Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].[ClH:31]>C(OCC)C>[ClH:31].[CH3:1][N:2]([C@@H:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:24])[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4]
Reactant: C[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCOCC
Product: C[C@H](c1ccccc1)N(C)C(=O)c1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1,1-dimethylethyl 4-[4-[[methyl[(1R)-1-phenylethyl]amino]carbonyl]-2-thiazolyl]-1-piperidinecarboxylate (2.0 g, 4.65 mmol) (see PCT Patent Publication WO 2007/014290 for a method of preparation) in diethyl ether was added hydrochloric acid (2 N in diethyl ether, 23 mL). The reaction mixture was stirred at room temperature for 3 h, and then the solid was collected by filtration to give N-methyl-N-[(1R)-1-phenylethyl]-2-(4-piperidinyl)-4-thiazolecarboxamide hydrochloride (1.2 g). A mixture of N-methyl-N-[(1R)-1-phenylethyl]-2-(4-piperidinyl)-4-thiazolecarboxamide hydrochloride (0.11 g, 0.30 mmol), (2-[(2,2,2-trifluoroethylidene)amino]oxy]acetic acid (prepared by the method described Example 1, Step E) (62 mg, 0.36 mmol), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol), N-hydroxybenzotriazole (5 mg) and triethylamine (0.10 mL, 0.72 mmol) in dry methylene chloride (8 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with methylene chloride and then washed with water, hydrochloric acid (0.1 N), water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound, a compound of the present invention, as a thick oil (130 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=2)[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[S-:28][C:29]#[N:30].[K+].BrBr>>[NH2:30][C:29]1[S:28][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=3)[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)=[O:11])[CH:26]=[CH:27][C:2]=2[N:1]=1
Reactant: Nc1ccc(Oc2cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Product: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)cc2s1
Yield: 79.3 %

Procedure:
Using 3-(4-aminophenoxy)-N-[3-(trifluoromethyl)phenyl]benzamide (2.45 g, 6.58 mmol), potassium thiocyanate (1.94 g, 20.0 mmol) and bromine (1.20 g, 7.50 mmol), and in the same manner as in Example A25(v), the title compound (2.24 g, 79%) was obtained as a pale-yellow powder.
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:12]=[CH:11][C:9](N)=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1.N([O-])=O.[Na+].C(N)CN.[BrH:21]>[Cu]Br>[N:1]1[N:2]([C:6]2[CH:12]=[CH:11][C:9]([Br:21])=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1
Reactant: Nc1ccc(-n2ncnn2)cc1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: NCCN
Product: Brc1ccc(-n2ncnn2)cc1
Reaction time: 0.25 h
Yield: 38 %

Procedure:
4-(Tetrazol-2-yl)aniline (450 mg, 2.8 mmol) in 48% HBr (10 ml) at -5° C. was stiired while sodium nitrite (193 mg, 2.8 mmol) was added portionwise over 5 minutes. The brown sludge was left stirring for 15 minutes and then added portionwise over 5 minutes to a refluxing mixture of copper (I) bromide (401 mg, 2.8 mmol) in 48% HBr (2 ml). The mixture was then heated at reflux for 1 minute, allowed to cool slightly, and poured into 10% ethylene diamine solution (20 ml). The aqueous solution was extracted with ethyl acetate, dried (Na2SO4), and evaporated to dryness under reduced pressure. The resulting mixture was purified by column chromatography on silica eluting with n-pentanelethyl acetate (4-10%) to afford the title compound as a white solid (238 mg, 38%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH2:16])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>O.C(Cl)(Cl)Cl>[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][CH2:15][NH:16][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][Cl:23])=[CH:6][CH:5]=1
Reactant: O=C(Cl)CCCCl
Reactant: COc1ccc2cccc(CCN)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2cccc(CCNC(=O)CCCCl)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.02 mol of 2-(7-methoxynaphth-1-yl)ethylamine hydrochloride is dissolved in a water/chloroform mixture. Potassium carbonate is added and the mixture is agitated for 15 minutes in an ice bath. 0.022 mol of 4-chlorobutyryl chloride is then added dropwise. The agitation is maintained for half an hour at room temperature; then the chloroform phase is dried, and the residue is recrystallized in a toluene/cyclohexane mixture (1:1).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:27])=[C:6]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:28]([O:27][C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[C:6]=1[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1cc2c(c(CN3CCN(C(=O)OC(C)(C)C)CC3)c1O)OCO2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C(C)=O)cc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of tert-butyl 4-[(6-acetyl-5-hydroxybenzo[d][1,3]dioxol-4-yl)methyl]piperazine-1-carboxylate (0.18 g, 0.48 mmol) in pyridine (1.0 mL) was added with acetic anhydride (1.0 mL) and 4-dimethylaminopyridine (0.010 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with ice water, the mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (7:3→3:7)) to obtain tert-butyl 4-[(5-acetoxy-6-acetylbenzo[d][1,3]dioxol-4-yl)methyl]piperazine-1-carboxylate (0.18 g, 87%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14]
Reactant: O=C(CBr)c1ccccc1F
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1ccccc1F
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A solution of 2-bromo-1-(2-fluorophenyl)ethanone (5.00 g, 23.0 mmol) and potassium thiocyanate (2.24 g, 23.0 mmol) in ethanol (50 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (60 ml) was poured into the reaction solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the desired product (4.29 g, 95.5%) as a solid.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC(S(O)(=O)=O)=CC=1.O.[N+:17]([O-:20])(O)=[O:18].[CH3:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=1[CH3:28]>>[N+:17]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=1[CH3:21])([O-:20])=[O:18]
Reactant: Cc1ccccc1C
Reactant: O=[N+]([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1S(=O)(=O)O
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
6 parts of diatomaceous earth the same as in Example 1 was thoroughly mixed with 5 parts of toluene-2,4-disulfonic acid and 10 parts of water. The mixture was dried at 100° to 105°C and further at 110°C under a pressure of 30 mm Hg for 5 hours, whereby dried solid catalyst was obtained. To the solid catalyst was added 40 parts of o-xylene and the mixture was cooled to -10°C. One part of fuming nitric acid having a specific gravity of 1.52 was added dropwise to the cooled mixture with stirring over a period of in 30 minutes. After the addition the mixture was stirred at -10°C for 3 hours and further at 20° to 25°C for 2 hours, whereby mononitroxylene was obtained with p/o ratio of 3.02. Yield was 91%.
Reaction SMILES: [C:1]([N:8]([CH2:15][C:16]1[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:31][CH2:32][CH3:33])[CH2:28][CH2:29][CH3:30])=[O:21])=[CH:18][CH:17]=1)[CH2:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1)(OC(C)(C)C)=O.C([C:38]1[S:39][CH:40]=[CH:41][N:42]=1)=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:28]([N:27]([CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:8]([CH2:9][C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH2:1][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[CH:35][CH:34]=1)[CH2:29][CH3:30]
Reactant: O=Cc1nccs1
Reactant: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)C(=O)OC(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccs2)cc1
Temperature: 25 °C
Reaction time: 39.5 h

Procedure:
The compound (39.8 mg) obtained in Example 1-3 and 2-formylthiazole (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (16.9 mg) were dissolved in anhydrous methanol (2.0 ml) and then added with sodium cyanoborohydride (18.9 mg). The solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 39.5 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and then washed with 1 mol/l sodium hydroxide and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. The residue was purified through silica gel column chromatography (chloroform/methanol/water) thereby obtaining hydrochloride (9.20 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20]([N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:22])=[O:21])=[C:4]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH:3]=1.C(#N)C.[OH2:40].CO>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[N:10][C:11]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:13]=2[C:14]#[N:15])=[CH:6][C:5]([S:20](=[O:22])(=[O:21])[N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[C:4]([CH:3]=1)[O:31][CH2:32][CH2:33][CH2:34][C:35]([OH:40])=[O:36]
Reactant: CN(c1ccccn1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCCO
Reactant: O
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: CN(c1ccccn1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(4-hydroxy-butoxy)-N-methyl-N-pyridin-2-yl-benzenesulfonamide (45 mg, 0.083 mmol) in a mixture of DCM (0.3 mL), acetonitrile (0.3 mL) and water (0.4 mL) was added NalO4 (54 mg, 0.25 mmol) and RuCl3 (2.7 mg, 0.013 mmol). After stirring at rt for 20 minutes, 0.5 mL of methanol was added. The mixture was stirred for 5 minutes, filtered, and purified by prep. LCMS to afford 4-[5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-pyridin-2-yl-sulfamoyl)-phenoxy]-butyric acid 18-1. MS: 555.1 (M+H)+; tR=7.61 min (method 2).
Reaction SMILES: [Li+].[OH-].[NH2:3][C@H:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19](Br)[C:20]#[CH:21]>CN(C=O)C.C1(C)C=CC=CC=1>[C:15]([O:14][C:12](=[O:13])[C@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:3][CH2:21][C:20]#[CH:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: C#CCBr
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#CCN[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
A solution of LiOH (400 mg, 16.7 mmol, 2.15 eq) in dry DMF (44 mL) containing activated 4 Å molecular sieves was stirred vigorously for 20 min, treated with Phe-Ot-Bu*HCl (2 g, 7.76 mmol, 1 eq), stirred for 45 min, treated with a solution 80% propargyl bromide (1.4 mL, 9.4 mmol, 1.21 eq) in toluene, stirred for 16 h and filtered through a pad of Celite™, which was washed with EtOAc (Cho, J. H. and B. M. Kim, Tetrahedron Lett. 2002, 43 1273-1276). The filtrate was washed three times with water, dried over MgSO4 and the volatiles were evaporated to provide an oil, which was purified by chromatography on silica gel using 30% EtOAc in hexane as eluent. Evaporation of the collected fractions gave ester 41 as yellow oil (1.66 g, 83%): Rf=0.53 (8:2 hexane/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 2H), 7.24 (m, 3H), 3.62 (t, J=6.9 Hz, 1H), 3.47-3.36 (m, 2H), 2.96 (m, 2H), 2.20 (m, 1H), 1.77 (s, 1H), 1.39 (s, 9H); 13C NMR (300 MHz, CDCl3) δ 172.9, 137, 129.2, 128.1, 126.4, 81.3, 81.0, 71.6, 61.5, 39.4, 36.5, 27.8. IR (thin film) v 3297, 2981, 2942, 1723, 1370, 1152, 700 cm−1; HRMS (LC-ESI) m/z calcd for C16H22NO2 [MH]+ 260.1645. Found 260.1634.
Reaction SMILES: [F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:24]([CH3:25])[C:23](=[O:26])[N:22]([CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:14]4=[CH:15][CH:16]=[N:17][C:18]([C:19]=2[O:20]C)=[C:13]34)=[O:9])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:24]([CH3:25])[C:23](=[O:26])[N:22]([CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:14]4=[CH:15][CH:16]=[N:17][C:18]([C:19]=2[OH:20])=[C:13]34)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1c(C(=O)NCc2ccc(F)cc2)nc2c3c(ccnc13)N(CCN1CCOCC1)C(=O)N2C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1C(=O)N(CCN2CCOCC2)c2ccnc3c(O)c(C(=O)NCc4ccc(F)cc4)nc1c23
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(4-fluorobenzyl)-6-methoxy-3-methyl-1-(2-morpholin-4-ylethyl)-2-oxo-2,3-dihydro-1H-pyrimido[4,5,6-de]-1,6-naphthyridine-5-carboxamide from step 1 (0.038 g, 0.077 mmol) in CH2Cl2 (1 mL) at −78 C was added boron tribromide (0.077 mL of a 1M solution in CH2Cl2, 0.077 mmol). The reaction was allowed to warm to room temperature and stirred an additional 16 hr. The solvent was evaporated in vacuo and the residue dissolved in methanol (2 mL) and the solvent again evaporated in vacuo. The residue was dissolved in DMF (1 mL) and purified by reverse phase HPLC. (Vydak C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 30 mL/min over 15 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH2:18][OH:19].CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=[O:40].CC1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C(O)=O.CS(C)=O>CO>[CH3:1][C:2]1=[CH:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])/[C:3]/1=[CH:10]/[CH:11]=[C:12](/[CH:13]=[CH:14]/[CH:15]=[C:16](/[CH:17]([OH:40])[CH2:18][OH:19])\[CH3:20])\[CH3:21]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Agent: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Solvent: CO
Solvent: CS(C)=O
Product: CC1=CCCC(C)(C)/C1=C/C=C(C)/C=C/C=C(\C)C(O)CO

Procedure:
All-trans retinol, all-trans retinal and all-trans retinoic acid were purchased from Sigma Chemical Co. (St. Louis, Mo.). The retinoids were dissolved at a concentration of 3×10-2M in methanol or DMSO with 10-4M butylated hydroxytoluene (Sigma Chemical Co.) added and stored in the dark at -20° C. in a nitrogen atmosphere. Immediately before use, the stock solutions were diluted in serum-free medium. 14-Hydroxy-retro-retinol (14HRR) was isolated from the pellets of HeLa cells fed with retinol by using a series of reversed-phase HPLC columns as described (33). 14HRR was pure according to the retention time on an analytical C18 reversed-phase column and the typical UV absorption spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]([NH2:33])[CH3:32])=[CH:27][CH:26]=1)([O-:24])=[O:23].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([NH:33][C@H:31]([C:28]4[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:30][CH:29]=4)[CH3:32])=[O:18])=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:19][CH:20]=1
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc2c(ccn2Cc2ccc(Br)cc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@H](NC(=O)c1ccc2c(ccn2Cc2ccc(Br)cc2)c1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of 1-(4-bromobenzyl)-1H-indole-5-carboxylic acid (1.03 g, 3.1 mmol, 1 equiv) in DMF (30 mL) were added the (S)-1-(4-nitrophenyl)ethanamine hydrochloride (695 mg, 3.4 mmol, 1.1 equiv), DIEA (600 μL, 3.4 mmol, 1.1 equiv), HOBt (525 mg, 3.4 mmol, 1.1 equiv) and EDC (658 mg, 3.4 mmol, 1.1 equiv). After stirring 4 h at room temperature, the mixture was diluted with AcOEt and washed with a 0.5 N HCl aqueous solution, a saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo. The crude was purified by flash chromatography (Hexane/AcOEt 1/1) to afford a yellow powder (1.3 g, 2.7 mmol, 87%). ESI-MS (m/z): 478/480 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(CBr)n1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
N-[6-(bromomethyl)-2-pyridinyl]-2,2-dimethylpropaneamide (21-2) (1.9 g) was dissolved in dimethylformamide (20 ml) and to the solution was added potassium phthalimide (1.43 g), followed by stirring at room temperature for 24 hours. The resulting mixture was concentrated under reduced pressure and extrated with water and dichloromethane. An organic layer was concentrated under reduced pressure to yield the compound 21-3 (2.27 g, 96%) as a bright yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:33]=[CH:32][C:15]2[NH:16][C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:18][C:14]=2[CH:13]=1.[H-].[Na+].CI.[CH3:38]COC(C)=O.O>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:33]=[CH:32][C:15]2[N:16]([CH3:38])[C:17]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH2:20]3)=[N:18][C:14]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(S(C)(=O)=O)cc4F)ccc3[nH]2)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1c(C2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(-c3ccc(S(C)(=O)=O)cc3F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-{5-[2-fluoro-4-(methylsulfonyl)phenyl]-1H-benzo[d]imidazol-2-yl}piperidine-1-carboxylate (85 mg, 0.17 mmol) dissolved in THF (15 ml) and cooled to 0° C. Sodium hydride (9 mg, 0.342 mmol) added to the above mixture and stirred at the same temperature for 30 mins. To this mixture methyl iodide (48 mg, 0.342 mmol) added at same temperature and stirred the reaction mixture at rt for 3 h. Reaction mixture diluted with ice and worked up (EtOAc/H2O). Crude was purified by column chromatography on 60-120 mesh silica gel using EtOAc:Petether (3:1) as eluent to afford the title compound (50 mg) as an orange solid. M.P.: 85-88° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.85-7.75 (m, 2H), 7.73-7.64 (m, 2H), 7.56-7.51 (m, 1H), 7.50-7.45 (m, 1H), 4.39-4.21 (m, 2H), 3.82 (s, 3H), 3.11 (s, 3H), 3.10-3.00 (m, 2H), 3.00-2.88 (m, 2H), 2.05-1.93 (m, 3H), 1.48 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:39]([O:40][CH3:41])=[CH:38][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:22][C:23]2[C:39]([O:40][CH3:41])=[CH:38][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33](=[O:34])[N:35]([CH3:36])[CH3:37])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: CNC(=O)c1cc(OC)ccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cc(OC)ccc1Nc1nc(Nc2cc3c(cc2OC)CCN(CC(=O)N(C)C)CC3)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-methoxy-N-methyl-benzamide of Example 607 was reacted with 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide, in a similar manner as Example 601b, to yield desired product 2-[5-Chloro-2-(3-dimethylcarbamoylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-5-methoxy-N-methyl-benzamide as a lyophylate (29%); 1H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H, exchangeable), 9.85 (bs, 1H, exchangeable), 8.77 (d, J=4.72 Hz, 1H, exchangeable), 8.39 (d, J=8.84 Hz, 1H) 8.27 (s, 1H, exchangeable), 8.17 (s, 1H), 7.66 (s, 1H), 7.31 (s, 1H), 6.98 (m, 2H), 4.33 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.7-3.5 (m, 2H), 3.4-3.0 (m, 4H), 2.95 (s, 6H), 2.80 (d, J=4.30 hz, 3H); MS (m/e) 568.43 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH:24]([CH3:26])[CH3:25])=[C:19]([Cl:27])[CH:18]=4)[O:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].CN1CCCC1=O>CO>[Cl:27][C:19]1[CH:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[CH:5]=[CH:4][N:3]=[C:2]4[NH:37][CH2:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:16]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(NCCC(=O)OC(C)(C)C)nccc34)no2)cc1Cl
Temperature: 180 °C
Yield: 14.9 %

Procedure:
1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 200 mg, 0.5 mmol), di-isopropylethylamine (0.873 ml, 1.0 mmol) and 1,1-dimethylethyl β-alaninate (726 mg, 5 mmol; available e.g. from Novabiochem) were placed into a 20 ml microwave vial, and N-methyl-2-pyrrolidinone (NMP, 8 ml) was added. The mixture was heated under microwave irradiation at 180° C. for one hour, diluted with methanol and chromatographed over an SCX cation exchange column (Biotage), which was washed with methanol and dichloromethane and eluted with methanolic ammonia. Washings and eluate from the SCX column were re-combined and evaporated in vacuo until only NMP remained. Water (20 ml) was added to the reaction mixture and a solid precipitate formed. The precipitate was collected by filtration and azeotroped twice with toluene. The solid was dissolved in dichloromethane (5 ml) and chromatographed on a silica column, eluting with dichloromethane to yield the title compound (38 mg) as a pale yellow solid.