Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>N1C=CC=CC=1>[CH2:24]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([F:30])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([C:3]4[S:4][CH:5]=[CH:6][C:2]=4[CH3:1])[CH2:12]3)[CH:23]=2)[C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20]1)[CH3:25]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Cc1ccsc1C1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4sccc4C)C3)cc21
Reaction time: 18 h

Procedure:
A 3.64 g portion of 2-(3-methyl-2-thienyl)piperazine was added to 10 ml of pyridine followed by 1.35 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. The mixture was placed in a pressure bottle, under argon, sealed and heated at 120°-130° C., with stirring for 18 hours. The solvent was removed and the residue purified by chromatography, eluting with chloroform:methanol (9:1), giving 135 mg of the desired product, mp 252°-255° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:24][C:23]=2[CH:36]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][N:30]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=3)=[O:9])=[N:24][C:23]=2[CH:36]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-c2ccnc(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccnc(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(2-methylpyridin-4-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 489 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH3:13][N:14]([CH3:16])[NH2:15]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][N:14]([CH3:16])[CH3:13])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CN(C)N
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: Cc1csc2c(NN(C)C)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
In DMF was dissolved 700 mg (3.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then a solution of 450 mg (7.5 mmol) of 1,1-dimethylhydrazine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction solution was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for further one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 173 mg (yield: 20.9%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][OH:23].C(=O)(O)[O-].[Na+]>O.CC(C)=O>[C:2]1([CH2:1][O:8][C:9]([NH:19][C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][OH:23])=[O:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](CCO)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (23.57 g., 94.58 mmol.) was added to a solution of L-homoserine (10.24 g., 85.98 mmol.) and sodium bicarbonate (7.95 g., 94.58 mmol., 1.1 eq.) in a mixture of water (100 ml.) and acetone (100 ml.). The mixture was stirred at room temperature overnight. The acetone was removed under reduced pressure (rotovap) and the aqueous solution was washed with methylene chloride (2×75 ml.). The aqueous layer was then acidified to pH 2 by addition of 6N hydrochloric acid and extracted with ethyl acetate (2×250 ml.). The combined ethyl acetate layers were washed with water (2×100 ml.) and brine, dried over sodium sulfate, filtered, concentrated and dried in vacuo to afford 19.54 g. of title product as a white solid. TLC (ethyl acetate:n-butanol:acetic acid:water; 2:1:1:1) Rf =0.74
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[CH:8]([CH3:10])[CH3:9].[I:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1.Cl>CN(C=O)C>[I:11][C:12]1[CH:13]=[C:14]([CH3:20])[C:15]([O:19][CH:8]([CH3:10])[CH3:9])=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1cc(I)c(C)cc1O
Reactant: CC(C)I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OC(C)C)c(C)cc1I
Temperature: 50 °C
Yield: 42 %

Procedure:
K2CO3 (1.23 g, 8.87 mmol) followed by 2-iodopropane (806 μL, 8.06 mmol) were added to a solution of 4-iodo-2,5-dimethyl-phenol (1.00 g, 4.03 mmol) in DMF (40 mL) and the solution was heated at 50° C. for 24 h. The mixture was then acidified with 1% aq HCl before it was extracted with EtOAc (3×100 mL). The combined organics were washed with 1 N NaOH (3×200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-10% ethyl acetate/hexanes) to provide 1-iodo-4-isopropoxy-2,5-dimethylbenzene (42%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)C1C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]([N:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
43 mL benzyloxycarbonyl chloride in 135 mL dichlormethane was added to 17.6 g 1-benzyl-2,5-dihydro-1H-pyrrole in 135 mL dichlormethane at 0° C. in 60 min. The mixture was stirred 3 h at RT and washed with saturated sodium hydrogencarbonate solution. The organic layer was dried and evaporated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate: 5/1) to give 19.7 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1.C(O)C.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:28][CH:29]=2)[N:14]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
tert-Butyl 4-(4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I5) (0.250 g, 0.420 mmol) was dissolved in EtOAc (8 mL) and absolute ethanol (10 mL) under an atmosphere of nitrogen. 10% Pd/C (0.200 g) in EtOAc (4 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon). The reaction was sealed with a balloon and stirred at room temperature for 18 hours. The catalyst was removed by filtration through Celite, which was washed with EtOAc (7×10 mL). The solvent was removed in vacuo to give the title compound (I6) (0.211 g, 84% yield) as a yellow solid. LCMS Method C: rt 6.78 min; m/z 600.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([O:27][S:29]([CH3:28])(=[O:31])=[O:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a stirred solution of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (1.0 g) in pyridine (10 ml) is added dropwise methanesulfonyl chloride (0.92 g) at ice-bath temperature. After stirring for 1 hour at ice-bath temperature, the mixture is stirred for 30 minutes at room temperature, and then cooled. After addition of water (1 ml), the mixture is stirred for 30 minutes at ice-bath temperature, and ice bath is removed. The mixture is stirred for 30 minutes at room temperature, diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract is washed successively with 10% hydrochloric acid, water, 0.1N sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and evaporated in vacuo to yield ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (1.1 g) as a colorless oil.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:9]([C:13]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:17]=[C:16]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=1[NH2:15])([CH3:12])([CH3:11])[CH3:10]>C(N(CC)CC)C.ClCCl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([NH:15][C:14]1[C:16]([C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:17][C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:19][C:13]=1[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH3:7]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(N)c(C(C)(C)C)c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1c(C(C)(C)C)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a 500 mL round bottom flask, 2,4,6-tri-tert-butylaniline (2.0 g) and 2.6 mL triethylamine were dissolved in dichloromethane (50 mL) and cooled to 0° C. A mixture of ethyl chloroglyoxylate (0.85 mL) and dichloromethane (33 mL) was slowly added via dropping funnel, after which the mixture was stirred at 0° C. for 1 h, and then at 25° C. for 3 h. The resultant mixture was quenched with 100 mL of water. The aqueous layer was extracted with 100 mL of dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure (20 mm Hg). The residue was purified by flash chromatography (silica; hexane/EtOAc; linear gradient). The N-(2,4,6-tri-tert-butylphenyl)oxalamic acid ethyl ester so obtained (201.5 mg) was reacted with excess hydrazine hydrate (81 μL) in 5 mL of EtOH at 50° C. for 14 h. The resultant solid was isolated by filtration and washed with EtOH to obtain compound a38.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH3:25])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:26])[CH:3]=1.[CH3:27][C@@H:28]1[CH2:32][O:31][C:30](=[O:33])[NH:29]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[C@H:28]([CH3:27])[CH2:32][O:31][C:30]5=[O:33])=[CH:3][C:4]=4[F:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH3:25])[CH:20]=2)[CH2:24][CH2:23]1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C2CC2)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)c(C2CC2)c1
Yield: 98.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazin-1-yl]methanone (962 mg) described in Preparation Example 109 and (R)-4-methyloxazolidin-2-one (354 mg) described in Preparation Example 25, the title compound (990 mg) was obtained.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 50 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide to yield 2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (51.78 mg, 50% yield) as a white powder. 1H-NMR (CDCl3) δ 11.05 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.47 (m, 2H), 7.34 (s, 1H), 7.25 (s, 1H), 7.04 (m, 2H), 6.89 (s, 1H), 6.15 (br s, 1H), 5.84 (s, 1H), 3.03 (m, 6H), 2.80 (m, 3H), 2.67 (m, 3H), 2.04 (m, 2H), 1.31 (m, 2H). LC/MS (ESI+)=501 (M+H). MP=182-183° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=1[OH:29])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N:31]1[C:40]2[C:35](=[C:36]([CH2:41][CH2:42]O)[CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:30])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][C:20]=1[O:29][CH2:42][CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:35]=1[CH:34]=[CH:33][CH:32]=[N:31]2)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1O
Reactant: OCCc1cccc2ncccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1cccc2ncccc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
3-(4-Acetylamino-2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (0.40 g, 0.9 mmol) was combined with 2-Quinolin-5-yl-ethanol (0.155 g, 0.9 mmol) and triphenyl phosphine (355 mg, 1.3 mmol) in 15 mL THF. The solution was cooled to 0° C. DEAD (0.21 mL, 1.3 mmol) was added. The reaction was slowly warmed to room temperature, and stirred overnight. The reaction mixture was concentrated in vacuo. The crude product was chromatorgraphed using 1:1 ethyl acetate/hexanes followed by ethyl acetate, and then 10% methanol in ethyl acetate to yield 3-[4-acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-N-methoxy-N-methyl-succinamic acid tert-butyl ester 450 mg (83%) of an off-white solid. MS (APCI) m/z 601.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:23]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[C:14]=2[CH3:23])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccc(F)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1ccc(F)cc1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
This compound was prepared according to the general procedure 3 described hereinabove. 2-chloro-4-[1-(4-fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-pyridine (200 mg, 0.607 mmol) was dissolved in 10 mL THF and cooled to −75° C. Lithiumdiisopropylamide (0.45 ml, 0.91 mmol) was added, and the mixture stirred for 15 min at −75° C. Iodomethane (0.05 ml, 0.85 mmol) was added and stirring was continued at −75° C. for 2 hrs. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 90:10→20:80 gradient) and by recrystallization from ethyl acetate. The desired compound was obtained as a white solid (40 mg, 19%), MS: m/e=326.5 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[N:15]([O-])=[O:16].[Na+].S(=O)(=O)(O)O>N1C=CC=CC=1>[N:15]([C:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[OH:1])=[O:16]
Reactant: O=N[O-]
Reactant: Oc1ccc2oc3ccccc3c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=Nc1c(O)ccc2oc3ccccc3c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In 100 g of pyridine was dissolved 10 g of 2-hydroxydibenzofuran, and the solution was cooled to 0° C. Then, 60 g of a 20% aqueous solution of sodium nitrite was added to the above solution and 100 g of a 30% aqueous solution of sulfuric acid was added dropwise to the mixture while stirring for 10 minutes. After the dropwise addition, the mixture was stirred at 0° C. for 1 hour and then filtered. The recovered solid was washed with water and dried to obtain 11 g of a red crystal of 1-nitroso-2-hydroxydibenzofuran.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[O:18][CH2:19][C:20](O)=[O:21])=[O:14])[CH3:11]>ClCCCl>[Cl:3][C:20](=[O:21])[CH2:19][O:18][C:17]1[CH:16]=[C:15]([CH:25]=[CH:24][CH:23]=1)[C:13]([O:12][CH2:10][CH3:11])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cccc(OCC(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)c1cccc(OCC(=O)Cl)c1

Procedure:
32.5 ml (0.45 mol) of thionyl chloride and 10 μl of N,N-dimethylformamide are added to a solution of 20.0 g (89.2 mmol) of [3-(ethoxycarbonyl)phenoxy]acetic acid (A. Banerjee, M. M. Adak, S. Das, S. Banerjee, S. Sengupta, Indian Chem. Soc., 1987, 64, 1, 34-37) in 200 ml of 1,2-dichloroethane. The mixture is refluxed for 1 hour and is then concentrated to dryness and dried under vacuum at 50° C. overnight and used as it is in the subsequent stage.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[CH:27](=O)[CH3:28].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]([CH3:22])=[C:6]([N:8]([CH2:27][CH3:28])[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
To a stirred solution of tert-butyl 4-((5-bromo-3-(methoxycarbonyl)-2-methylphenyl)amino)piperidine-1-carboxylate (5 g, 11.70 mmol) and acetaldehyde (1.58 g, 35.12 mmol) in dichloroethane (60 mL), acetic acid (4.24 g, 70.66 mmol) was added and reaction stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (7.44 g, 35.09 mmol) was added at 0° C. and reaction stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, organic phase was separated and aqueous phase was extracted with dichloromethane. Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to give crude material was purified by column chromatography to afford the desired product (5 g, 93.45%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>>[CH2:18]([NH:20][C:21]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)=[O:22])[CH3:19]
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Reactant: CCN=C=O
Product: CCNC(=O)N1C2=NC(C)(C)N(C)C(=O)N2c2ccccc21
Yield: 96 %

Procedure:
The title compound was prepared by reaction of 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one (see Example 1 (B)) with ethyl isocyanate according to the general procedure of Example 10. The product, mp 127°-131° C., was obtained as a white solid in 96% yield. The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=4[F:32])(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(F)cccc4F)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,6-difluoro-benzenesulfonyl chloride. Purity (ELSD, based on MW=597.6)=80%.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[CH2:4]Br.Cl.C(=O)(O)[O-].[Na+].[I:14][C:15]1[CH:20]=[C:19](OC)[N:18]=[C:17]([NH2:23])[CH:16]=1>O.C(OCC)(=O)C>[I:14][C:15]1[CH:4]=[C:3]([O:2][CH3:1])[N:23]2[CH:20]=[CH:19][N:18]=[C:17]2[CH:16]=1
Reactant: COC(CBr)OC
Reactant: COc1cc(I)cc(N)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(I)cc2nccn12
Temperature: 80 °C

Procedure:
To a mixture of bromoacetaldehyde dimethylacetal (4.50 ml, 37.1 mmol) in water (126 ml) was added a 1M solution of hydrochloric acid (8.40 ml, 8.40 mmol). After 2.5 h the reaction mixture was heated to 80° C. resulting in a clear solution. After 40 minutes the reaction mixture was cooled to ambient temperature and sodium bicarbonate (3.83 g, 45.6 mmol) and 4-iodo-6-methoxypyridin-2-amine (5.25 g, 21.0 mmol) were added. After 16 hours the reaction mixture was diluted with ethyl acetate, washed with water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane gradient) to give 7-iodo-5-methoxyimidazo[1,2-a]pyridine. LRMS (ESI) calculated for C8H8IN2O [M+H]+, 275.0 found 274.9.