Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.Cl.[CH2:33]([O:35][C:36](=[O:44])[CH2:37][NH:38][CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:34]>O1CCCC1.C(Cl)(Cl)Cl>[CH2:33]([O:35][C:36](=[O:44])[CH2:37][N:38]([C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:34]
Reactant: CCOC(=O)CNC1CCCC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN(C(=O)[C@H](C)NC(=O)OCc1ccccc1)C1CCCC1
Temperature: -10 °C
Reaction time: 8 h
Yield: 60.7 %

Procedure:
N-Carbobenzoxy-L-alanine (11.4 g) and triethylamine (6.7 ml) are dissolved in 100 ml of tetrahydrofuran and under stirring at -10° C., 6.5 ml of isobutyl chlorocarbonate is added in small portions. Then, at -10° C. to -5° C., a solution of N-cyclopentylglycine ethyl ester hydrochloride (10 g) and triethylamine (6.7 ml) in chloroform (100 ml) is added and the mixture is allowed to stand at room temperature overnight. The reaction mixture is filtered and the filtrate is concentrated. To the residue is added 300 ml of water, followed by extraction with 200 ml of ethyl acetate. The ethyl acetate layer is washed with 5% hydrochloric acid, aqueous sodium hydrogen carbonate and water in that order and dried over sodium sulfate. Removal of the solvent by distillation gives an oil, which is separated and purified by column chromatography using 150 g of silica gel. The fractions eluted with toluene-ethyl acetate (5:1) are collected to give 11 g of N-carbobenzoxy-L-alanyl-N-cyclopentylglycine ethyl ester as an oil. This product (10 g) is dissolved in 100 ml of ethanol, then 16 ml of 2N sodium hydroxide is added, and the mixture is stirred at room temperature for 5 hours. The reaction mixture is concentrated and the concentrate is diluted with 100 ml of water and acidified with 10% hydrochloric acid, whereupon an oil separates out. This oil is extracted with 300 ml of ethyl acetate and the extract is washed with water, dried and concentrated to give 8 g of N-carbobenzoxy-L-alanyl-N-cyclopentylglycine as colorless oil.
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[CH:19]=[CH:20][CH:21]=1)C.[NH2:31][NH:32][C:33](=O)[CH2:34][N:35]([CH3:37])[CH3:36].C[O-].[Na+]>CO>[CH3:36][N:35]([CH2:34][C:33]1[NH:32][N:31]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[O:24])[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:37]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)c4cccnc4)c3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1nc(-c2ccc3[nH]nc(-c4cccc(NC(=O)c5cccnc5)c4)c3c2)n[nH]1

Procedure:
The title compound was prepared according to example Example 329 C using N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-3-pyridylcarboxamide hydrochloride (0.400 g, 0.873 mmol), N-amino-2-(dimethylamino)acetamide (0.306 g, 2.62 mmol) and sodium methoxide in methanol (0.609 mL, 4.37 M). The title compound was isolated after purification by preparative HPLC (0.037 g, 10% yield): 1H NMR (CD3OD) δ 9.16 (dd, 1H), 8.79 (d, 1H), 8.75 (dd, 1H), 8.43 (dt, 1H), 8.39 (s, 1H), 8.09 (dd, 1H), 7.89-7.83 (m, 2H), 7.72 (d, 1H), 7.65-7.56 (m, 2H), 4.06 (br s, 2H), 2.61 (br s, 6H); ES-MS (m/z) 439 [M+H]+.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[OH-].[Na+].CO.Cl>O>[CH2:1]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCOc1ccc(C(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 99.3 %

Procedure:
A solution of 5.80 g (18.2 mM) of ethyl p-(10-undecenyl)oxybenzoate and 2.18 mg (54.6 mM) of sodium hydroxide in 4 ml of water, and 30 ml of methanol were stirred for 3 hours under heating. After the reaction, 20 ml of distilled water was added, followed by distilling-off of methanol and acidification of the solution with 6M-hydrochloric acid. The thus-produced p-(10-undecenyl)oxybenzoic acid was recovered by filtration and dried under vacuum in a dessicator to obtain 5.25 g (18.1 mM) of p-(10-undecenyl)oxybenzoic acid. Yield: 99.5% %.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=2F)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O-:24].[Na+]>C(Cl)Cl.CO>[CH2:1]([N:8]1[C:12]([C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:24][CH3:23])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cccc(F)c1-c1nnnn1Cc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cccc([N+](=O)[O-])c1-c1nnnn1Cc1ccccc1
Reaction time: 4 h

Procedure:
1-Benzyl-5-(2-fluoro-6-nitrophenyl)-1H-tetrazole (Intermediate 18, 0.3 g) was dissolved in DCM (4 mL) and a solution of sodium methoxide in methanol (20%; 2 mL) was added. The mixture was stirred for 4 hours and then the solvent was removed by evaporation under vacuum. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid and then brine. The organic solution was dried with sodium sulfate, filtered and the solvent was removed by evaporation under vacuum. The residue was purified by flash chromatography on silica, eluting with a mixture of DCM and methanol. The fractions containing the desired product were combined and evaporated to give the title compound as a pale yellow solid (0.14 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]([OH:36])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[O:21][C:22]=1[CH3:23])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[C:38]([O:36][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[C:9]([CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:10]=1)([CH3:45])[CH3:44])[CH3:43]
Reactant: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(O)cc1CCc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c(CCc2ccccc2)c1
Temperature: 55 °C

Procedure:
A mixture of 3-phenethyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-phenethylphenoxy}-2-methylpropionic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ8.03 (d, J=8.3 Hz, 2H), 7.64 (t, J=8.3 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 7.26-7.17 (m, 2H), 7.13 (dd, J=12.3, 7.3 Hz, 3H), 4.24-4.19 (m, 4H), 2.98 (t, J=6.6 Hz, 2H), 2.81 (s, 4H), 2.32 (s, 3H), 1.48 (s, 6H). 1.27 (t, J=7.1 Hz, 3H), MS (ES) m/e 590 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:10]1(Br)[CH2:12][CH2:11]1.N12CCCN=C1CCCCC2>O>[CH:10]1([O:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[CH2:12][CH2:11]1
Reactant: BrC1CC1
Reactant: N#Cc1cccc(O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: N#Cc1cccc(OC2CC2)c1
Yield: 35.8 %

Procedure:
Irradiate (200 C, ˜6 W [150 W max.], ˜25 psi) a solution of 3-cyanophenol (9.5 g, 80 mmol), cyclopropyl bromide (8.0 mL; 100 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (18 mL, 120 mmol) divided equally into five 10-mL tubes for 15 min. with stirring and cooling. After cooling, take the dark reaction mixtures together in water (200 mL) and extracted with ether (200 mL). Wash the organic layer with 0.2 M aq NaOH (40 mL, salted), 0.2 M aq HCl (100 mL, salted), and water (100 mL, salted). Dry the organic layer (Na2SO4) and rotary evaporate (30° C.) yielding 3-cyclopropoxybenzonitrile (4.56 g, 28.65 mmol, 36% yield) as a dark brown liquid. GCMS: 4.20 min.; EIMS m/z 159.
Reaction SMILES: FC(F)(F)C(O)=[O:4].FC(F)(F)C([O-])=O.[C:15]([C:18]1[CH:19]=[C:20]([CH:45]=[CH:46][CH:47]=1)[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([O:31][CH3:32])[CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:33]([NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][N+:41](C)=[CH:40][CH:39]=1)=[O:34])(=[NH:17])[NH2:16].Cl.NO.C(N(CC)CC)C>C(O)C>[N:41]1[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][NH:35][C:33]([C:23]2[N:22]([CH2:21][C:20]3[CH:45]=[CH:46][CH:47]=[C:18]([C:15](=[NH:17])[NH:16][OH:4])[CH:19]=3)[C:30]3[C:25]([CH:24]=2)=[C:26]([O:31][CH3:32])[CH:27]=[CH:28][CH:29]=3)=[O:34])=[CH:39][CH:40]=1
Reactant: COc1cccc2c1cc(C(=O)NCCc1cc[n+](C)cc1)n2Cc1cccc(C(=N)N)c1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: NO
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc2c1cc(C(=O)NCCc1ccncc1)n2Cc1cccc(C(=N)NO)c1
Yield: 54 %

Procedure:
The starting material 1-(3-cyano-benzyl)-4-methoxy-1H-indole-2-carboxylic acid 2-(4-pyridyl)-ethyl amide (example 41) was dissolved in ethanol, 2.4 equivalents of hydroxylamine hydrochloride and 2.4 equivalents of triethylamine were added and the mixture was refluxed for 6.5 h. The precipitate was filtered off to give 54% of the desired product. M.p. 220-222° C. MS: 444.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:25])=[C:11]2[CH3:26])[CH3:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:47]([CH3:52])[C:48]([O:50][CH3:51])=[O:49].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:51][O:50][C:48](=[O:49])[C@@H:47]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:25])=[C:11]2[CH3:26])[CH3:9])=[CH:6][CH:7]=1)[CH3:52]
Reactant: COC(=O)[C@@H](C)O
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)c1ccc(O[C@@H](C)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To allyl 1-(1-(4-hydroxyphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxylate (0.286 g, 0.82 mmol) in THF (0.8 mL) in an ice bath was added triphenylphosphine (0.28 g, 1.07 mmol) and then (R)-methyl 2-hydroxypropanoate (0.093 mL, 0.98 mmol). DIAD (0.24 mL, 1.23 mmol) was added dropwise to the cold solution. The mixture was stirred at room temperature for 16 hr. The solvent was removed and the residue was purified by silica gel chromatography to obtain the title compound. ESI-MS (m/z): 436 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:27]([O-:29])=[O:28])=[C:6]([CH:26]=1)[C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:12][N:11]=1)=[O:8].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:27]([C:5]1[CH:4]=[CH:3][C:2]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:12][N:11]=1)=[O:8])([O-:29])=[O:28]
Reactant: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 5-chloro-2-nitro-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide (2.0 g, 4.73 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL), piperidine (1.0 g, 11.74 mmol, 2.50 equiv), and potassium carbonate (2 g, 14.47 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was diluted with 150 mL of ethyl acetate. The resulting mixture was washed with 1×50 mL of water and 3×50 of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.7 g (76%) of product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH3:19])=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH3-]C#N.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH3:19])[CH:11]=2)[CH2:29][CH2:28]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCc1cc(CCC=O)n(-c2ccc(C)cc2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(C)cc2)n1

Procedure:
93 mg (59.7%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-methylphenyl)-3-propyl-1H-pyrazol-5-yl)propanal (95 mg, 0.371 mmol), 1-(2-fluorophenyl)piperazine (76 mL, 0.482 mmol), and NaCNBH3 (70 mg, 1.112 mmol).
Reaction SMILES: C[O:2][C:3]1[C:13]2[CH2:12][CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.[Cl-].[NH4+]>C(Cl)Cl>[F:18][C:15]([F:16])([F:17])[C:14]([N:10]1[CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([OH:2])[C:13]=2[CH2:12][CH2:11]1)=[O:19]
Reactant: COc1cccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.4 %

Procedure:
6-Methoxy-3-(trifluoroacetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (11.5 g, 42.0 mmol) was dissolved in CH2Cl2 (200 mL) and cooled to 0° C. under nitrogen. Boron tribromide (10.0 mL, 0.105 mol) was added via syringe, and the solution was stirred at room temperature for 16 hours. Saturated ammonium chloride was added slowly with stirring over 2 hours. Additional CH2Cl2 was added and the solution was partitioned between CH2Cl2 and water. The resulting mixture was concentrated and repartitioned between ethyl acetate and H2O. The organic layer was concentrated to give a white solid. Crystallization from EtOAc/hexane gave 9.95 g (91%) of the title compound as a white crystalline solid: mp 183–186° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.93 (dt, J=2, 8 Hz, 1 H), 6.71 (dd, J=4, 8 Hz, 1 H), 6.61 (t, J=6 Hz, 1 H), 3.68–3.60 (m, 4 H), 3.00–2.88 (m, 4 H); IR (diffuse reflectance) 3311, 1671, 1466, 1375, 1337, 1313, 1277, 1217, 1199, 1175, 1160, 1147, 949, 785, 739 cm31 1; MS (EI) m/z 259 (M+); Anal. Calcd for C12H12F3N O2: C, 55.60; H, 4.67; N, 5.40; F, 21.99. Found: C, 55.24; H, 4.75; N, 5.36.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:9][CH2:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:5]=[CH:6][CH:7]=1.ClCCl>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: Cc1cccc(C(CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2)c1
Yield: 27.9 %

Procedure:
The acid prepared in Example 47 (8.2 g, 21.6 mmol) was dissolved in methanol (150 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (35% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a residue which was disolved into dichloromethane and dried (Na2SO4). The solvent was evaporated in vacuo to give 2.3 g (28 %) of the title compound as a foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][C:13]1[C:14]([C:19]([CH3:23])([CH3:22])[CH:20]=[O:21])=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:7]2.[CH3:24][Mg]Cl.O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([O:12][C:13]1[C:14]([C:19]([CH3:23])([CH3:22])[CH:20]([OH:21])[CH3:24])=[N:15][CH:16]=[CH:17][CH:18]=1)=[CH:7]2
Reactant: C[Mg]Cl
Reactant: CC(C)(C=O)c1ncccc1Oc1cnc2c(F)cccc2c1
Solvent: O
Solvent: C1CCOC1
Product: CC(O)C(C)(C)c1ncccc1Oc1cnc2c(F)cccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.10 g of 2-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-2-methyl-propioaldehyde were dissolved in 3 ml of tetrahydrofuran. 0.2 ml of a 3.0 M tetrahydrofuran solution of methylmagnesium chloride were added thereto followed by stirring for 30 minutes at 0° C. Subsequently, water was added thereto to stop the reaction. The resultant was then extracted with ethyl acetate followed by distilling off the solvent of the organic layer and purifying by silica gel column chromatography to obtain 0.07 g of 3-[3-(8-fluoro-quinolin-3-yloxy)-pyridin-2-yl]-3-methyl-butan-2-ol.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[C:16]2/[CH:20]=[C:21]1\[O:22][C:23]2[C:30]([CH2:31][N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[C:29]([OH:45])[CH:28]=[CH:27][C:24]=2[C:25]\1=[O:26])C)=O)(C)(C)C.[ClH:46]>C(Cl)Cl.O1CCOCC1>[ClH:46].[ClH:46].[ClH:46].[OH:45][C:29]1[CH:28]=[CH:27][C:24]2[C:25](=[O:26])/[C:21](=[CH:20]/[C:16]3[C:15]4[C:19](=[C:11]([CH2:10][NH:8][CH3:6])[CH:12]=[CH:13][CH:14]=4)[NH:18][CH:17]=3)/[O:22][C:23]=2[C:30]=1[CH2:31][N:32]1[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1
Reactant: CN(Cc1cccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c12)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCc1cccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(7-{[tert-butoxycarbonyl(methyl)-amino]methyl}-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.044 g, 0.071 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 4 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of chloroform and methanol and thereby washed to obtain (Z)-6-hydroxy-2-({7-[(methylamino)methyl]-1H-indol-3-yl}methylene)-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.025 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9](Br)[CH:8]=[N:7][C:6]=12.[CH3:12][N:13]1[CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:15]=[N:14]1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:16]3[CH:15]=[N:14][N:13]([CH3:12])[CH:17]=3)[CH:8]=[N:7][C:6]=12
Reactant: Brc1cnc2c(Br)cnn2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnc3c(Br)cnn3c2)cn1
Temperature: 85 °C

Procedure:
3,6-Dibromopyrazolo[1,5-a]pyrimidine (2.0 g, 7.22 mmol) was mixed with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.51 g, 7.22 mmol). Dioxane (36 mL) and 1M Na2CO3 (10.8 mL) were added. The mixture was evacuated and flushed with nitrogen under stirring, then Pd(Ph3P)4 (0.42 g, 0.36 mmol) was added in a counter flow of nitrogen. The reaction mixture was heated to 85° C. under stirring for 16 h, cooled, and poured into a 5-fold excess of water. The product was extracted thrice with CH2Cl2. The organic layer was washed with brine, dried with MgSO4, filtered, and evaporated. The residue was purified by column chromatography (1-5% methanol/DCM) to give 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine as a yellow solid: LC/MS [M+H]=277.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([F:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:22][C:23]2[CH:24]=[C:25]([F:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(F)c1=O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(C)c(C)c1C(Nc1cc(F)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 28.2) and 5-amino-3-fluoro-1-methylpyridin-2(1H)-one (Step 14.2). tR: 4.17 min (HPLC 1); tR: 0.93 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.77 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:27][C:17]1[C:18]([NH:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([OH:26])[CH2:24][CH2:25]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CC[C@H](O)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CC[C@H](O)CC1
Temperature: 50 °C

Procedure:
Crude trans 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol (65.0 g, approx. 148 mmol) was suspended in ethanol (1000 mL, IMS grade) and water (300 mL). Ammonium chloride (47.5 g, 888 mmol) was added, and the mixture was stirred at 50° C. Powdered iron (33.0 g, 592 mmol) was added slowly and the resulting mixture was stirred at reflux for 2 h, then cooled to room temperature. The mixture was filtered and the filter cake washed with further ethanol, then the combined filtrate was concentrated under vacuum. The residue was suspended in water and extracted with dichloromethane (×2) and the combined organic extracts were dried (Na2SO4) and concentrated under vacuum. The residue was triturated with methanol then water to give 19.0 g (33%) of trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol. The methanol mother liquor was concentrated and the resulting residue triturated with acetonitrile to give a further 11.0 g (19%) of trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol. NMR (400 MHz, DMSO) δ: 8.04 (m, 2H), 7.68 (m, 2H), 7.59 (m, 3H), 6.76 (d, 1H), 5.68 (br s, 1H), 3.71 (br s, 1H), 1.91 (m, 2H), 1.84 (m, 2H), 1.34 (m, 4H), further signals partially obscured residual water peak.