Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].[Br-].O.Cl>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[CH2:8][CH2:7][CH:6]=[CH2:4])[CH2:11][CH2:10]2)=[N:13][CH:14]=1
Reactant: CON(C)C(=O)C1CCN(c2ccc(Cl)cn2)CC1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)C1CCN(c2ccc(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 185.3 %

Procedure:
While under a nitrogen atmosphere, a solution of 5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid, methoxy-methyl-amide (1.0 g, 3.5 mmol), in tetrahydrofuran (10 mL) was cooled to 0° C. and treated with 4-butenylmagnesiun bromide (0.5 M in THF, 17.6 mL, 8.8 mmol) dropwise. After stirring for 1 hour at 0° C. and room temperature overnight the reaction mixture was poured into water, acidified to pH 3-4 with 1N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (silica gel, 0-25% ethyl acetate in heptane) gave 1-(5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-pent-4-en-1-one as a colorless oil (904 mg, 93%); 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, J=2.5 Hz, 1H), 7.42 (dd, J1=9.0 Hz, J2=2.5 Hz, 1H), 6.62 (d, J=9.0 Hz, 1H), 5.80 (m, 1H), 5.04 (m, 2H), 4.23 (m, 2H), 2.92 (m, 2H), 2.59 (m, 3H), 2.36 (m, 2H), 1.98 (m, 2H) and 1.70 (m, 2H); MS (+CI): m/z for C15H19ClN2O: expected 278.1. found 279.2 (M+H)+.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[OH:6][CH2:7][CH2:8][O:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1>CO>[OH:6][CH2:7][CH2:8][O:9][C:10]1[N:11]=[N:12][C:13]([S:5][CH2:2][CH:3]=[CH2:4])=[CH:14][CH:15]=1
Reactant: C=CCS
Reactant: OCCOc1ccc(Cl)nn1
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccc(OCCO)nn1

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 1.00 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.75 g(0.01 mol) of 3-(2-hydroxyethoxy)-6-chloropyridazine. The reaction solution was refluxed for 24 hours and then treated according to the same manner as Example 1 to obtain the title compound as a pale white needle crystal.
Reaction SMILES: [C:1]1([P:7](=O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(=S)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: S=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Yield: 71 %

Procedure:
To an oven-dried 50-ml autoclave liner were added 16.68 g of triphenylphosphine oxide (.06 mole) and 0.057 g of sulfur (.0018 mole). The solids were treated with 11.12 g of silicon tetrachloride (.066 mole) and the mixture was placed in an autoclave which was then charged to a pressure of 715 p.s.i.g. (48 atm.) with hydrogen. The mixture was heated to 250°C for 15 hours at a maximum pressure of 77 atm. After cooling and venting, the reaction mixture was worked up by first partitioning between warm 30% by weight aqueous sodium hydroxide solution and toluene. The aqueous layer was extracted once with toluene and the combined organic layers were washed with water and with brine and dried over anhydrous sodium sulfate. Filtration and solvent removal gave 13.66 g (86.9%) of crude triphenylphosphine, mp 68°-77° which contained 2% triphenylphosphine oxide and 3% triphenylphosphine sulfide by gas-liquid chromatographic (glc) analysis. Recrystallization from methanol gave 11.25 g (71%) of purified triphenylphosphine, mp 75°-9°, still containing 1-2% triphenylphosphine sulfide by glc analysis.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:32]=[CH:33][C:28]([C:26]([NH:25][CH3:24])=[O:27])=[CH:29][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CNC(=O)c1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 48 mg, 0.129 mmol) and 4-(N-methylaminocarbonyl)phenylboronic acid (ABCR, Karlsruhe, Germany, 27 mg, 0.153 mmol) to give the title compound as a white solid. (HPLC: tR 2.40 min (Method A); M+H=427 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.54-8.48 (m, 1H), 8.19-8.15 (m, 1H), 8.13-8.07 (m, 1H), 7.98-7.89 (m, 3H), 7.61-7.53 (m, 3H), 3.94 (s, 3H), 3.57 (s, 3H), 2.79 (d, 3H), 1.95 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14]Br)=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])=[O:4].[C:26]([O-:29])(=[O:28])[CH3:27].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][O:29][C:26](=[O:28])[CH3:27])=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])=[O:4]
Reactant: COC(=O)c1cc2cc(CBr)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(COC(C)=O)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.5 %

Procedure:
1-BOC-5-bromomethyl-7-nitro-indole-2-carboxylic acid methyl ester (10.0 g, 24.2 mmol) prepared in Step B of Preparation 37 was dissolved in N,N-dimethylformamide (50 mL). Sodium acetate (2.4 g, 29.0 mmol) was added thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was purified by column chromatography to give the title compound (4.7 g, Yield 50%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2/[CH:20]=[CH:21]/[C:22]([CH3:25])([OH:24])[CH3:23])[C@H:12]([CH3:26])[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pd].C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[C@H:12]([CH3:26])[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(/C=C/C(C)(C)O)cccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(CCC(C)(C)O)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
Add a solution of (E)-4-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-but-3-en-2-ol (68 g, 168.83 mmol) in ethanol (816 mL) to a pressure hydrogenation vessel and add 5% palladium on activated carbon (35.83 g, 16.84 mmol). Purge the vessel with hydrogen gas, pressurise to 470 kPa of hydrogen gas and stir at 25° C. After 16 hours, vent the vessel and filter the reaction mixture through diatomaceous earth. Wash the diatomaceous earth with ethyl acetate and concentrate the filtrate under reduced pressure to give an oil. Dissolve the oil in ethyl acetate (1 L) and concentrate under reduced pressure to give the title compound (64 g, 161 mmol). MS (m/z): 378.2 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1COCC1>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: C=Cc1ccc(CN2CCNCC2)cc1
Yield: 81.2 %

Procedure:
Synthesized according to General Procedure A: 4-vinylbenzyl chloride (7, 5.56 g, 32.8 mmol, 1 equiv.), piperazine (16.9 g, 196.6 mmol, 6 equiv.), THF (71.8 mL). Purification with flash column chromatography on silica gel (gradient, 4:1 to 1:4 EtOAc:MeOH) afforded 8 (5.39 g, 81%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.32 (d, 2H, J=8.0 Hz), 7.24 (d, 2H, J=8.0 Hz), 6.66 (dd, 1H, J=11.0, 18.0 Hz), 5.69 (dd, 1H, J=0.5, 18.0 Hz), 5.18 (dd, 1H, J=0.5, 11.0 Hz), 3.43 (s, 2H), 2.84 (t, 4H, J=5.0 Hz), 2.63 (br s, 1H), 2.37 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 137.5, 136.4, 136.2, 129.1, 125.8, 113.3, 63.1, 54.0, 45.7.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[Cl-].[NH4+]>CN(C)C=O>[F:18][C:19]([F:27])([F:28])[C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[CH:11])[N:5]=[CH:4][N:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: C#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cc(Oc2cccc(C(F)(F)F)c2)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 75.4 %

Procedure:
To 5 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-propynyloxy)pyrimidine, 0.25 g of potassium carbonate, and 0.19 g of 3-trifluoromethylphenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 4-(3-trifluoromethylphenoxy)-6-(2-propynyloxy)pyrimidine (the present compound (17)).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@:10]23[O:27][C@@:14]4([CH2:17][O:18][CH:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[O:20][C@H:13]4[C@H:12]([OH:28])[C@H:11]2[OH:29])[CH2:15][O:16]3)=[CH:6][C:5]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=1.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:40]([O:29][C@H:11]1[C@:10]2([C:7]3[CH:8]=[CH:9][C:4]([Cl:3])=[C:5]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH3:39])=[CH:35][CH:36]=4)[CH:6]=3)[O:27][C@@:14]3([CH2:17][O:18][CH:19]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[O:20][C@H:13]3[C@@H:12]1[O:28][CH2:30][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1)[CH2:15][O:16]2)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: BrCc1ccccc1
Reactant: CCOc1ccc(Cc2cc([C@@]34OC[C@]5(COC(c6ccccc6)O[C@H]5[C@H](O)[C@H]3O)O4)ccc2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@]34OC[C@]5(COC(c6ccccc6)O[C@H]5[C@H](OCc5ccccc5)[C@H]3OCc3ccccc3)O4)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 182.8 %

Procedure:
To a mixture of sodium hydride (6.5 g, 163.8 mmol, 60% dispersion in Mineral oil) in anhydrous tetrahydrofuran (30 mL) was added dropwise a solution of (4aS,7S,8R,9R,9aS)-7-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2-phenylhexahydro-4a,7-epoxy[1,3]dioxino[5,4-c]oxepine-8,9-diol 28b (14.3 g, 27.3 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and room temperature for 1 hour. To the mixture were added benzyl bromide (13 g, 109.2 mmol) and a catalytic amount of tetrabutylammonium iodide at 0° C. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water at 0° C., adjusted with saturated aqueous ammonium chloride till pH becomes 7 and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 28c as a white solid (17.6 g, 91.4%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.44-7.41 (m, 4H), 7.37 (m, 4H), 7.35-7.30 (m, 5H), 7.21 (d, 1H), 7.16 (m, 2H), 7.08 (d, 2H), 6.86 (d, 2H), 6.78 (d, 2H), 5.67 (s, 1H), 4.94 (d, 1H), 4.79 (d, 1H), 4.73 (s, 1H), 4.64 (d, 1H), 4.39 (d, 1H), 4.25 (d, 1H), 4.18 (d, 1H), 4.07-3.94 (m, 6H), 3.87 (d, 1H), 3.72 (d, 1H), 1.41 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:30])[N:23]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=2)=[O:20])[C:3]=1[N+:31]([O-])=O.O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:31][C:3]1[C:4]([NH:18][C:19]([C:21]2[N:22]([CH3:30])[N:23]=[C:24]([C:26]([CH3:28])([CH3:27])[CH3:29])[CH:25]=2)=[O:20])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:17])[F:16])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2cc(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2cc(C(C)(C)C)nn2C)c1N
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide (226 mg, 0.490 mmol, prepared as described in the previous step) in ethanol (10 mL) and water (5 mL) was treated with ammonium chloride (262 mg, 4.90 mmol) and iron powder (137 mg, 2.45 mmol), and the mixture was heated to 50° C. for 4 h. Ethanol was removed in vacuo, and the resulting residue was diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=20 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 10 min, then 1:99 to 1:4 v/v over 40 min) to yield 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [5-amino-6-methyl-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide as an off-white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C21H23F3N6O: 433.2 (M+H); Measured: 433.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:6][CH:5]=1.[C:22]([O:26][C:27](=[O:33])[N:28]([CH3:32])[CH2:29][CH:30]=O)([CH3:25])([CH3:24])[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:22]([O:26][C:27](=[O:33])[N:28]([CH2:29][CH2:30][N:19]1[CH2:20][CH2:21][N:16]([C:11]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][O:2][CH3:1])=[CH:5][CH:6]=3)=[N:15][CH:14]=[CH:13][N:12]=2)[CH2:17][CH2:18]1)[CH3:32])([CH3:25])([CH3:24])[CH3:23]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: COCc1ccc(-c2nccnc2N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COCc1ccc(-c2nccnc2N2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
Dissolve 3′-(4-methoxymethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (1.76 g, 6.2 mmol, 1 eq.) in 1,2 dichloroethane (20 mL). Add methyl-(2-oxo-ethyl)-carbamic acid tert-butyl ester (1.13 g, 6.51 mmol, 1.05 eq.). Add sodium triacetoxyborohydride (1.97 g, 9.3 mmol, 1.5 eq.). Stir at room temperature for 18 hr. Partition the reaction mixture between aqueous saturated NaHCO3 and dichloromethane. Separate the layers. Extract the organic layer with dichloromethane (2×100 mL). Combine the organic layers, dry over anhydrous Na2SO4, filter and concentrate. Purify by normal phase chromatography with 30% EtOAc/hexane—100% EtOAc to afford the title preparation (1.01 g, 37% yield). MS (loop): m/z=442.3 [M+H].
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22](=C)[N:21]([CH3:27])[CH:20]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:30])C>>[CH2:1]([N:8]1[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[N:16]=[C:17]1[C:19]1[CH:24]=[C:23]([CH3:25])[C:22](=[O:30])[N:21]([CH3:27])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C1C(C)=CC(C(=O)Nc2ccc(F)cc2NCc2ccccc2)=CN1C
Reactant: CC(=O)O
Product: Cc1cc(-c2nc3ccc(F)cc3n2Cc2ccccc2)cn(C)c1=O
Temperature: 150 °C
Reaction time: 1 h

Procedure:
1,5-Dimethyl-6-methylene-1,6-dihydro-pyridine-3-carboxylic acid (2-benzylamino-4-fluoro-phenyl)-amide I-12′ (186.000 mg; 0.509 mmol) is dissolved in acetic acid and stirred at 150° C. for 1 h in the microwave. The reaction mixture is then concentrated under reduced pressure and purified on silica chromatography Combiflash (Column: Redisep Rf, 12 g; gradient: DCM/MeOH=100%/0% to 90%/10%; flow rate=30 ml/min; 28 column volumes; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduce pressure. The product is then dissolved in acetonitrile:water 1:1 and freeze dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 70.5 %

Procedure:
A solution of 11.0 g (0.041 mole) of 4-fluorophenylmethyl 3-fluoro-4-nitrophenyl ether in 100 mL of glacial acetic acid and 10 mL of water was heated to 50° C. To this hot solution was added 1.0 g (0.18 mole) of powdered iron. The reaction mixture was allowed to cool to ambient temperature, where it stirred for an additional hour. The reaction mixture was filtered through a bed of Celite® filter aid, and the Celite bed was washed in succession with ethyl acetate and 200 mL of water. The washes and the filtrate were combined, and the organic phase was separated. The organic phase was dried with anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure, leaving a dark oil as a residue. This oil was placed on a silica gel column and eluted with methylene chloride. The product-containing fractions were combined and the solvent evaporated under reduced pressure, leaving 6.8 g of 4-fluorophenylmethyl 4-amino-3-fluorophenyl ether as a solid, m.p. 42°-43° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:20][C:19]2[C:14](=[N:15][CH:16]=[CH:17][C:18]=2[NH:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)[CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Brc1cc2nccc(Nc3ccc4[nH]ccc4c3)c2s1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-fluorobenzeneboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 17. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 10.7 (s, 1H), 8.28 (d, 1H), 7.50 (m, 9H), 7.05 (d, 1H), 6.49 (s, 1H); LC-MS: 360 (MH+); HPLC RT: 5.40 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CC(C)(N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(CO)NCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-amino-2-methyl-1-propanol (18 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(2-hydroxy-1,1-dimethylethyl)aminomethyl]indol-2-yl)isoindolinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:19]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.[OH-].[Na+].[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH:24]([OH:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:19]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccnc(C(=O)C(=O)N(C)C)c3)cc12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccnc(C(O)C(=O)N(C)C)c3)cc12
Reaction time: 4 h
Yield: 14.1 %

Procedure:
2-{4-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-2-yl}-N,N-dimethyl-2-oxo-acetamide (100 mg, 0.18 mmol) was dissolved in ethanol (2.0 mL) and treated with 4 N aqueous sodium hydroxide (49.6 μL, 0.198 mmol). After 4 h, an additional 22.5 μL (0.09 mmol) 4 N aqueous sodium hydroxide was added. After 19 h, sodium borohydride (7.5 mg, 0.198 mmol) was added to the mixture at 0° C. After 55 min., the mixture was concentrated in vacuo and purified by preparative HPLC to afford 2-{4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-2-yl}-N,N-dimethyl-2-hydroxy-acetamide (10.2 mg, 14.1%). 1H-NMR (500 MHz, dimethylsulfoxide-d6) δ 2.85 (s, 3H), 3.00 (s, 3H), 3.82 (s, 3H), 5.53 (d, J=7.5 Hz, 1H), 5.95 (d, J=7.5 Hz, 1H), 7.06 (dt, J=7.0, J=1.0 Hz, 1H), 7.15 (br d, J=8.5 Hz, 1H), 7.27 (dd, J=1.0, J=5.0 Hz, 1H), 7.32 (dt, J=2.0, J=7.0 Hz, 1H), 7.56 (dd, J=1.0, J=8.0 Hz, 1H), 7.73 (d, J=3.0 Hz, 1H), 7.99 (br s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.62 (d, J=5.0 Hz, 1H), 8.94 (d, J=2.0 Hz, 1H), 11.99 (s, 1H). MS: m/z 403 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:17]=[C:16]([NH2:18])[NH:15][N:14]=2)=[O:12])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:33])[C:23](=[CH:29]OCC)[C:24](OCC)=[O:25])[CH3:20]>C(O)(=O)C>[CH2:19]([O:21][C:22]([C:23]1[C:24](=[O:25])[N:15]2[N:14]=[C:13]([C:11](=[O:12])[NH:10][CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:17]=[C:16]2[NH:18][CH:29]=1)=[O:33])[CH3:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(C(=O)NCCc2ccc(Cl)cc2)n[nH]1
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cc(C(=O)NCCc3ccc(Cl)cc3)nn2c1=O
Temperature: 120 °C
Yield: 35.4 %

Procedure:
To a solution of 5-amino-1H-pyrazole-3-carboxylic acid [2-(4-chloro-phenyl)-ethyl]-amide (100 mg, 0.4 mmol, 1 eq) in acetic acid (2 mL) was added 2-ethoxymethylene-malonic acid diethyl ester (80 μL, 0.44 mmol, 1.1 eq). The mixture was heated at 120° C. for 16 h in a sealed tube. After cooling, the precipitate was filtered and washed with ethanol (2×10 mL) to afford the expected compound as white powder (55 mg, 38% yield).