Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1[O:9][CH2:8]1)[CH:2]1[O:4][CH2:3]1.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].N1C=CN=C1>CN(C)C=O>[CH2:1]([O:5][CH2:6][CH:7]1[O:9][CH2:8]1)[CH:2]1[O:4][CH2:3]1.[C:10]([O-:13])(=[O:4])[CH:11]=[CH2:12]
Reactant: C=CC(=O)Cl
Agent: C(OCC1CO1)C1CO1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CC(=O)[O-]
Reaction time: 14 h

Procedure:
1 part by weight of glycidyl ether and 2.5 to 5 parts by weight of acryloyl chloride are added into a three-neck flask, and then 15 to 25 parts by weight of N,N-dimethyl formamide as a solvent, and 0.1 to 0.5 parts by weight of imidazole as a reaction promoter are added therein. The reactants are heated to 90° C. to 140° C. with stirring under N2 atmosphere and the reaction is kept for 4 to 24 h. Then the solvent of N,N-dimethyl formamide is removed by reduced pressure distillation, and the residual is dried under vacuum to obtain the glycidyl ether-acrylate polymerizable monomer.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[N:6]=1)=[O:4].[OH-].[Na+]>O1CCCC1>[CH3:14][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:3]([OH:4])=[O:2])=[N:6]1
Reactant: COC(=O)c1nn(C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nc(C(=O)O)c2ccccc21

Procedure:
Methyl-1-methylindazole-3-carboxylate (3.1 g, 0.016 mol) was stirred with a solution of sodium hydroxide (0.78 g, 0.02 mol) in tetrahydrofuran (100 ml) for 2 hours at room temperature, the solution evaporated and the yellow residue were dissolved in water. Acidification with methanesulfonic acid precipitated 1-methylindazole-3-carboxylic acid (2.19 g). A further crop (0.3 g) was obtained by extraction of the aqueous acid solution with a mixture of ether and methylene chloride. Total yield 2.49 g (87%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:8]=2)[CH2:3][CH2:2]1.C([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[O:34][CH3:35])C>>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][C:30]([CH2:32][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[CH:8]=3)[CH2:3][CH2:2]2)=[CH:31][C:26]=1[C:25]([OH:36])=[O:24]
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: c1csc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Product: COc1ccc(CN2CCC(c3cn(Cc4cccs4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 25 (part C) starting with 1.90 g (0.065 mol) of 3-piperidin-4-yl-1-thiophen-2-ylmethyl-1H-indole and 1.92 (0.071 mol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard purification and recrystallization with ethanol, 1.2 g (40% of yield) of the expected acid.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[H-].[Na+].[CH:21]1[C:26]([C:27]([CH2:29]Br)=[O:28])=[CH:25][CH:24]=[C:23]([Cl:31])[CH:22]=1>CN(C)C=O>[CH2:11]([C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH2:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([Cl:31])=[CH:22][CH:21]=1)=[O:28])[C:4]([OH:3])=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)c1ccc(Cl)cc1)(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
5.0 g (20 mmol) of benzylmalonic acid diethyl ester were added dropwise at room temperature to a suspension of 0.87 g of sodium hydride dispersion (55% in oil) in 20 ml of dimethylformamide. Subsequently, the reaction mixture was stirred at room temperature for 20 minutes and thereafter 4.67 g (20 mmol) of omega-bromo-4-chloroacetophenone in 25 ml of dimethylformamide were added dropwise. After completion of the addition, the deep brown colored reaction mixture was stirred at room temperature overnight and thereafter evaporated in a high vacuum. The residue was dissolved in methylene chloride, washed with water and dried over sodium sulfate. Thereafter, the solvent was evaporated under reduced pressure and the residue, for purification, was chromatographed on silica gel with a 6:1 mixture of hexane and ether, to obtain 5.17 g (64%) of 2-(RS)-benzyl-2-carbethoxy-4-(4-chloro-phenyl)-4-oxobutyric acid as a yellowish solid. MS: 357 (M-OC2H5)+, 311 (M-benzyl)+.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-].[CH3:19][C@H:20]1[N:25]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[N:38]=[CH:37][CH:36]=[N:35]2)=[O:27])[CH2:24][C@H:23]([CH:39]=O)[CH2:22][CH2:21]1>CO>[C:39]([C@H:23]1[CH2:24][N:25]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:34]2[N:38]=[CH:37][CH:36]=[N:35]2)=[O:27])[C@H:20]([CH3:19])[CH2:21][CH2:22]1)#[CH:1]
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1CC[C@@H](C=O)CN1C(=O)c1ccccc1-n1nccn1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#C[C@@H]1CC[C@@H](C)N(C(=O)c2ccccc2-n2nccn2)C1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A mixture of potassium carbonate (0.556 g, 4.02 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.837 g, 4.36 mmol) in methanol (35 mL) under an atmosphere of nitrogen was cooled to 0° C. To this mixture was added a solution of (3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine-3-carbaldehyde (1.00 g, 3.35 mmol) in methanol (12 mL) dropwise. The reaction was allowed to warm slowly to RT and stir for 17 h. The mixture was concentrated in vacuo, treated with water, and extracted with ethyl acetate. The organic fraction was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 0-50% ethyl acetate in hexanes to provide [(2R,5S)-5-ethynyl-2-methylpiperidin-1-yl][2-(2H-1,2,3-triazol-2-yl)phenyl]methanone which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 295.3 for M+H+, and [(2R,5R)-5-ethynyl-2-methylpiperidin-1-yl][2-(2H-1,2,3-triazol-2-yl)phenyl]methanone which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 295.2 for M+H+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][C:13]([CH3:15])=[CH2:14])[C:9]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2]>C(OCC)(=O)C.C(O)C.C(O)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]2[N:16]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:18][C:8]=2[C:7]=1[OH:25])=[O:5])[CH3:2]
Reactant: C=C(C)Cc1nc(C(=O)OCC)c(O)c2sc(-c3ccccc3)nc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O=CO
Product: CCOC(=O)c1nc(CC(C)C)c2nc(-c3ccccc3)sc2c1O
Yield: 27.3 %

Procedure:
A mixture of 7-hydroxy-4-(2-methyl-allyl)-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (128 mg, 0.36 mmole) and 10% Pd/C (100 mg) in ethyl acetate (12 ml), ethanol (3 ml) and formic acid (15 μl) was hydrogenated at 20 psi for a week before it was filtered, concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The sodium bicarbonate layer was washed with dichloromethane. The organic layer was combined and washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (35 mg). MS: (+) m/z 356.96 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:41](=[O:43])[CH3:42].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:41](=[O:43])[CH3:42])[N:23]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C)[Si](OCc1cn(COCC[Si](C)(C)C)cn1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cn1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in (1) (30.0 g) was dissolved in tetrahydrofuran (hereinafter sometimes referred to as THF) (500 mL) and cooled to −78° C. with stirring under an argon atmosphere. n-Butyllithium (a 2.66 M hexane solution, 36.2 mL) was slowly added dropwise to this solution by using a syringe, and stirring was conducted at the same temperature for 30 minutes. N-Methoxy-N-methylacetamide (13.1 mL) was then added by using a syringe, and stirring was continued for 90 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution to stop the reaction, and extraction was conducted by using ethyl acetate. The combined extract liquid was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=5%→30%) using a silica gel column (trade name: Hi-Flash column 5L, manufactured by Yamazen Corporation) to give the title compound (24.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)[CH3:2].C([Li])CCC.C[O:17]B(OC)OC.OO.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[C:8]([OH:17])[CH:9]=1)[CH3:2]
Reactant: COB(OC)OC
Reactant: CCOc1ccc(F)cc1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(O)c1

Procedure:
To 150 ml of a THF solution containing 10.5 g of 1-ethoxy-4-fluorobenzene, 50 ml of n-butyllithium (1.58 M, hexane solution) was added dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred for 4 and a half hours, then 8.9 ml of trimethoxy boron was added thereto. Then, the temperature of the mixture was slowly allowed to rise to room temperature. The reaction mixture was stirred for 3 and a half hours, then 12.9 ml of acetic acid and 12.7 ml of a 30% hydrogen peroxide aqueous solution were added thereto at 0° C. The mixture was stirred at room temperature overnight, and then a saturated sodium sulfite aqueous solution was added thereto. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was crudely purified by silica gel column chromatography (ethyl acetate-heptane) to give a crude product of 5-ethoxy-2-fluorophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](Cl)(=[O:13])=[O:12])[C:7](=[O:15])[CH2:6][CH2:5]2.[NH3:16]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11](=[O:13])(=[O:12])[NH2:16])[C:7](=[O:15])[CH2:6][CH2:5]2
Reactant: N
Reactant: O=C1CCc2cc(Cl)c(S(=O)(=O)Cl)cc21
Product: NS(=O)(=O)c1cc2c(cc1Cl)CCC2=O

Procedure:
99.6 Grams of 5-chloro-6-chlorosulfonyl-1-indanone are introduced portionwise into 700 ml of liquid ammonia. The solvent is allowed to evaporate and the residue is dissolved in water, is heated within a short time on the water-bath and is filtered after the addition of active charcoal. The solution is acidified with hydrochloric acid to a pH of 2, the precipitate is filtered off with suction and is washed with water. The melting point of 5-chloro-6-sulfamoyl-1-indanone is in the range of from 205° to 208° C., and after recrystallization from a mixture of acetone and water it is 216° to 218° C.
Reaction SMILES: CS(O)(=O)=O.C([O:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([O:24]CC2C=CC=CC=2)[CH:17]=[CH:16][C:15]=1[C:32](=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35])C1C=CC=CC=1>CSC>[OH:13][C:14]1[C:19]([C:20]([F:21])([F:22])[F:23])=[C:18]([OH:24])[CH:17]=[CH:16][C:15]=1[C:32](=[O:37])[CH2:33][CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)CC(=O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1OCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CSC
Product: CC(C)CC(=O)c1ccc(O)c(C(F)(F)F)c1O
Reaction time: 1 h
Yield: 51.9 %

Procedure:
Add methanesulfonic acid (41 mL) to a solution of 1-(2,4-bis-benzyloxy-3-trifluoromethyl-phenyl)-3-methyl-butan-1-one (19.1 g, 38.9 mmol) in dimethyl sulfide (146 mL) at room temperature under argon gas. Heat the reaction mixture gently to reflux overnight. Quench the reaction mixture with ice-water and stir for 1 hr. Separate the organic layer and extract the aqueous with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to give a crude oil. Purify the resulting crude oil by flash column chromatography (silica gel) eluting with 25% ethyl acetate/hexane to provide the title compound as a tan solid (5.3 g, 20.2 mmol, 52% yield). MS (m/z): 263 (M+1).
Reaction SMILES: C1(OC)C=CC=CC=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[C:22]2[NH:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[NH:26][C:27](=O)[C:21]=2[CH:20]=[CH:19][CH:18]=1.N>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(C)C>[Cl:16][C:17]1[C:22]2[NH:23][C:24]3[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=3[N:26]=[C:27]([N:13]3[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccccc2Nc2c(Cl)cccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccccc3Nc3c(Cl)cccc32)CC1
Temperature: 60 °C

Procedure:
To a stirred solution of anisole (0.40 mL, 3.68 mmol) in dry toluene (2.00 mL) was added titanium tetrachloride (0.24 mL, 2.18 mmol) at room temperature under argon. The mixture was then treated with 1-methylpiperazine (1.04 mL, 0.94 g, 9.40 mmol) and 4-chloro-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine (0.49 g, 2.00 mmol) (Giani et al, supra) and diluted with toluene (1.00 mL). After more 1-methylpiperazine (0.60 mL, 0.54 g, 5.40 mmol) was added, toluene (8.00 mL) was added and the resulting reaction mixture was heated at reflux for 6 h before it was cooled to 60° C. Isopropanol (0.80 mL), celite (0.40 g) and ammonia (30%, 0.50 mL) were added sequentially and the whole mixture was filtered hot. Upon cooling to room temperature, the filtrate was concentrated in vacuo to dryness. The purification was carried out either by acidic (3M HCl) extraction and basification (30% ammonia) or column chromatography using ethyl acetate/methanol (3/1) as the eluent. The title compound was obtained as a light yellow solid in 0.60 g (91%); m.p. 168°-170° C.; MS (EI) 326 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I.C([O-])(=O)C.[Na+].[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[CH:24]=[CH2:25]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:28]([O:27][C:23](=[O:26])/[CH:24]=[C:25]1/[C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]/1=2)[CH3:29]
Reactant: Fc1ccc(Br)c(OCc2ccccc2I)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CCOC(=O)/C=C1\c2ccccc2COc2cc(F)ccc21
Temperature: 145 °C
Yield: 60.6 %

Procedure:
Heat 1-bromo-4-fluoro-2-(2-iodo-benzyloxy)-benzene (50 g, 0.123 mol), sodium acetate (30.2 g, 0.369 mol), tetrabutylammonium bromide (39.6 g, 0.123 mol), and palladium acetate (1 g) in N-methylpyrrolidine (250 mL) to 60° C. Add ethyl acrylate (12.91 g, 0.129 mol) in N-methylpyrrolidine (50 mL) dropwise over 20 min. After the addition is complete, heat the reaction mixture to 145° C. for 3 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, and wash the solids with methyl t-butyl ether (2×150 mL). Dilute the filtrate with methyl t-butyl ether (0.5 L) and wash with water (0.5 L). Separate the organic layer and extract the aqueous layer with methyl t-butyl ether (2×300 mL). Wash the combined organic layers with water (2×200 mL). Dry the organic portion over magnesium sulfate, treat with charcoal, filter, wash the solids with methyl t-butyl ether (100 mL) and concentrate. Slurry the residue in isopropanol (20 mL) in a Buchi flask at 55° C. without vacuum. Add heptanes (100 mL) with stirring. Place the dark suspension in a cold room overnight. Filter the solids, rinse with cold heptane/isopropanol (9:1, 2×100 mL), then heptane (50 mL) and dry to a constant weight in a vacuum oven at 35° C. to obtain the title compound as a tan powder (22.25 g, 61%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:17]1[C:18]([N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36]2)=[C:19]2[C:25]([NH:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.CC#N.O>O1CCOCC1.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>[C:27]([NH:26][C:25]1[C:19]2[C:20](=[N:21][CH:22]=[C:17]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:18]=2[N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:36]2)[NH:23][CH:24]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Reactant: OB(O)c1ccccc1
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: O
Solvent: CC#N
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(-c3ccccc3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 150 °C
Yield: 60.3 %

Procedure:
Phenylboronic acid (28.4 mg, 0.233 mmol), PS-palladium tetrakis (88.2 mg, 0.00970 mmol, 0.10 mmol/1 g) and 2N sodium carbonate (194 μL, 0.388 mmol) were added to (R)-tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (100 mg, 0.194 mmol; Example 1A, Step 1) in degassed dioxane (1 mL). The reaction was heated to 150° C. for 1 hour under microwave irradiation. Phenylboronic acid (28.4 mg, 0.233 mmol) and 2N sodium carbonate (194 μL, 0.388 mmol) were added, and the reaction was heated to 150° C. for an additional 2 hours under microwave irradiation and then cooled down and filtered. The filtrate was diluted with DCM, dried with MgSO4, filtered, and concentrated. The resulting residue was purified by reverse phase chromatography (Biotage Horizon, C-18 25M+, 10-90% CH3CN/water) to yield (R)-tert-butyl 1-(3-(nicotinamido)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (60 mg, 60% yield) as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([CH3:14])[NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].Cl>[OH-].[Na+]>[CH3:14][C:8]1[NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=2[CH:7]=1
Reactant: COC(=O)c1cccc2[nH]c(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc2c(C(=O)O)cccc2[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
To a solution of 2-methylindole-4-carboxylic acid methyl ester (4.3 g; prepared in Reference Example 9) in methanol-dioxane (10 ml+10 ml) was added 5N aqueous solution of sodium hydroxide (10 ml), and the mixture was stirred at 60° C. overnight. To the reaction solution was added 2N hydrochloric acid, and then extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform-methanol) to give the title compound (1.6 g) having the following physical data.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[C:8]2[N:9]([CH:13]=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH3:4].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:19]=1[CH2:20]Br>O>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:19]=1[CH2:20][N:6]([C:7]1[C:8]2[N:9]([CH:13]=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1)[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)Nc1cccn2cc(C)nc12
Reactant: Clc1cccc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N(Cc1c(Cl)cccc1Cl)c1cccn2cc(C)nc12
Reaction time: 0.5 h
Yield: 63.3 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 17 mg) was added 8-acetylamino-2-methylimidazo[1,2-a]pyridine (73 mg), and the mixture was stirred for 30 minutes, 2,6-dichlorobenzyl bromide (97 mg) was added thereto, and the mixture was stirred for 1 hour. Water was added thereto, and the mixture was extracted with methylene chloride three times. The combined organic layer was washed with water four times and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was crystallized with diethyl ether to give 8-[N-(2,6-dichlorophenyl)methyl-N-acetylamino]-2-methylimidazo[1,2-a]pyridine (85 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 2 from 6-[4-(4-methylphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH3:15])=[C:10]([Cl:17])[CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:40]=[N+:41]=[N-:42].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.ClCCl>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([N:40]=[N+:41]=[N-:42])[CH3:15])=[C:10]([Cl:17])[CH:9]=1
Reactant: [N-]=[N+]=N
Reactant: CC(O)c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(N=[N+]=[N-])c1ccc(NC(=O)OCC[Si](C)(C)C)cc1Cl

Procedure:
To a solution of [3-chloro-4-(1-hydroxy-ethyl)-phenyl]-carbamic acid 2-trimethylsilanyl-ethyl ester (1.25 g) in tetrahydrofuran (20 mL) at 0° C. under an atmosphere of argon is added triphenyl-phosphine (2.6 g), hydrazoic acid (approximately 2.5 molar equivalents in dichloromethane, prepared by the method of Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, pg. 446; Wiley, New York) and diethyl azodicarboxylate (1.72 g). After approximately 10 minutes the solvent is removed under reduced pressure and the residue is chromatographed over silica gel (5% ethyl acetate in hexanes is used as the eluant) to provide the desired product as a colorless oil.