Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21])=[O:4].[CH3:22][O:23][NH2:24]>>[CH3:22][O:23][NH:24][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21])=[O:4]
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(I)cc1F
Reactant: CON
Product: CONC(=O)c1ccc(=O)n(C)c1Nc1ccc(I)cc1F

Procedure:
2-(2-Fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester was coupled as described previously in Example 155 using O-methyl-hydroxylamine. MS ESI (+) m/z 418 (M+1) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.Cl[C:16]1[N:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][C:19]1[N:18]=[N:17][C:16]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: Nc1ccc2sc3ccccc3c2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2ccc3sc4ccccc4c3c2)nn1
Temperature: 80 °C
Yield: 34.7 %

Procedure:
A mixture of 2-aminodibenzothiophene (0.90 g, 4.52 mM), 3-chloro-6-methyl-pyridazine (0.58 g, 4.52 mM), sodium t-butoxide (0.61 g, 6.33 mM), tris(dibenzylidene-acetone)dipalladium(0) (0.083 g, 0.09 mM) and S-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.113 g, 0.18 mM) in toluene (23 ml) was heated to 80° C. for 18 hours under an inert atmosphere. On cooling to room temperature the mixture was diluted with DCM, washed with aqueous potassium carbonate, dried over sodium sulphate and concentrated. Chromatography (eluent gradient of DCM to EtOAc then MeOH:EtOAc (1:9)) gave the product as an off white solid (0.456 g). NMR: 9.38 (brs, 1H), 8.81 (brs, 1H), 8.18 (m, 1H), 8.01 (m, 1H), 7.94 (d, 1H), 7.75 (dd, 1H), 7.50 (m, 1H), 7.36 (d, 1H), 7.14 (d, 1H), 2.50 (s, 3H); m/z 292.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.O[NH:16][C:17](=[NH:36])[C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[N:21][N:22]2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:16]=[C:17]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][C:28]([CH3:34])([CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:36]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CCOC(=O)C(C)(C)Cn1ncc2c(C(=N)NO)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Cn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A mixture of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (245 mg, 1.143 mmol), ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}-2,2-dimethylpropanoate (D103) (348 mg, 1.143 mmol), in DMF (5 ml) at room temperature was treated with N-ethyl-N-(1-methylethyl)-2-propanamine (0.240 ml, 1.372 mmol) followed by HATU (522 mg, 1.372 mmol). The resulting mixture was stirred at room temperature for 1 hour and at 80° C. overnight and then for a further 4 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed twice with H2O then brine, dried and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (233 mg, 39%) as a cream solid. MS (ES) C25H27ClN4O4 requires 482, found 483 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Cl:22][CH:23]([CH2:27][CH3:28])[C:24](Cl)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH:23]([Cl:22])[CH2:27][CH3:28])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: CCC(Cl)C(=O)Cl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Product: CCC(Cl)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 2, 7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl-hydrazine was reacted with α-chlorobutyryl chloride (CHE--CH2 --CHCl--COCl) to give 8-chloro-1-(α-chloropropyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:38]=[CH:37][CH:36]=[C:35]([O:34][CH3:33])[CH:40]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 73 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-methoxyphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (73%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:33]1[C:41]2[C:36](=[C:37](B3OC(C)(C)C(C)(C)O3)[C:38]([F:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1)(C(C)(C)C)(C)C>>[F:42][C:38]1[C:37]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]3[N:11]=[C:10]([CH2:12][NH:13][CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:36]2[C:41](=[CH:40][CH:39]=1)[NH:33][CH:34]=[CH:35]2
Reactant: Clc1nc(N2CCOCC2)c2nc(CNC3CCOCC3)ccc2n1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CNC3CCOCC3)ccc2n1

Procedure:
N-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)tetrahydro-2H-pyran-4-amine (0.17 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 79.1 mg of 142 following reverse phase HPLC purification. MS (Q1) 463.2 (M)+
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O)([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[BrH:26].S(=O)(=O)(O)O>O>[C:1]([C:5]([C:8]([C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Br:26])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: OCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 19.52 g of CF3(CF2)3(CH2)10CH2OH and 200 mL of 48 weight percent aqueous hydrobromic acid was slowly added 20 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 24 hr, and poured into 1 liter of water. The mixture was extracted with hexanes, and the combined organic phases were washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The solution was concentrated to an amber liquid, which was eluted through 3 inches of silica with hexanes. Concentration of the eluent yielded a light amber liquid, and bulb-to-bulb distillation gave 19.82 g of CF3(CF2)3(CH2)10CH2Br as a clear, colorless liquid, b.p. 120-170° C. at 0.06 torr (8 Pa).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:25]=[C:24]([CH2:26][C:27]([NH:29][CH:30]([C:43]([OH:45])=[O:44])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:28])[CH:23]=[CH:22][C:11]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:8].CI>CN(C)C=O>[CH2:7]([O:9][C:10]1[CH:25]=[C:24]([CH2:26][C:27]([NH:29][CH:30]([C:43]([O:45][CH3:1])=[O:44])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)=[O:28])[CH:23]=[CH:22][C:11]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:8]
Reactant: CCOc1cc(CC(=O)NC(C(=O)O)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOc1cc(CC(=O)NC(C(=O)OC)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (0.28 g, 2 mmol) is added to a solution of benzyl 2-ethoxy-4-[N-(α-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (1.06 g, 2 mmol) in anhydrous dimethyl formamide (8 ml). The mixture is stirred for 10 minutes at ambient temperature, then methyl iodide (0.125 ml, 2 mmol) is added and the resulting mixture is stirred overnight at ambient temperature. It is filtered and the filtrate is concentrated by evaporation to dryness in vacuo. The evaporation residue is partitioned between aqueous sodium bicarbonate solution (pH=9) and methylene chloride. The organic phase was poured over sodium sulphate, filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (toluene/acetone=4/1) and crystallised from ether/petroleum ether.
Reaction SMILES: BrC1C=CC=C2C=1C1(CCN(C(OC(C)(C)C)=O)CC1)CC2CC(OCC)=O.[Br:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:57]=1[C:37]1([CH2:42][CH2:41][N:40]([C:43](=[O:56])/[CH:44]=[CH:45]/[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:55])([F:54])[F:53])[CH2:39][CH2:38]1)[CH2:36][CH:35]2[CH2:58][C:59]([OH:61])=[O:60].[C:62]([OH:68])([C:64]([F:67])([F:66])[F:65])=[O:63]>C(Cl)Cl>[Br:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:57]=1[C:37]1([CH2:38][CH2:39][N:40]([C:43](=[O:56])/[CH:44]=[CH:45]/[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:53])([F:55])[F:54])[CH2:41][CH2:42]1)[CH2:36][CH:35]2[CH2:58][C:59]([OH:61])=[O:60].[F:65][C:64]([F:67])([F:66])[C:62]([O-:68])=[O:63]
Reactant: O=C(O)C(F)(F)F
Agent: CCOC(=O)CC1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2c(Br)cccc21
Agent: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2c(Br)cccc21
Solvent: ClCCl
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate isomer 1 (200 mg, 0.44 mmol) in anhydrous CH2Cl2 (2 mL) was added 20% TFA in CH2Cl2 (10 mL) at 0° C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated to give ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate isomer 1 as its trifluoroacetate salt (156 mg, 100%), which was used to the next step without purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][S:22]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)(=[O:24])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([O:35][P:36]([CH2:41]OS(C(F)(F)F)(=O)=O)([O:38][CH2:39][CH3:40])=[O:37])[CH3:34].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH:19]=[CH:18][C:17]([N:21]([CH2:41][P:36](=[O:37])([O:38][CH2:39][CH3:40])[O:35][CH2:33][CH3:34])[S:22]([C:25]1[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=1)(=[O:24])=[O:23])=[CH:16]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)c1cccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc12
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(CN(c1ccc2c(C(=O)NCc3ccccc3)cccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 200 mg 6-(3,5-dichloro-phenylsulphonylamino)-naphthalene-1-carboxylic acid-benzylamide, 180 mg diethylphosphonomethyltriflate (prepared analogously to Tetrahedron Letters 1986, 27, 1477) and 100 mg potassium carbonate in 4 ml N,N-dimethylformamide is stirred for three hours at ambient temperature. Then it is combined with ethyl acetate, washed with water and saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (40:60 to 0:100) as eluant.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][CH2:8][NH2:9].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][C:26](Cl)=[O:27])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][CH2:8][NH:9][C:26](=[O:27])[CH2:25][C:19]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1ccc(OCCN)cc1OC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)NCCOc2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.4 %

Procedure:
To a cold (0° C.) solution of 2-(3,4-dimethoxy-phenoxy)-ethylamine (2.3 g, 11.8 mmol) in anhydrous THF (21 ml), were added TEA (1.4 ml, 19.2 mmol) and portionwise 3,4-dimethoxyphenylacetylchloride (2.49 g, 11.6 mmol). The resulting mixture was stirred at RT for 20 h under nitrogen. The mixture was combined with H2O and extracted three times with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude solid. Recrystallisation from diethylether gave the title product (3.59 g, 80%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C.C1COCC1>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:25][CH2:26][N:21]([C:16]4[N:15]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:22][CH2:23]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ccc2nc(CN3CCN(c4ncccn4)CC3)cn2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 41.6 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.335 g), 1-(pyrimidin-2-yl)piperazine dihydrochloride (Aldrich; 0.395 g), triethylamine (Aldrich; 0.522 g), THF (5 mL), and dichloromethane (5 mL) is heated at 80° C. for 45 min and then at 60° C. for 5 h, at which time DMF (1 mL) is added. After stirring for a total of 10.5 h, the mixture is allowed to cool and stir at room temperature for an additional 12 h. The solvents are then removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel using methanol/dichloromethane (4/96) and the appropriate fractions are combined and concentrated to give 0.228 g of the title compound. Crystallization from methanol-dichloromethane-hexane gives 0.315 g of the title compound in two crops; mp 114-115° C.; MS m/z 328, 330; IR (mineral oil) 1481, 1357, 1584, 1439, 1253, 1548 cm-1. 1H NMR (CDCl3) δ2.64, 3.76, 3.87, 6.48, 7.12, 7.52, 7.54, 8.14, 8.30.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.C([C:15]1[C:16]([C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])CCCC>ClC1C(Cl)=C(Cl)C=CC=1.O>[CH2:22]([C:15]1[C:16]2[C:24](=[O:31])[C:25]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:18](=[O:19])[C:17]=2[CH:21]=[CH:22][CH:23]=1)[CH2:23][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCc1cccc(C(=O)O)c1C(=O)c1ccccc1
Agent: Clc1cccc(Cl)c1Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: CCCCCc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
The strength of the oleum employed was 8.8%, and the concentration of amylbenzoylbenzoic acid in trichlorobenzene solution was 20%. To 447 grams of the oleum mixture there was added 406 grams of 20 % solution of amylbenzoylbenzoic acid in trichlorobenzene. The addition was made gradually over a 10 minute period while holding the temperature in the reaction mass below 20° C. The temperature was raised to 90° C and held at that level for 4 hours. Then, the reaction mixture was drowned in 2000 ml of cold water. The temperature was next adjusted to just below 70° C and the organic layer was separated by decantation. It was washed twice with 800 ml portions of water, then with 800 ml of water containing 5 grams of 30% sodium hydroxide and finally with another 800 ml of water. The washed trichlorobenzene-amylanthraquinone solution weighed 345 g. Vacuum distillation at 3 mm absolute pressure indicated 18.5% organic solids that were analyzed by vapor phase chromatography and found to be 94.2% amylanthraquinone. The yield of 100% of amylanthraquinone was 92.8% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:22][C@@H:23]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[OH:37][C:34]1[CH:33]=[CH:32][C:31]([C@H:23]([NH:22][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[CH:36][CH:35]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)c1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N[C@H](C(=O)OC(C)(C)C)c3ccc(O)cc3)cc2)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 4-(2-(4-methoxyphenyl)acetamido)benzoic acid INT-12 (500 mg, 1.75 mmol) and (S)-tert-butyl 2-amino-2-(4-hydroxyphenyl)acetate (391 mg, 1.75 mmol) in DMF (10 mL) was added TEA (611 μL, 4.38 mmol) and HATU (700 mg, 1.84 mmol). After stirring for 2 h the reaction was diluted with EA (10 mL) and washed with brine (2×100 mL). The crude material was purified by chromatography (EA/hexanes) to give 860 mg (100%) of (S)-tert-butyl 2-(4-hydroxyphenyl)-2-(4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-13. LCMS-ESI (m/z) calculated for C28H30N2O6: 490. Found 489, [M−H]−, tR=2.14 min (Method 4).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][CH2:7][C:8]1[C:9]([NH2:15])=[N:10][CH:11]=[C:12]([Br:14])[CH:13]=1)C.[H-].[Na+]>CS(C)=O.O>[Br:14][C:12]1[CH:11]=[N:10][C:9]2[NH:15][C:4](=[O:3])[CH2:5][NH:6][CH2:7][C:8]=2[CH:13]=1
Reactant: CCOC(=O)CNCc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CNCc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 27 h
Yield: 72.5 %

Procedure:
A solution of [(2-amino-5-bromo-pyridin-3-ylmethyl)amino]acetic acid ethyl ester (1.79 g, 6.21 mmol) in DMSO (70 mL) was treated with NaH (60% dispersion in mineral oil, 0.25 g, 6.2 mmol). After stirring at room temperature for 27 h, the mixture was diluted with H2O (300 mL), and extracted then with EtOAc (4×150 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to give the title compound (1.09 g, 72%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=2.1 Hz, 1H), 8.17 (s, 1H), 7.54 (d, J=1.9 Hz, 1H), 4.03 (s, 2H), 3.93 (s, 2H), 1.85 (br s, 1H); MS (ESI) m/e 242 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:26][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])[C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[NH:26][C:12]4[N:13]=[CH:14][N:15]=[C:16]([NH:17][C@@H:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH3:19])[C:11]=4[CH:10]=3)=[CH:5][CH:4]=2)[CH2:30][CH2:29]1
Reactant: CN1CCNCC1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CCl)cc3)cc12)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN4CCN(C)CC4)cc3)cc12)c1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 10.8 g (30 mmol) [6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine in 450 ml DMF is treated with 6.8 ml (63 mmol) N-methylpiperazine and 20.7 g (150 mmol) anhydrous potassium carbonate and the mixture heated to 65° C. for 1 hour. The reaction mixture is cooled and the inorganic salts removed by filtration (Hyflo Super Cel®; Fluka, Buchs, Switzerland). The DMF is evaporated under reduced pressure and the residue purified through flash chromatography using first dichloromethane/ethanol 9:1 and then dichloromethane/ethanol 9:1 plus 1% conc. ammonia. Crystallization of the pure fractions from THF (20 ml) and hexanes (80 ml) gives the title compound; m.p. 248-250° C.; MS-ES+: (M+H)+=427.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[OH:9])([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 27.7 %

Procedure:
3-cyanophenol (2.38 g, 20 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.88 g, 22 mmol). The addition of sulfuric acid (20 mL/3 M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(910 mg, 28%). 1H NMR (CD3COCD3): δ 8.30 (d,1H), 7.67 (s,1H), 7.49 (d, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2C2C=NN(C)C=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.N[CH2:36][C@@H:37]1[C@H:42](C)[CH2:41][CH2:40][CH2:39][N:38]1C(C1C=C(C)C=CC=1C1C=CC=C(C)N=1)=O>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:39]2[CH:40]=[CH:41][CH:42]=[C:37]([CH3:36])[N:38]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][N:26]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Reactant: Cc1ccc(-c2cccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2cccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(6-methylpyridin-2-yl)phenyl)methanone. ESI-MS (m/z): 483 [M+1]+.