Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].[C:3]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([F:24])[CH:16]=1)#[N:4]>C(O)C.O.CO.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:6]2[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][NH:9][C:5]=2[C:3]#[N:4])=[CH:16][C:17]=1[F:24]
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccc([N+](=O)[O-])c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c[nH]c(C#N)c1-c1ccc(N)c(F)c1
Temperature: 70 °C
Yield: 94 %

Procedure:
Iron (Alrich cat#20930-9, 24.9 g, 445 mmol) and ammonium chloride (4.80 g, 89.7 mmol) were added to a suspension of ethyl 5-cyano-4-(3-fluoro-4-nitrophenyl)-1H-pyrrole-3-carboxylate (45.0 g, 148 mmol) in ethanol (540 mL) and water (180 mL) equipped with an overhead stirrer. The reaction was warmed (70° C.) for 2 h, and then cooled to rt. The mixture was diluted with methanol (500 mL) and then filtered through a well-packed pad of Celite®. The filter cake was thoroughly rinsed with methanol (1 L) and acetonitrile (2 L) and the combined filtrate was evaporated. The residue was dissolved in ethyl acetate (1.5 L) then washed with water (500 mL) and brine (500 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to afford the desired product (38.0 g, 94%) containing trace impurities (<5%). The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 13.36 (s, 1H), 8.25 (dd, J=12.8, 2.0 Hz, 1H), 6.92-6.97 (m, 1H), 6.72-6.79 (m, 1H), 5.35 (s, 2H), 4.10 (q, J=7.0 Hz, 2H), 1.16 (t, J=7.0 Hz, 3H); ES-MS m/z 274.3 (MH)+; HPLC RT (Method A) 2.62 min.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[N:36]=[CH:35]1.O1CCCCC1OCCN1C([Sn](CCCC)(CCCC)CCCC)=CN=C1>>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:38]5[N:34]([CH2:33][CH2:32][OH:31])[CH:35]=[N:36][CH:37]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCOC2CCCCO2)cn1
Agent: CCCC[Sn](CCCC)(CCCC)c1cncn1CCOC1CCCCO1
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cncn4CCO)ccc2-3)n(C(C)C)n1

Procedure:
Similar to described in General Procedure G: 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with a mixture of 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazole and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-5-(tributylstannyl)-1H-imidazole to give 441 after THP-removal with aqueous HCl purification by reverse phase HPLC (4.8 mg). LCMS: 437.1.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH:17]([C:19]2[S:23][N:22]=[CH:21][CH:20]=2)[OH:18])=[C:5]([C:24]([F:27])([F:26])[F:25])[N:4]=1.[CH3:29]I>>[F:28][CH:2]([F:1])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]([CH:17]([O:18][CH3:29])[C:19]2[S:23][N:22]=[CH:21][CH:20]=2)=[C:5]([C:24]([F:27])([F:26])[F:25])[N:4]=1
Reactant: CI
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(O)c2ccns2)c1CC(C)C
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(OC)c2ccns2)c1CC(C)C

Procedure:
Methyl 2-(difluoromethyl)-5-[(isothiazol-5-yl) hydroxymethyl]-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (prepared by the procedure similar to example H of U.S. Pat. No. 5,260,262) was alkylated with methyl iodide by the procedure in example 61 of U.S. Pat. No. 5,169,432.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH:18]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[C:21]([SH:27])=[CH:20][CH:19]=1>>[C:24]([C:22]1[CH:23]=[CH:18][CH:19]=[CH:20][C:21]=1[S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)([OH:26])=[O:25]
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Reactant: O=C(O)c1ccccc1S
Product: O=C1CCc2cc(OCCCCSc3ccccc3C(=O)O)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril and 2-thiobenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15][C:6]=2[C:5]([CH3:16])=[CH:4][C:3]=1[C:17]([OH:19])=[O:18])[S:12][CH2:11][CH2:10][S:9]3.BrBr.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:16][C:5]1[C:6]2[S:15][CH2:14][C:13]3[S:9][CH2:10][CH2:11][S:12][C:8]=3[C:7]=2[C:2]([CH3:1])=[C:3]([C:17]([OH:19])=[O:18])[CH:4]=1
Reactant: Cc1cc(C(=O)O)c(C)c2c1SCCC21SCCS1
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(=O)O)c(C)c2c1SCC1=C2SCCS1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
A mixture of 0.62 g of 2,3-dihydro-5,8-dimethylspiro[4H-1-benzothiopyran-4,2'-[1,3]dithiolane]-6-carboxylic acid in 200 mL of chloroform was cooled to 0° C. To this mixture was added a solution of 0.38 g of bromine in 20 mL of chloroform dropwise. The resulting mixture was stirred overnight at room temperature. To this reaction mixture was added 10% aqueous sodium thiosulfate. The organic layer was separated and dried over MgSO4, filtered, and concentrated under reduced pressure to dryness. The resulting residue was crystallized from 1-chlorobutane to gave 0.29 g of the title compound of Step A as a purple solid melting at 250° C. (dec.). 1H NMR (CDCl3): δ 2.35 (s, 3H), 2.70 (s, 3H), 3.05 (m, 2H), 3.39 (br s, 2H), 3.41 (m, 2H), 7.66 (s, 1H).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([O:10][C@@H:11]2[O:16][C@H:15]([C:17](O)=[O:18])[C@@H:14]([OH:20])[C@H:13]([OH:21])[C@H:12]2[OH:22])[CH:2]=1>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[O:10]([C:3]1[CH:2]=[CH:1][C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=1)[CH:11]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:20])[C@H:13]([OH:21])[C@H:12]1[OH:22]
Reactant: O=C(O)[C@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(OC2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 1 h

Procedure:
A colorimetric pNPG (p-nitrophenyl-(β-D-glucopyranoside)-based assay was used for measuring β-glucosidase activity. In a total volume of 100 μL, 20 μL clear media supernatant containing β-glucosidase enzyme was added to 4 mM pNPG (Sigma-Aldrich, Inc. St. Louis, Mo.) solution in 50 mM sodium phosphate buffer at pH6.5. The reactions were incubated at pH 6.5, 45° C. for 1 hour. The reaction mixture was quenched with 100 μL of 1M sodium carbonate pH 11 solution. The absorbance of the solution was measured at 405 nm to determine the conversion of pNPG to p-nitrophenol. The release of p-nitrophenol (ε=17,700 M−1 cm−1) was measured at 405 nm to calculate β-glucosidase activity. Detectable β-glucosidase activity was observed under high throughput screening conditions (pH 7, 50° C.).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[F:33][C:34]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([F:53])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37].[NH2:54][C:55]1[CH:56]=[C:57]([C:62]([N:64]2[CH2:69][CH2:68][O:67][CH2:66][CH2:65]2)=[O:63])[CH:58]=[CH:59][C:60]=1[NH2:61]>>[F:33][C:34]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([F:53])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44]2[NH:61][C:60]3[CH:59]=[CH:58][C:57]([C:62]([N:64]4[CH2:65][CH2:66][O:67][CH2:68][CH2:69]4)=[O:63])=[CH:56][C:55]=3[N:54]=2)=[N:41][NH:42][CH:43]=1)=[O:37]
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1N
Reactant: COc1cc(F)c(C(=O)Nc2c[nH]nc2C(=O)O)c(F)c1
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: COc1cc(F)c(C(=O)Nc2c[nH]nc2-c2nc3cc(C(=O)N4CCOCC4)ccc3[nH]2)c(F)c1

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), however using 4-(2,6-difluoro-4-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 96A) and (3,4-diamino-phenyl)-morpholin-4-yl-methanone (Example 94B) to give 2,6-difluoro-4-methoxy-N-{3-[5-(morpholine-4-carbonyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide (24 mg) as a beige solid. (LC/MS: Rt 2.94, [M+H]+ 483.20).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[BH3-]C#[N:16].[Na+].[ClH:18]>CO>[ClH:18].[NH2:16][CH:8]1[CH2:7][CH2:6][CH2:5][C:4]2[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: [BH3-]C#N
Reactant: COc1cccc2c1CCCC2=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1CCCC2N
Yield: 79 %

Procedure:
50 mmol of 5-methoxy-1-tetralone, 0.5 mol of NH4OAc and 35 mmol of NaBH3CN are stirred in 150 ml of absolute MeOH at room temperature for 24 hours. The mixture is acidified to pH 2 with concentrated HCl and evaporated, the residue is taken up in 50 ml of H2O and the mixture is extracted by shaking 2-3 x with ether. Any precipitates which arise are filtered off and combined with the H2O phase. The H2O phase is brought to pH 10 with solid KOH, saturated with NaCl and extracted by shaking 3 x with ethyl acetate. After drying with Na2SO4, the organic phase is evaporated, the residue is dissolved in ether and the product is precipitated as the hydrochloride by passing in HCl. Yield: 79%; melting point: 250° C.
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C.O>O1CCCC1>[F:24][C:23]([F:25])([F:26])[C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:2]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=3)[C:6]([O:8][CH3:9])=[O:7])[CH:16]=2)=[CH:22][CH:21]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cccc(C(Cl)=NO)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(-c2cc(-c3ccc(C(F)(F)F)cc3)on2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution (60 ml) of methyl 3-[chloro(hydroxyimino)methyl]benzoate (2.14 g) and 1-ethynyl-4-trifluoromethylbenzene (1.73 g) in tetrahydrofuran was added dropwise a solution (40 ml) of triethylamine(2.79 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-ethyl acetate to give methyl 3-[5-(4-trifluoromethylphenyl)-3-isoxazolyl]benzoate (1.64 g, yield 47%) as a colorless crystalline powder. melting point: 139–140° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])C(OCC)=O)[CH3:2].[Cl-].[Li+].O.CS(C)=O>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccncc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ccncc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 68.2 %

Procedure:
To a 100 ml RB flask was added 1.5 g (5.3 mmol) of 3-nitro-4-pyridinyl-propanedioic acid diethyl ester, 0.450 g (10.6 mmol) of lithium chloride, 0.095 g (5.3 mmol) of water and 35 mL of DMSO. The solution was heated at 100° C. for 4 h. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated, and the residue was chromatographed on silica gel eluting with a hexane-10% EtOAc/hexane gradient to give 0.76 g of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ1.14 (t, J=7.1 Hz, 3H), 4.06 (q, J=7.1 Hz, 2H), 4.12 (s, 2H), 7.63 (d, J=4.9 Hz, 1H), 8.82 (d, J=4.9 Hz, 1H), 9.21 (s, 1H); C9H10N2O4: APES+MS m/z 211 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10](Br)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:11]=[C:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccccc2F)cc1N
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Step 1 A mixture of methyl 2-amino-4-bromobenzoate (3.06 g, 13.3 mmol), 2-fluorophenylboronic acid (2.23 g, 16.0 mmol), tetrakis(triphenylphosphine)palladium (1.54 g, 1.33 mmol) and 1 M aqueous sodium carbonate (16.6 mL, 16.6 mmol) in 1,2-dimethoxyethane (66.5 mL) was stirred at 90° C. overnight. The mixture was cooled to rt, filtered through a pad of Celite and the solids were rinsed with EtOAc. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 90:10 hexane-EtOAc) to provide methy 3-amino-2′-fluorobiphenyl-4-carboxylate (2.63 g, 81%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 7.90 (d, J=8.25 Hz, 1H), 7.38-7.46 (m, 1H), 7.27-7.35 (m, 1H), 7.08-7.22 (m, 2H), 6.85 (s, 1H), 6.82 (d, J=8.25 Hz, 1H), 5.83 (br s, 1H), 3.88 (s, 3H). Mass spectrum m/z 246.1 (M+H)+.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:19][C:20](=[O:36])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]=[CH2:35])=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:36])[NH:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]2[CH2:35][O:6]2)=[CH:28][CH:27]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Product: O=C(NCCCCc1ccc(OCC2CO2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
3-Chloro-peroxybenzoic acid (2.46 g, 14.25 mmol) was added into a methylene chloride solution (100 mL) of 38 (1.86 g, 5.48 mmol), and the reaction was stirred at room temperature overnight. After that, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, 8:1:1 methylene chloride/hexane/ethyl acetate). To eliminate the admixture of benzoic acid the methylene chloride solution of the product was sequentially washed with a saturated aqueous solution of sodium hydrogen carbonate and water, then dried over anhydrous sodium sulfate and evaporated to provide 1.4 g (72%) of 39 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.57 (m, 4H), 2.56 (m, 2H), 2.78 (m, 1H), 2.91 (m, 1H), 3.21 (m, 2H), 3.36 (m, 1H), 3.97 (m, 1H), 4.19 (m, 1H), 5.08 (s, 2H), 6.82 (d, 2H), 7.06 (d, 2H), 7.72 (s, 5H).
Reaction SMILES: BrC1C=C(C=CC=1)C(NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C)=O.[NH2:32][CH:33]([C:35]1[N:40]=[N:39][C:38]([NH:41][C:42]2[CH:47]=[C:46]([O:48][CH3:49])[C:45]([O:50][CH3:51])=[C:44]([O:52][CH3:53])[CH:43]=2)=[N:37][CH:36]=1)[CH3:34].[CH3:54][N:55]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:57]([C:64](O)=[O:65])=[CH:56]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:54][N:55]1[C:63]2[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:57]([C:64]([NH:32][CH:33]([C:35]2[N:40]=[N:39][C:38]([NH:41][C:42]3[CH:43]=[C:44]([O:52][CH3:53])[C:45]([O:50][CH3:51])=[C:46]([O:48][CH3:49])[CH:47]=3)=[N:37][CH:36]=2)[CH3:34])=[O:65])=[CH:56]1
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: Cn1cc(C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cn(C)c4ccccc34)nn2)cc(OC)c1OC
Yield: 70.2 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 1-methyl-1H-indole-3-carboxylic acid (150 mg, 0.85 mmol), diisopropylethylamine (0.34 mL, 1.95 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (350 mg, 0.92 mmol) in dimethylformamide (5 mL) gave 1-methyl-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1H-indole-3-carboxamide (211 mg, 70%) as a yellow solid. MS m/z 462 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and 4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 9.77 (br s, 1H, NH), 8.40 (dm, 1H, J=1.8 Hz), 7.77 (dm, 1H, J=8.6 Hz), 7.71 (dd, 1H, J=8.1 Hz, J=2.2 Hz), 7.58 (dm, 2H, J=8.6 Hz), 7.50 (dd, 1H, J=9.0 Hz, J=2.4 Hz), 7.32 (d, 1H, J=2.2 Hz), 7.29 (dm, 2H, J=8.6 Hz), 7.23 (d, 1H, J=8.1 Hz), 2.63 (s, 3H), 1.20 (s, 9H). MS: m/z 443 (M+1).
Reaction SMILES: [OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@@H:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:3]([CH3:5])[CH3:4].N1C=CC=CC=1.[C:23]1([P:29](Cl)(Cl)=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CC(OC)(C)C>[CH:3]([C@H:2]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C@H:12]([CH:13]([CH3:15])[CH3:14])[O:16][P:29](=[O:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:1]1)([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](O)c1ccccc1[C@@H](O)C(C)C
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CC(C)[C@@H]1OP(=O)(c2ccccc2)O[C@@H](C(C)C)c2ccccc21
Reaction time: 1.5 h

Procedure:
A solution of (S)-1-[2-((S)-1-Hydroxy-2-methylpropyl)phenyl]-2-methyl-propan-1-ol (1.0 g, 4.9 mmol) in pyridine (1.16 g 14.7 mmol) was cooled with an ice-bath. To this mixture was then added drop wise phenyl phosphonic acid dichloride (0.96 g, 4.9 mmol). After stirring for 90 minutes the reaction was complete by 31P-NMR. To the mixture was then added TBME (ca. 20 ml) and hydrochloric acid (ca. 5 ml 4N-solution). The organic layer was separated, dried (Na2SO4), and removal of the solvent left the product as an oil. Yield 1.50 g (89%). 1H/13C-NMR (CDCl3, HSQC/HMBC) δ/δ 0.965 (d, J=6.5 Hz)/20.38 (CH3); 1.075 (d, J=6.5 Hz)/19.05 (CH3); 1.106 (d, J=6.5 Hz)/17.71 (CH3); 1.112 (d, J=6.7 Hz)/20.38 (CH3); 2.37 (m)/34.58 (d, J=8.3 Hz) (CHMe2); 2.49 (m)/31.28 (d, J=7.6 Hz) (CHMe2); 5.17 (dd, J=5.6 Hz, J=7.6 Hz)/83.85 (d, J=8.9 Hz) (CH(i-Pr)); 5.53 (dd, J=3.8 Hz, J=5.9 Hz)/84.36 (d, J=7.6 Hz) (CH(i-Pr)); 7.24 (m)/127.28 (Ar CH); 7.24 (m)/127.93 (Ar CH); 7.24 (m)/127.95 (Ar CH); 7.27 (m)/128.31 (Ar CH); 7.37 (m)/128.43 (d, J=15.1 Hz) (Ph meta-CH); 129.12 (d, J=193 Hz) (Ph ipso-C); 7.47 (m)/132.38 (d, J=3.0 Hz) (Ph para-CH); 7.70 (m)/131.63 (d, J=9.8 Hz) (Ph ortho-CH); 137.23 (s), 138.48 (d, J=1.0 Hz) (2 Ar ipso-C). 31P-NMR (CDCl3) δ 18.72.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[C:25](=[O:26])[NH:24][C:23]([CH:27]([C:41]2[CH:46]=[C:45]([CH2:47][CH3:48])[CH:44]=[C:43]([O:49][CH2:50][C:51](=[O:55])[N:52]([CH3:54])[CH3:53])[C:42]=2[F:56])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[N:39]=[C:38]([CH3:40])[O:37][N:36]=3)=[CH:31][CH:30]=2)=[N:22]1)(C)(C)C>ClCCl>[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[C:25](=[O:26])[NH:24][C:23]([CH:27]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[N:39]=[C:38]([CH3:40])[O:37][N:36]=3)=[CH:33][CH:34]=2)[C:41]2[C:42]([F:56])=[C:43]([CH:44]=[C:45]([CH2:47][CH3:48])[CH:46]=2)[O:49][CH2:50][C:51]([N:52]([CH3:54])[CH3:53])=[O:55])=[N:22]1
Reactant: CCc1cc(OCC(=O)N(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3NC(=O)OC(C)(C)C)c(=O)[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(OCC(=O)N(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3N)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.7 %

Procedure:
After adding 2 ml of trifluoroacetic acid to a solution of 0.135 g of [2-(3-{(3-dimethylcarbamoylmethoxy-5-ethyl-2-fluorophenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-1-yl)phenyl]carbamic acid t-butyl ester in 10 ml of dichloromethane, the reaction mixture was stirred at room temperature for 4 hours, and the solvent was removed under reduced pressure. Next, 50 ml of ethyl acetate and 5 ml of 5% aqueous potassium carbonate were added to the residue, and the organic layer was washed with 20 ml of water and 20 ml of saturated aqueous sodium chloride in that order. The aqueous layer was extracted with 50 ml of ethyl acetate, and then the organic layers were combined and dried over anhydrous magnesium sulfate, the desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The title compound (0.100 g) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[C:10]=1[CH3:17])([CH3:7])[CH3:6])[CH3:2].[F:19][C:20]([F:39])([F:38])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:32][CH2:31][CH2:30][C:29]#[C:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:20]([F:19])([F:38])[F:39])=[CH:23][CH:24]=2)=[C:11]([F:16])[C:10]=1[CH3:17])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)c(F)c1C
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(OC(F)(F)F)cc2)c(F)c1C

Procedure:
In analogy to the procedure described in example 20A], 2-(3-fluoro-4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 33H]) and methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 1G]) yielded the title compound as light yellow viscous oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:32])=[O:31])=[CH:26][CH:25]=1)[C:18]([CH3:33])=[C:17]2[CH2:34][C:35]([OH:37])=[O:36])#[N:13]>CC(C)=O>[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:32])(=[O:9])=[O:31])=[CH:26][CH:25]=1)[C:18]([CH3:33])=[C:17]2[CH2:34][C:35]([OH:37])=[O:36])#[N:13]
Reactant: CC1=C(CC(=O)O)c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: CC1=C(CC(=O)O)c2cc(C#N)ccc2C1=Cc1ccc(S(C)(=O)=O)cc1

Procedure:
5-Cyano-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid is prepared by the addition of 1.0 mole of m-chloroperbenzoic acid per mole of 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid in an acetone solution.