Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][CH:15]=1.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C>C1COCC1>[F:13][C:14]1[N:19]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][C:15]=1[B:26]([OH:31])[OH:27]
Reactant: Fc1cccc(-c2cccnc2)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OB(O)c1ccc(-c2cccnc2)nc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of diisopropylamine (0.531 ml, 3.79 mmol) (Aldrich) in THF (4 mL) was treated with 1.6 M n-butyllithium in hexanes (2.368 ml, 3.79 mmol) (Aldrich) at −40° C. and the pale yellow solution was stirred for 1 h and then cooled to −78° C. A solution of 6-fluoro-2,3′-bipyridine (550 mg, 3.16 mmol) in THF (5 mL) was added by cannula slowly over 2 min. The resulting bright orange solution was stirred at −78° C. for 1.5 h and then a solution of triisopropyl borate (1.089 ml, 4.74 mmol) (Aldrich) in THF (4 mL) was added slowly. The resulting mixture was stirred at −78° C. for 30 min and then the cooling bath was removed. After the reaction mixture had warmed up to room temperature, the yellow heterogeneous mixture was quenched with 1 N NaOH(aq) (10 mL) and stirred for 30 min. The separated aqueous layer was removed and carefully acidified with 5 N HCl until acidic (pH 5about6) and the resulting cloudy mixture was extracted with EtOAc (20 mL). Most of the product remained in the aqueous phase so the water was removed on the freeze-dryer overnight resulting in a white fluffy product contaminated with salt. m/z (ESI, +ve ion) 219.1 (M+H)+. 1H NMR (400 MHz, MeOH) δ 9.22 (1H, s); 8.62 (1H, d, J=4.5 Hz); 8.51 (1H, d, J=8.0 Hz); 8.12 (1H, t, J=7.9 Hz); 7.89 (1H, dd, J=7.3, 2.8 Hz); 7.59 (1H, dd, J=8.0, 4.9 Hz).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:37][C:38](=[O:40])[CH3:39])[CH2:7][NH:8][C:9](=[O:36])[C:10]1[C:15]([I:16])=[C:14]([N:17]=[C:18]=[O:19])[C:13]([I:20])=[C:12]([C:21](=[O:34])[NH:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:11]=1[I:35])(=[O:3])[CH3:2].[OH:41][CH2:42][C:43]([CH2:47][OH:48])([CH2:45][OH:46])[CH3:44]>ClCCl>[C:31]([O:30][CH:24]([CH2:23][NH:22][C:21](=[O:34])[C:12]1[C:11]([I:35])=[C:10]([C:9](=[O:36])[NH:8][CH2:7][CH:6]([O:37][C:38](=[O:40])[CH3:39])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:15]([I:16])=[C:14]([NH:17][C:18]([O:41][CH2:42][C:43]([CH2:47][O:48][C:18](=[O:19])[NH:17][C:14]2[C:13]([I:20])=[C:12]([C:21](=[O:34])[NH:22][CH2:23][CH:24]([O:30][C:31](=[O:33])[CH3:32])[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:11]([I:35])=[C:10]([C:9](=[O:36])[NH:8][CH2:7][CH:6]([O:37][C:38](=[O:40])[CH3:39])[CH2:5][O:4][C:1](=[O:3])[CH3:2])[C:15]=2[I:16])([CH3:44])[CH2:45][OH:46])=[O:19])[C:13]=1[I:20])[CH2:25][O:26][C:27](=[O:29])[CH3:28])(=[O:33])[CH3:32]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N=C=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: CC(CO)(CO)CO
Solvent: ClCCl
Product: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)OCC(C)(CO)COC(=O)Nc2c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reaction time: 18 h

Procedure:
To a solution of acetic acid 1-acetoxymethyl-2-[3-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-5-isocyanato-benzoylamino]-ethyl ester in dichloromethane was added 1,1,1-tris(hydroxymethyl)ethane (0.3 equivalent). The reaction mixture was stirred for 18 hours and then purified by column chromatography to give acetic acid 2-acetoxy-3-[3-{2-[3,5-bis-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-phenylcarbamoyloxymethyl]-3-hydroxy-2-methyl-propoxycarbonylamino}-5-(2,3-diacetoxy-propylcarbamoyl)-2,4,6-triiodo-benzoylamino]propyl ester. This was dissolved in methanol and treated with aquesous ammonia. The material was purified by preparatie HPLC to give 1,3-bis-[N,N′-Bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-5-carbamido-isophthalamide]-2-methyl-2-hydroxymethylpropane as a white powder after freeze drying.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([NH:26]CC5C=CC=CC=5)[NH:23][N:22]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1>[Pd].CO>[CH3:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([NH2:26])[NH:23][N:22]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: CC1CCN(C(=O)N2CCOc3ccc(-c4cc(NCc5ccccc5)[nH]n4)cc3C2)CC1
Agent: [Pd]
Solvent: CO
Product: CC1CCN(C(=O)N2CCOc3ccc(-c4cc(N)[nH]n4)cc3C2)CC1
Reaction time: 18 h
Yield: 54.4 %

Procedure:
A mixture of 3-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-N-(phenylmethyl)-1H-pyrazol-5-amine (example 6) (39 mg, 0.088 mmol), 10% palladium on charcoal (37 mg) and methanol (15 mL) was hydrogenated in a Parr apparatus at 45 psi for 18 hours. The suspension was filtered, concentrated and the residue purified by preparative reverse phase HPLC to give 3-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1H-pyrazol-5-amine (17 mg, 55% yield). 1H NMR (400 MHz, methanol-d4): 7.50 (br, 1H), 7.46 (dd, 1H), 6.98 (d, 1H), 5.86 (s, 1H), 4.44 (s, 2H), 4.18 (m, 2H), 3.68 to 3.60 (m, 4H), 2.80 (t, 2H), 1.67 to 1.51 (m, 3H), 1.23 to 1.15 (m, 2H), 0.97 (d, 2H); MS (EI) for C19H25N5O2: 356 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1[C:38]([F:41])([F:40])[F:39]>CN(C=O)C.CCOC(C)=O>[F:39][C:38]([F:40])([F:41])[C:29]1[CH:30]=[C:31]([C:34]([F:37])([F:35])[F:36])[CH:32]=[CH:33][C:28]=1[CH2:27][O:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C(F)(F)F)cc3C(F)(F)F)cc21
Temperature: 70 °C

Procedure:
To a mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.130 g, 0.5 mmol) and K2CO3 (0.069 g, 0.500 mmol) in DMF (1 mL) was added 1-(bromomethyl)-2,4-bis(trifluoromethyl)benzene (0.154 g, 0.500 mmol). The mixture was heated at 70° C. overnight, taken up in EtOAc, washed with water (thrice) and brine. The organics were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound an orange solid (0.195 g). LCMS m/z 486.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16]C(=O)OCC2C=CC=CC=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.C(O)C>[Pd].C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[NH2:16]
Reactant: COc1cc(NC(=O)OCc2ccccc2)ccc1C1CCN(C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(N)ccc1C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
To a mixture of benzyl [3-methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (Preparation Example 464) (1.26 g), ethanol (20 mL) and THF (10 mL), 5% palladium on carbon (0.38 g) was added and stirred overnight at room temperature under a hydrogen atmosphere at normal pressure. After filtration through celite, the filtrate was distilled off under reduced pressure to give 3-methoxy-4-(1-methylpiperidin-4-yl)aniline (0.80 g) as a light pink solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 102.9 %

Procedure:
To a mixed solution of a commercially available product of 4-bromo-3-fluorophenol (15.0 g, 78.5 mmol) and DMF (30 mL) were added potassium carbonate (21.7 g, 157 mmol) and benzyl bromide (10.2 mL, 86.4 mmol) at room temperature, and the resultant mixture was stirred at room temperature for 20 minutes and then at 70° C. for 40 minutes. The reaction mixture was cooled to room temperature, then water was added to the reaction mixture, and the resultant solution was extracted with ethyl acetate. An organic layer was washed with water and then with saturated brine. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to give the title compound (22.7 g, yield: quantitative).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15](=O)[CH:16]([NH:24][C:25](=O)[CH2:26][CH2:27][O:28][CH3:29])[C:17]4[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=4)=[CH:14][C:9]=3[N:8]([CH3:32])[C:7]2=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C([O-])=O.[NH4+:41].CO>C(OCC)(=O)C>[CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]4[NH:41][C:25]([CH2:26][CH2:27][O:28][CH3:29])=[N:24][C:16]=4[C:17]4[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=4)=[CH:14][C:9]=3[N:8]([CH3:32])[C:7]2=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COCCC(=O)NC(C(=O)c1ccc2c(c1)n(C)c(=O)n2C1CCCC1)c1cccc(C)c1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCc1nc(-c2cccc(C)c2)c(-c2ccc3c(c2)n(C)c(=O)n3C2CCCC2)[nH]1
Yield: 85.8 %

Procedure:
N-[2-(1-Cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-2-oxo-1-m-toly-ethyl]-3-methoxy-propionamide (294 mg, 0.65 mmol) was stirred with ammonium trifluoroacetate (857 mg, 6.5 mmol) and the mixture was heated to 150 deg C. in an oil bath. Occasionally, the sides of the flask were rinced down with methanol to insure all reactants were heated uniformly. A TLC (ethyl acetate) of the reaction mixture after 1 hour of heating showed complete reaction. The oil bath was removed, and hot water was added to the reaction mixture as it cooled. When the mixture reached room temperature, no precipitate formed, so the aqueous mixture was extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with water and dried over anhydrous sodium sulfate to afford 240 mg of a tan solid. MS (M+1)=431.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=CCCCCCC
Product: CCCCCCC=Cc1ccc([N+](=O)[O-])cc1
Yield: 66.8 %

Procedure:
The procedure described in Example 26 is repeated, but using 5.05 g (25 mmols) of 4-bromonitrobenzene and 4.33 ml (27.5 mmols) of 1-octene. After a reaction time of 10 hours at 130° C. and working up as described in Example 1, distillation of the crude product gives 3.90 g (16.7 mmols) of 4-nitrophenyloctene of boiling point 140°-150° C./27 Pa in the form of a yellow liquid; yield 67% of theory (conversion figure 6700; Pd content 0.01 mol %). The product is a mixture of isomers. Analysis for C14H19NO2 (molecular weight 233.21): calculated C 70.08; H 8.21; N 6.01, found C 71.75; H 8.10; N 6.16.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([NH2:12])[NH:9][N:8]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=O)[CH2:24][C:25](OCC)=[O:26])=[CH:22][C:17]=2[N:16]=[N:15]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[NH:16]1[C:17]2[CH:22]=[C:21]([C:23]3[NH:12][C:10]4[N:9]([N:8]=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=5[CH3:13])[N:11]=4)[C:25](=[O:26])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[N:14]=[N:15]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Reactant: Cc1ccccc1-c1n[nH]c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: Cc1ccccc1-c1nc2[nH]c(-c3ccc4nn[nH]c4c3)cc(=O)n2n1
Temperature: 120 °C
Reaction time: 5 h
Yield: 39.8 %

Procedure:
To a solution of 3-o-tolyl-1H-1,2,4-triazol-5-amine (150 mg, 1.0 eq) in n-BuOH (2 ml) was added ethyl 3-(1H-benzo[d][1,2,3]triazol-5-yl)-3-oxopropanoate (240 mg, 1.2 eq) and TsOH (20 mg) and the reaction was stirred for 5 h at 120° C. in an oil bath. The product was collected by filtration and washed with MeOH (3×1 ml) to afford 5-(1H-benzo[d][1,2,3]triazol-6-yl)-2-o-tolyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one (117.6 mg, 40% yield) as a yellow solid.
Reaction SMILES: Br[C:2]1[N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([Br:7])=[CH:5][CH:6]=1.C([Li])CCC.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[Cl-].[NH4+]>C(OCC)C>[Br:7][C:4]1[N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:6][CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(Br)ccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)n1c(Br)ccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
t-Butyl 2,5-dibromo-1H-pyrrole-1-carboxylate (10.98 g, 33.8 mmol) synthesized in Example (66a) was dissolved in diethyl ether (135 mL), and cooled to −78° C. n-Butyl lithium (2.77M hexane solution, 12.8 mL, 35.5 mmol) was added dropwise slowly, and stirring was carried out for 1 hour. To the reaction solution, benzyl chloroformate (6.25 mL, 44.0 mmol) was added dropwise slowly, and stirring was carried out for 30 minutes. With the temperature of the reaction solution being gradually raised to room temperature, stirring was carried out for 1 hour. To the reaction solution, were added a saturated aqueous ammonium chloride solution (200 mL) and diethyl ether (300 mL), and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=5%-45%) to afford the desired compound (8.80 g, yield 68%) as a reddish brown oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][CH:10]=[N:11]O)[CH:4]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.N#N.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]2[N:11]=[CH:10][N:9]=[C:5]2[CH:4]=1
Reactant: ON=CNc1cc(CCl)ccn1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: ClCc1ccn2ncnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
To a solution of N-(4-(chloromethyl)pyridin-2-yl)-N′-hydroxyformimidamide (4-2) (820 mg, 4.4 mmol) in anhydrous THF (5 mL) cooled to 0° C. was added TFAA (1.1 g, 5.28 mmol) dropwise under N2. The reaction mixture was stirred at room temperature for 3 h. Then the mixture was treated with aqueous NaHCO3 to pH 8, concentrated and purified by chromatography on silica gel to afford the title compound (400 mg). MS (m/z): 168 (M+1)+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:14]=[CH:15][C:16]([F:21])=[C:17]([CH:20]=1)[C:18]#[N:19])#[CH:12].N>>[F:21][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:12]=2)=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1ccc(F)c(C#N)c1
Agent: N
Product: N#Cc1cc(-c2cc(-c3cnccn3)no2)ccc1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and the product of Example 68A (73 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 57.57 (t, J=8.9 Hz, 1H), 7.55 (s, 1H), 8.30 (ddd, J=8.9, 5.0, 2.4 Hz, 1H), 8.40 (dd, J=5.9, 2.0 Hz, 1H), 8.71 (d, J=2.8 Hz, 1H), 8.74-8.80 (m, 1H), 9.30 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:15])[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:16](O)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[OH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([NH:1][CH2:2][CH2:3][N:4]([CH3:15])[CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:24]
Reactant: CN(CCN)CCNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)OC(C)(C)C)CCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
tert-Butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate (500 mg, 2.3 mmol) was taken up in 10 mL of CH3CN along with salicylic acid (310 mg, 2.3 mmol) and EDCI (485 mg, 2.53 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (95% CH2Cl2, 5% MeOH) to afford 380 mg of tert-butyl 2-((2-(2-hydroxybenzamido)ethyl)(methyl)amino)ethylcarbamate (49% yield). MS (EI) calcd for C17H27N3O4: 337.2. found: 338 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccccc1
Product: N#Cc1cc(-c2ccccc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (58 mg, 81%), MS (ISP) m/z=288.5 [(M+H)+], mp 265.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[NH2:14][C:15]1[S:16][C:17]([C:27]([NH2:29])=[O:28])=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O.CN(C)C=O>[C:27]([C:17]1[S:16][C:15]([NH:14][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6])=[N:19][C:18]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)(=[O:28])[NH2:29]
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1sc(Nc2cc(C(=O)O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reaction time: 16 h
Yield: 55.9 %

Procedure:
A mixture of 0.222 g (1.2 mmole) of 3-fluoro-4-nitrobenzoic acid, 0.30 g (1.2 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 1.5 g (4.6 mmole) of cesium carbonate and 40 mL of dimethylformamide was stirred at 60 degrees for 16 hours. The mixture was cooled and poured into water. The dark mixture was made acidic by addition of hydrochloric acid, and the resulting orange precipitate was collected by filtration, washing, water to give 0.281 g of 3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazol-2-ylamino]-4-nitro-benzoic acid (VI.10).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][C:7]=1[O:12][CH2:13][CH3:14]
Reactant: CCOC(=O)c1ccc(Cl)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1cc(CO)ccc1Cl
Temperature: -78 °C
Yield: 100 %

Procedure:
The title compound was prepared from commercially available 4-chloro-3-hydroxy-benzoic acid as follows: 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17 mmol) was dissolved in DMF (15 ml) and K2CO3 (4.7 g, 34.0 mmol) and EtI (6.0 g, 38 mmol) were added and the reaction stirred for 6 h. The reaction was then diluted with water and extracted with EtOAc. The organic extracts were dried (Na2SO4) and concentrated to afford 3.6 g (91% yield) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to −78° C. under Ar. Di-isobutylaluminium hydride (95 mL, 1M in THF, 95 mmol) was then slowly added (15 min), the cooling bath removed on completion of addition and the reaction allowed to reach 0° C. (1 h). The reaction was then cooled to −78° C., the excess hydride was quenched by cautious addition of 1N HCl. The mixture was brought to room temperature, the organic separated and the aqueous extracted with EtOAc. The combined organic were dried (Na2SO4) and concentrated to afford 2.9 g (100% yield) of 4-chloro-3-ethoxy-benzyl alcohol. 2.94 g (16 mmol) of the crude alcohol was dissolved in DCM (15 mL) and MnO2 (5.5 g, 63 mmol) was added. The reaction was stirred for 16 h, after which time the reaction was filtered through Hyflo and concentrated. The residue was purified by flash column chromatography (EtOAc:Heptane 1:4) to yield 1.5 g (52% yield) of the title aldehyde.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C-:21]#[N:22].[Na+].O>CN(C=O)C>[C:9]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:3]=2[CH2:2][C:21]#[N:22])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: BrCc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of 2′-bromomethyl-[1,1′:3′,1″]terphenyl (Tetrahedron Lett. 42; 5467-5472 (2001)) (1.65 g, 5.1 mmol) and sodium cyanide (0.27 g, 5.6 mmol) in 10 mL of DMF was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with diethyl ether and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel chromatography (eluting with 0-4% ethyl acetate in hexane) to give [1,1′;3′,1″]terphenyl-2′-yl-acetonitrile as a white solid (0.78 g, 57%): MS (ESI) m/z 270.1 (M+H); HRMS calcd for C20H15N, 270.1277. Found (ESI+): 270.1274; 1H NMR (DMSO-d6): δ 3.57 (s, 2H), 7.20-7.50 (m, 13H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:37])[CH2:9]1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:38][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:37][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC[C@@H](N(C)C)C1
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A solution of acryloyl chloride (64 μL, 0.79 mmol) in CH2Cl2 (4 mL) was added dropwise over 10 minutes to 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 153, 336 mg, 0.76 mmol) in CH2Cl2 (11 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h, and was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat.NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (296 mg, 79%) as an orange solid after trituration with diethyl ether; 1H NMR: 1.70-1.81 (1H, m), 2.05-2.13 (1H, m), 2.18 (6H, s), 2.68-2.76 (1H, m), 3.17-3.27 (3H, m), 3.35-3.42 (1H, m), 3.84 (3H, s), 5.67 (1H, dd), 6.17 (1H, dd), 6.51 (1H, dd), 6.56 (1H, s), 7.05 (1H, dd), 7.21 (1H, d), 7.40-7.45 (1H, m), 7.84 (1H, s), 8.02 (1H, s), 8.30 (1H, d), 8.46 (1H, d), 8.76 (1H, s), 8.78 (1H, d), 9.35 (1H, s); m/z: ES+ MH+ 499.69.