Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>CS(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:7][C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([NH2:8])[CH:2]=2)=[N:11][CH:12]=1)([O-:18])=[O:17]
Reactant: Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(F)nc1
Solvent: CS(C)=O
Product: Nc1cccc(Nc2ccc([N+](=O)[O-])cn2)c1
Temperature: 80 °C

Procedure:
m-Phenylenediamine (2.8 mmol, 0.30 g) and 2-fluoro-5-nitropyridine (0.92 mmol, 0.13 g) were dissolved in 6 mL of DMSO. The solution was heated to 80° C. for 18 hours. The solution eventually turned dark red. The reaction mixture was cooled to room temperature and purified directly by flash column chromatography (silica, EtOAc:Hexanes=1:3) to give N1-(5-nitropyridin-2-yl)benzene-1,3-diamine as a reddish crystalline compound (0.19 g, 89% yield): 1H NMR (500 MHz, CDCl3) δ 9.08 (d, 1H, J=2.5 Hz), 8.24 (dd, 1H, J1=2.5 Hz, J2=9.5 Hz), 7.281 (s, 1H), 7.19 (t, 1H, J=8.0 Hz), 6.82 (d, 1H, J=9.5 Hz), 6.74 (s, 1H), 6.70 (d, 1H, J=8.0 Hz), 6.56 (d, 1H, J=7.5 Hz), 3.80 (br, 2H); 13C NMR (125 MHz, CDCl3) δ 159.91, 148.05, 146.93, 139.09, 137.15, 133.59, 130.77, 112.80, 112.66, 109.13, 106.67. The nitro compound (0.43 mmol, 0.10 g) and 10% Pd/C (10 mg) were added to a 20 mL test tube equipped with a stir bar, dry ice (0.5 g) was added to the mixture just before MeOH (7 mL) was added. The suspension was then put into a pressure vessel under 80 psi of H2. The reaction mixture was stirred for 2 hours. The solution turned from yellow to colorless. The reaction mixture was transferred into a 10 mL syringe and filtered through an Acrodisc syringe Filter into a 100 mL round bottom flask containing 37% aqueous HCl (3 mL). The solvent was then evaporated and azeotroped to dryness with toluene and absolute ethanol (3×30 mL of 1:1 mixture). The product was obtained as a grayish yellow powder in quantitative yield. B. Primary Intermediates of Formula (5)
Reaction SMILES: [CH3:1][NH:2][C:3]12[CH2:12][CH:8]([CH2:9][CH2:10][CH2:11]1)[CH:7]1[CH2:13][CH:4]2[CH2:5][CH2:6]1.[Cl:14][CH2:15][C:16](Cl)=[O:17]>>[CH3:1][N:2]([C:3]12[CH2:12][CH:8]([CH2:9][CH2:10][CH2:11]1)[CH:7]1[CH2:13][CH:4]2[CH2:5][CH2:6]1)[C:16](=[O:17])[CH2:15][Cl:14]
Reactant: O=C(Cl)CCl
Reactant: CNC12CCCC(C1)C1CCC2C1
Product: CN(C(=O)CCl)C12CCCC(C1)C1CCC2C1
Yield: 85 %

Procedure:
Under the same conditions as described in section (A) of Example 4, 1-methylaminotricyclo[4.3.1.12,5 ]undecane was reacted with 2-chloroacetyl chloride to obtain N-methyl-N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-chloroacetamide in a yield of 85%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Br)nccc3c2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Br)nccc2c1
Reaction time: 0.5 h

Procedure:
1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (see Example 70, step 3; 0.100 g, 0.150 mmol) was dissolved in DCM (1 mL). TFA (0.1 mL, 1.298 mmol) was added and the reaction was stirred for 30 minutes. The reaction was concentrated and the material was purified via silica gel column chromatography (12 g, gradient elution 0 to 10% MeOH:DCM) to afford 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.92 (br. s., 1H), 8.74 (d, J=5.8 Hz, 1H), 8.62 (d, J=1.4 Hz, 1H), 8.31-8.18 (m, 2H), 7.97 (d, J=7.9 Hz, 1H), 7.91 (dd, J=1.7, 8.9 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.29 (d, J=4.3 Hz, 1H), 6.88 (d, J=4.5 Hz, 1H). m/z (ESI) 514.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(NC1CCCC1)c1ccc(Cl)nc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CN(C1CCCC1)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 80 °C
Yield: 94 %

Procedure:
A mixture of 2 g (7.67 mmol) of 6-chloro-N-cyclopentylpyridine-3-sulfonamide, 0.7 mL (7.67 mmol) of methyl bromoacetate and 1.2 g (8.4 mmol) of K2CO3 in 15 mL of CH3CN is heated for 12 hours at 80° C. After cooling to room temperature, the medium is filtered and the filtrate is concentrated. The residue is taken up in 100 mL of DCM, washed successively with 50 mL of saturated NaHCO3 solution and 50 mL of water, and the organic phase is then dried over Na2SO4, concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with an 8/2 heptane/EtOAc mixture. 2.4 g of methyl N-[(6-chloropyridin-3-yl)sulfonyl]-N-cyclopentylglycinate are obtained in the form of an oil.
Reaction SMILES: [CH:1]([N:4]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[C:5](=[O:28])[CH2:6][N:7]1[C:16](=[O:17])[CH2:15][C:14]2[N:10]([C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:12][N:13]=2)[C:9]2[CH:24]=[CH:25][CH:26]=[CH:27][C:8]1=2)([CH3:3])[CH3:2].[H-].[Na+].[C:39]([O:43][C:44]([N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([CH2:55]Br)=[N:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C.[Cl-].[Na+].O>[C:39]([O:43][C:44]([N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:48]([CH2:55][CH:15]2[C:14]3[N:10]([C:11]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:12][N:13]=3)[C:9]3[CH:24]=[CH:25][CH:26]=[CH:27][C:8]=3[N:7]([CH2:6][C:5](=[O:28])[N:4]([CH:1]([CH3:3])[CH3:2])[C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:16]2=[O:17])=[N:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of N-isopropyl-N-(6-methoxy-pyridin-3-yl)-2-(5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-acetamide (Preparation 11) (520 mg, 1.079 mmol) in DMF (10 mL) at 0° C. was added NaH (60% in oil, 50 mg, 1.27 mmol). The reaction was stirred at 0° C. for 45 minutes and 3-bromomethyl-indazole-1-carboxylic acid tert-butyl ester (423 mg, 1.36 mmol) in DMF (5 mL) was added. The reaction was stirred at room temperature for 24 hours and was diluted with brine. The aqueous solution was washed with EtOAc (3×). The combined organic solutions were washed with brine (1×), dried (MgSO4), filtered and concentrated in vacuo to provide 3-(6-{[isopropyl-(6-methoxy-pyridin-3-yl)-carbamoyl]-methyl}-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl)-indazole-1-carboxylic acid tert-butyl ester. 1H NMR (CD3OD) δ 8.05 (d, 1H), 6.80-7.75 (m, 15H), 4.75 (m) and 4.60 (t, total 3H), 3.85-4.20 (m, 6H), 1.65 (m, 9H), 0.98 (m, 6H); MS 713.6 (M+1), 711.5 (M−1).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Product: Cc1ccc(S(=O)(=O)Nc2cc3nc(-c4ccccc4)n(-c4ccccc4)c3cc2OCCCCCC(=O)OC(C)C)cc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 4-methylbenzenesulfonic acid chloride.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[C:15]#[C:16][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O>CN(C=O)C.[Cu]I>[C:1]([N:5]1[C:6]2[C:7](=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=2)[CH:15]=[CH:16]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1ccc([N+](=O)[O-])cc1C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (10 mg, 0.035 mmol) in DMF (2 mL), was added CuI (13 mg, 0.07 mmol) under N2 protection. The reaction mixture was stirred at 100° C. overnight. At this time, EtOAc (4 mL) was added to the mixture. The mixture was filtered and the filtrate was washed with water, brine, dried over Na2SO4 and concentrated under vacuum, to obtain 1-tert-butyl-5-nitro-1H-indole (7 mg, 93%). 1H-NMR (CDCl3, 300 MHz) δ 8.57 (d, J=2.1 Hz, 1H), 8.06 (dd, J=2.4, 9.3 Hz, 1H), 7.65 (d, J=9.3 Hz, 1H), 7.43 (d, J=3.3 Hz, 1H), 6.63 (d, J=3.3 Hz, 1H), 1.76 (s, 9H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH3:11])[C:3]([C:5]1[O:6][CH:7]=[CH:8][N:9]=1)=[O:4].Cl.[CH3:13][C:14]([CH3:33])([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:15][C@H:16]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[C:17](O)=[O:18]>>[O:6]1[CH:7]=[CH:8][N:9]=[C:5]1[C:3]([C@@H:2]([NH:1][C:17](=[O:18])[C@@H:16]([CH2:20][C:21]([N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:15][C:14]([CH3:13])([CH3:33])[CH2:29][CH:30]([CH3:31])[CH3:32])[CH2:10][CH3:11])=[O:4]
Reactant: CC(C)CC(C)(C)C[C@H](CC(=O)N1CCOCC1)C(=O)O
Reactant: CC[C@H](N)C(=O)c1ncco1
Agent: Cl
Product: CC[C@H](NC(=O)[C@@H](CC(=O)N1CCOCC1)CC(C)(C)CC(C)C)C(=O)c1ncco1

Procedure:
It is similarly prepared according to the general procedure for Example 10 using (S)-2-Amino-1-oxazol-2-yl-butan-1-one; hydrochloride as the amino component and (R)-4,4,6-Trimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-heptanoic acid as the acidic component but without further oxidation step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[N:13]=[N:12][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Br[CH2:19][CH2:20][CH3:21].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[N:13]([CH2:19][CH2:20][CH3:21])[N:12]=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCBr
Reactant: O=c1nn[nH]n1-c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1nnn(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 55 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a stirred solution of 1-(4-nitrophenyl)-5-tetrazolone (6 g) in anhydrous N,N-dimethylformamide (30 mL) was added powdered 85% potassium hydroxide (1.9 g) and 1-bromopropane (3.9 g). The mixture was stirred at 55° C. for 2 hours and then poured into 300 mL of water. The biphasic mixture was extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate:hexane) to afford 7.2 g of the title compound as a pale yellow solid. 1H NMR (CDCl3) δ 8.32 (ABq, JAB =9.6 Hz, 4 H), 4.02 (t, J=7.2 Hz, 2 H), 1.93 (m, 2 H), 1.03 (t, J=7.5 Hz, 3 H); MS (CI) m/z 250 (MH+); Rf =0.6 (25% ethyl acetate/hexane).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[O:7][C@@H:6]1[S:25][C:26](=N)N)(=[O:3])[CH3:2].C(Br)[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)(Cl)Cl>CCOC(C)=O>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][S:21]([CH3:24])(=[O:23])=[O:22])[O:7][C@@H:6]1[S:25][CH2:26][CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:3])[CH3:2]
Reactant: BrCC=Cc1ccccc1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SC(=N)N)O[C@H](COS(C)(=O)=O)[C@H]1OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SCC=Cc2ccccc2)O[C@H](COS(C)(=O)=O)[C@H]1OC(C)=O

Procedure:
The title compound is prepared from 2-S-(2,3,4-tri-O-acetyl-6-O-methylsulfonyl-α-D-mannopyranosyl)-2-thiopseudourea and cinnamyl bromide in the usual manner. The desired product is isolated by column chromatography (silica gel; CHCl3 --EtOAc, 92:8, v/v) in 65-70% yield: m.p. 111°-113° C. (ether-petroleum ether); [α]D27 +175±1.1° (C 1.0, chloroform).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.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:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)=[CH:3][C:4]=1[N+:13]([O-:15])=[O:14])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)(C)Nc1ccc(Br)cc1[N+](=O)[O-]
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of (4-bromo-2-nitro-phenyl)-tert-butyl-amine (7.2 g, 0.026 mol) in DMF (100 mL) and H2O (10 mL) are added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-ylamine (8.7 g, 0.04 mol), Pd(PPh3)4 (3 g, 0.003 mol) and K2CO3 (7.3 g, 0.053 mol) at room temperature. The solution is heated to 100° C. for 2 hours. The solution is cooled down, washed with H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layer is dried with MgSO4 and filtered. The filtrate is concentrated and the residue is re-crystallized in CH2Cl2 (10 mL) to afford 5-(4-tert-butylamino-3-nitro-phenyl)-pyrimidin-2-ylamine as a scarlet solid (6.3 g, 83%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4=[N:21][CH:22]=[C:23]([C:25]([OH:27])=O)[CH:24]=[C:19]4[N:18]=[CH:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[N:53]1([CH2:59][CH2:60][NH2:61])[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C1COCC1>[F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4=[N:21][CH:22]=[C:23]([C:25]([NH:61][CH2:60][CH2:59][N:53]5[CH2:58][CH2:57][O:56][CH2:55][CH2:54]5)=[O:27])[CH:24]=[C:19]4[N:18]=[CH:17]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cnc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)c1cnc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 3-{4-[(4-(trifluoromethoxy)benzyl)oxy]phenyl}-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (42 mg, 0.1 mmol), CDI (32.4 mg, 0.2 mmol) and DIPEA (87 μL, 0.5 mmol) in dry THF (2 mL) was stirred at 60° C. for 2 h and then treated with 2-(morpholin-4-yl)ethylamine (26 μL, 0.2 mmol). After a further 2 h at 60° C. the mixture was concentrated in vacuo and the residue chromatographed over silica gel eluting with 5% MeOH/CHCl3 to give 3-{4-[(4-(trifluoromethoxy)benzyl)oxy]phenyl}-N-(2-morpholin-4-ylethyl)-3H-imidazo[4,5-b]pyridine-6-carboxamide. 1H NMR (400 MHz, D4-MeOH) δ 2.57 (br.s, 4H), 2.65 (t, J=8 Hz, 2H), 3.60 (t, J=8 Hz, 2H), 3.71 (t, J=8 Hz, 4H), 5.21 (s, 2H), 7.22 (dd, J=6.8 and 2 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 7.71 (dd, J=6.8 and 2 Hz, 2H), 8.57 (d, J=1.6 Hz, 1H), 8.71 (s, 1H) and 8.90 (d, J=1.6 Hz, 1H); MS (ES+): m/z 542 [MH+].
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](F)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[C:11](=[O:13])[CH3:12])=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: CC(=O)Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(F)cc1)c1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
To a room temperature suspension of sodium hydride (33.4 mmol, 1.34 g of 60% in mineral oil) in 60 mL of THF was added a solution of the N-(4-fluorophenyl)acetamide (4.1 g, 26.8 mmol) in THF (30 mL) over a 5 minute period. After 30 minutes, a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.2 mL, 26.8 mmol) in THF (10 mL) was added. After 15 hours, the reaction was concentrated in vacuo, the residue was diluted with 1 N sulfuric acid (300 mL) and extracted with three 100 mL portions of methylene chloride. The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a brownish oil. The residue was purified by column chromatography over silica gel eluting with 0-100% ethyl acetate in hexanes to afford 3.7 g of N-(4-bromo-2-nitrophenyl)-N-(4-fluorophenyl)acetamide as a thick yellow oil. MS m/z 353/355 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]2[N:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[N:18]1)[CH3:16].[H-].[Na+].O>CN(C=O)C>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26]2[CH:27]=[CH:28][C:29]([O:32][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:30][N:31]=2)=[N:18]1)[CH3:16]
Reactant: CCn1nc(-c2ccc(O)cn2)c2ncccc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(Oc3nc4cccnc4n3C)cn2)c2ncccc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) and 6-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-3-ol (68 mg) in DMF (1 mL) was added NaH (60% in oil, 18.11 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The eluent was evaporated and the residue was crystallized from EtOH/hexane to give the title compound (38.1 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:12]([CH3:11])[CH2:13][CH2:14][OH:15]
Reactant: CNCCO
Reactant: COc1ccccc1CBr
Product: COc1ccccc1CN(C)CCO

Procedure:
2-Methoxybenzyl bromide [J.Med. Chem., 32, 1761 (1989)] was reacted with N-methylethanolamine as described in the three previous examples to give N-(2-methoxybenzyl)-N-methylethanolamine which was reacted with 3-chloro-2-(dimethylaminomethyl)phenol in a similar manner to Example 1 (except that conversion into the dihydrochloride salt was omitted) to give the title compound b.p. 100° C. at 0.01 mbar.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C:12](=[O:14])[N:11]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=2)[C@H:10]1[CH2:24][CH3:25])(C(C)(C)C)(C)C.CO.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:23][C:17]1[CH:16]=[C:15]([N:11]2[C:12](=[O:14])[CH2:13][C@H:9]([OH:8])[C@@H:10]2[CH2:24][CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: CC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.3 %

Procedure:
To a solution of 4-[(2S,3S)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-chlorobenzonitrile (550 mg) in tetrahydrofuran (3 mL)-methanol (3 mL) was added 6 mol/L hydrochloric acid (4 mL), and the mixture was stirred at room temperature for 72 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/3) to give the title compound as a colorless solid (yield: 93.3 mg, 24%).
Reaction SMILES: O.Br[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][C:4]=1[F:12].C(=O)([O-])[O-].[Na+].[Na+].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[F:12][C:4]1[CH:5]=[C:6]([CH2:9][C:10]#[N:11])[CH:7]=[CH:8][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: N#CCc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCc1ccc(-c2ccccc2)c(F)c1

Procedure:
A biphasic mixture of water (3 mL) and toluene (10 mL) containing (4-bromo-3-fluoro-phenyl)-acetonitrile (457 mg, 2.14 mmol), sodium carbonate (1.00 g, 9.45 mmol), phenyl boronic acid (781 mg, 6.41 mmol) was sparged with nitrogen for 10 min, tetrakis(triphenylphosphine)palladium (250 mg) was added and the mixture heated to reflux for 48 hrs. After cooling, the solution was diluted with EtOAc, washed with water, the organic phase dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography (0 to 10% EtOAc in hexanes) to afford (2-fluoro-biphenyl-4-yl)-acetonitrile as a colorless solid. 1H NMR (500 MHz, CDCl3) δ 7.54 (2H, m), 7.46 (3H, m), 7.40 (1H, m), 7.17 (2H, m), 3.79 (3H, s).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1)(=O)=O.CCN(C(C)C)C(C)C.[CH3:29][NH:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1>[CH3:29][N:30]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:5]1[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1
Reactant: CS(=O)(=O)c1nc(C(N)=O)cc(-c2ccccc2)n1
Reactant: CNCCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccc1)c1nc(C(N)=O)cc(-c2ccccc2)n1
Temperature: 85 °C
Yield: 51.7 %

Procedure:
2-Methanesulfonyl-6-phenylpyrimidine-4-carboxamide (70 mg, 0.25 mmol), 1,4-dioxane (4 mL), DIPEA (0.3 mL, 2.0 mmol) and N-methylphenethylamine (82 mg, 0.6 mmol) were added to a 8 mL vial. The vial was sealed and heated at 85° C. for two days. The reaction mixture was allowed to cool to room temperature, and the solvent then removed by centrifugal evaporation. The residue was purified by preparative HPLC to afford 43 mg of 2-(N-methylphenethylamino)-6-phenylpyrimidine-4-carboxamide. 1H NMR (CDCl3, 300 MHz) δ 8.14 (m, 2H), 7.74 (s, 1H), 7.67 (br s, 1H), 7.47 (m, 3H), 7.25 (m, 5H), 5.79 (br s, 1H), 3.95 (t, J=6.9 Hz, 2H), 3.21 (s, 3H), 2.97 (t, J=6.9 Hz, 2H). HPLC ret. time 3.25 min, 10-100% CH3CN, 5 min run. ESI-MS m/z 333.3 (M+H)+.