmol) of diethyl bromo-malonate, 11.3 g (82.2 mmol) of potassium carbonate and 50 ml of ethyl methyl ketone was boiled at reflux for 3 hours while stirring, filtered and concentrated in a vacuum. The brown oil obtained was dissolved in 65 ml of ethanol, treated with 6.5 g of potassium hydroxide pellets and heated at reflux for one hour while stirring. The mixture was concentrated in a vacuum and the residue was treated with 65 ml of water and 65 ml of 3N sulfuric acid and heated at reflux over 30 minutes. Subsequently, the mixture was filtered and the residue was washed with water and triturated in 50 ml of hexane over 30 minutes. The solid was filtered off and dried. There were obtained 4.95 g (60%) of 5,6-difluorobenzofuran-2-carboxylic acid as a light yellow solid with m.p. 270°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.Cl.O>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1cccc(Cl)n1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of zinc chloride (9.0 g, 66.15 mmol) in diethyl ether (200 ml) was added sodium borohydride (5.0 g, 132 mmol), and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off to give a solution of zinc borohydride in diethyl ether. To a solution of ethyl 3-(6-chloro-2-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (12.7 g, 33.1 mmol) in diethyl ether (100 ml) was dropwise added slowly at −20° C. the solution of zinc borohydride in diethyl ether prepared in advance. The reaction solution was stirred at −20° C. for 30 min., and 1N hydrochloric acid was added to quench the reaction. Water (200 ml) was added and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(6-chloro-2-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (4.1 g, 32%, (2RS,3RS) form: (2RS,3SR)form=1:1, crude) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][CH2:13][C:14](=O)[CH3:15])[N:7]=1)=[O:5])[CH3:2].Cl.[Cl:18][C:19]1[CH:20]=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:22]3[C:21](=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:14]=2[CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(SCC(C)=O)n1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)n1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 6-(2-oxo-propylsulfanyl)-pyridine-2-carboxylic acid ethyl ester and (3-chloro-phenyl)-hydrazine hydrochloride.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:22]3[CH:23]=[N:24][C:25]([N:28](CC4C=CC=CC=4)CC4C=CC=CC=4)=[CH:26][CH:27]=3)[N:6]=[C:5]2[C:43]2[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][CH:44]=2)[CH2:3][CH2:2]1>Br.C(O)(=O)C>[NH2:28][C:25]1[N:24]=[CH:23][C:22]([C:7]2[N:6]=[C:5]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][CH:44]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[C:8]=2[C:9]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:15][CH2:16]2)=[O:10])=[CH:27][CH:26]=1
Reactant: O=C(c1c(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Agent: Br
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc(-c3ccc(OC(F)(F)F)cc3)n(C3CC3)c2C(=O)N2CCC(N3CCCC3)CC2)cn1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
0.2 g (0.2 mmol) of [3-cyclopropyl-5-(6-dibenzylamino-pyridin-3-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 11) was dissolved in 3 ml of HBr/acetic acid and the mixture heated to 100° C. for 24 h. The solvent was evaporated and the residue taken up in CH2Cl2, washed with saturated sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. Purification by flash column chromatography [CH2Cl2/MeOH 8:2] afforded 0.05 g (39%) of the title compound as a colorless amorphous solid. MS: 541.2 (MH+)