Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C)C.[CH2:5]([NH2:15])[C:6]1[CH:14]=[CH:13][C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C(N(CC)CC)C>[CH2:10]1[O:11][C:12]2[CH:13]=[CH:14][C:6]([CH2:5][NH:15][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]#[N:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)=[CH:7][C:8]=2[O:9]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: N#Cc1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N#Cc1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 89 %

Procedure:
15 ml of isopropyl alcohol, 75 mg of triethylamine and 125 mg of piperonylamine were added to 140 mg of 4-chloro-6-cyanoquinazoline. The obtained mixture was heated under reflux for 5 hours and filtered to recover a precipitate. This precipitate was introduced to a silica gel column, followed by eluting with ethyl acetate to give 200 mg of the title compound.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:60]=[CH:59][C:33]([CH2:34][C:35]3([C:47]([NH:49][CH2:50][CH:51]([OH:58])[CH2:52][C:53]([CH3:57])([CH3:56])[CH2:54][CH3:55])=[O:48])[CH2:39][CH2:38][CH2:37][N:36]3[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:32][CH:31]=2)=[N:28][CH:29]=1>ClCCl>[CH3:56][C:53]([CH3:57])([CH2:54][CH3:55])[CH2:52][C:51](=[O:58])[CH2:50][NH:49][C:47]([C:35]1([CH2:34][C:33]2[CH:59]=[CH:60][C:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][N:28]=3)=[CH:31][CH:32]=2)[CH2:39][CH2:38][CH2:37][N:36]1[C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])=[O:48]
Reactant: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CCCN1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dess-Martin periodinane (1.08 g, 2.56 mmol) was added to an ambient temperature solution of tert-butyl 2-[4-(5-fluoropyridin-2-yl)benzyl]-2-{[(2-hydroxy-4,4-dimethylhexyl)amino]carbonyl}pyrrolidine-1-carboxylate (674 mg, 1.28 mmol) in dichloromethane (13 mL). After stirring at ambient temperature for 1 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate (1:1) and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded tert-butyl 2-{[(4,4-dimethyl-2-oxohexyl)amino]carbonyl}-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate.
Reaction SMILES: [Na].CO[C:4](=[O:9])[C:5]([O:7][CH3:8])=[O:6].[CH3:10][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12]>CCCCCC>[CH3:8][O:7][C:5](=[O:6])[C:4]([CH2:10][C:11](=[O:12])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:9]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)C(C)(C)C
Agent: [Na]
Solvent: CCCCCC
Product: COC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
54 g (1 mol) of sodium are suspended in 300 g of n-hexane. 118 g (1 mol) of oxalic acid dimethyl ester, warmed to 60° C., are added dropwise at 0°-5° C. in the course of 1 hour. 100 g of pinacolin are then added rapidly at the same temperature. The mixture is stirred at room temperature for 15 minutes and 222 g of a n-hexane/methanol mixture are then distilled off, at boiling point760 : 50° C., over a 50 cm high packed column in the course of 6 hours. 234.5 g of aqueous sulphuric acid (20.9% strength by weight) are stirred into the bottom product. Separation of the phases and subsequent distillation of the organic phase give, at boiling point8 : 105° C., 159 g of pivaloylpyruvic acid methyl ester (85.0% of the theoretical yield) with a purity of 99.4% (by analysis by gas chromatography).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:10]=[C:9]([C:20]3[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1>>[N:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:10]=[C:9]([C:20]3[CH:26]=[CH:25][C:23]([NH:24][C:34]([NH:33][C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[O:35])=[CH:22][CH:21]=3)[N:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(-c2nc(OC3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: O=C=Nc1cccnc1
Product: O=C(Nc1ccc(-c2nc(OC3CCOCC3)nc(N3CCOCC3)n2)cc1)Nc1cccnc1

Procedure:
1-{4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]phenyl}-3-pyridin-3-ylurea was prepared by reacting the 4-[4-morpholin-4-yl-6-(tetrahydro-2H-pyran-4-yloxy)-1,3,5-triazin-2-yl]aniline and the corresponding 3-pyridylisocyanate. Product was purified by Gilson, HPLC. MS (ESI) m/z 477.53.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=[C:2]12.[NH2:12][C@@H:13]([CH3:30])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[C:26]([F:28])[C:23]([C:24]#[N:25])=[C:22]([Cl:29])[CH:21]=2)=[N:16]1.CN(C=O)C>O.C(OCC)(=O)C>[Cl:29][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:7]3[N:8]=[C:2]4[N:3]([CH:6]=3)[CH:4]=[CH:5][S:1]4)=[O:11])[CH3:30])[N:16]=2)[CH:27]=[C:26]([F:28])[C:23]=1[C:24]#[N:25]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2ccsc2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2ccsc2n1
Reaction time: 48 h
Yield: 41.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from imidazo[2,1-b]thiazole-6-carboxylic acid (1.041 mmol, 0.175 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.041 mmol, 0.290 g). DMF (10 ml) was used as the solvent and the reaction time was 2 days. The work up was done by diluting the reaction mixture with water and ethyl acetate and washing it with 2M Na2CO3, water and brine. The combined organics were dried, filtered and eveaporated. The crude product was purified by flash chromatography. 0.186 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.24 (d, 3H), 4.32-4.39 (m, 1H), 4.40-4.47 (m, 1H), 4.53-4.61 (m, 1H), 6.79 (d, 1H), 7.20 (d, 1H), 7.73 (d, 1H), 7.76 (d, 1H), 7.77-7.81 (m, 1H), 7.89-7.91 (m, 1H), 8.10 (s, 1H).
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22].C(#N)C.[OH-].[Na+]>O>[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][C:15](=[O:17])[C@H:10]([CH2:11][C:12](=[O:13])[OH:14])[NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
1.19 g (5.0 mmol) of N-benzoyl-L-aspartic acid and 1.79 g (10.0 mmol) of L-phenylalanine methyl ester were added to a flask which contained 50 ml of 50% acetonitrile in water containing 5 mM CaCl2. The pH of the solution was adjusted to 6.0 with 10M NaOH. The solution was admixed with 4 g of suction filtered immobilized enzyme prepared above. Thereafter, the reaction were carried out with stirring for 4 hours at 40° C. After completion of the reaction, the immobilized enzyme was separated by filtration. The pH of the filtrate was then adjusted to 3.7 by 10 molar hydrochloric acid. Resulting slurry was filtered and washed with water to give N-benzoyl-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=[S:2].[C:13]([O:17][C:18](=[O:26])[N:19]([CH3:25])[CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:17][C:18](=[O:26])[N:19]([CH3:25])[CH:20]1[CH2:24][CH2:23][N:22]([C:1](=[S:2])[NH2:3])[CH2:21]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(C(N)=S)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a stirring solution of thiocarbonyldiimidazole (1.23 g, 6.91 mmol) in THF (10 mL) under N2 was added methylpyrrolidin-3-yl-carbamic acid tert-butyl ester (1.20 g, 5.99 mmol) in THF (7 mL). The reaction mixture was stirred at room temperature of 1 h, and then at 55° C. for 2 h. The reaction was cooled to room temperature, and most (˜14 mL) of THF was removed. The reaction was transferred to a sealable reaction tube, 2N ammonia in methanol (6 mL) was added, and the reaction was stirred at room temperature overnight. Another portion of 2N ammonia in methanol (6 mL) was added, and the reaction was heated to 45° C. for 8 h. The reaction was concentrated to ˜5 mL, and diethyl ether was added to precipitate product. The product was filtered, washed with diethyl ether, and dried to obtain 0.920 g (64.9%) of pure methyl-(1-thiocarbamoyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (132) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH2:31]([CH2:33][NH2:34])[OH:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](=[O:20])[NH:34][CH2:33][CH2:31][OH:32])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:25])[O:26][CH:27]([CH3:29])[CH3:28])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCO)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 48) (116 mg, 0.283 mmol) and ethanolamine (0.034 mL, 0.565 mmol) in DMF (3 mL) were added HATU (161 mg, 0.424 mmol) and DIPEA (0.148 mL, 0.848 mmol). The resulting mixture was stirred at room temperature for 1 h, then water and EtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 1:1 MeOH/DMSO and was purified by MDAP (formate). The appropriate fractions were combined and concentrated under reduced pressure to give isopropyl ((2S,4R)-1-acetyl-6-(4-((2-hydroxyethyl)carbamoyl)phenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (102 mg, 80%) as a white solid. LCMS (Formate, 2 min), Rt=0.76 min, MH+=454.
Reaction SMILES: I[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]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4nc(C)c(C)cc4C)CC3)cc2)C1=O
Yield: 87 %

Procedure:
Using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (1.31 g) described in Preparation Example 120 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.14 g) was obtained.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([Cl:15])[CH:7]=1>OS(O)(=O)=O>[Cl:5][C:6]1[C:11]([N+:1]([O-:4])=[O:3])=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([Cl:15])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Ml. 11.3 of fuming nitric acid (0.275 mole) in 96% H2SO4 (50 ml) was dropwise added under stirring at room temperature to 48 g of 1,3-dichloro-4-nitrobenzene (0.25 mole) in 96% H2SO4 (350 ml). The mixture was stirred for two hours, then poured into crushed ice. The separated solid was washed with cold water to neutrality, dried under vacuum and crystallized from ethanol (170 ml) to give the dinitro compound (A), 45.5 g, yield 76.8%, as yellow prisms.
Reaction SMILES: Br[CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CN(C=O)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([S:3][CH2:2][O:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:5][CH:6]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Clc1ccc(SCBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(OCSc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
1-Bromomethylthio-4-chlorobenzene (20 mmol) in DMF (10 ml) was added with stirring at room temperature to a solution prepared from potassium tert-butoxide (20 mmol) and 4-chlorophenol (20 mmol) in DMF (50 ml). The resultant mixture was stirred at 80° C. for 1 h, the solvent was then distilled off, the residue triturated with water, the residual material extracted with chloroform, the dried (MgSO4) chloroform solution evaporated and the residue distilled; yield 3.65 g (64%), b.p. 135°-140° C./0.01 mmHg. 1H NMR (CDCl3): δ 5.29 (CH2), 6,6-7.4 (Ph's). MS [70 eV, m/Z (rel. int.)]; 2.84 (3,M), 159(36), 157 (100), 111 (15), 105 (13), 75 (21).
Reaction SMILES: C([O:5][C:6](=[O:43])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]=[C:30]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[O:31][C:32]=4[C:33]([F:36])([F:35])[F:34])=[O:27])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[C:37]1([C:30]2[O:31][C:32]([C:33]([F:34])([F:35])[F:36])=[C:28]([C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([CH:16]4[CH2:15][CH2:14][N:13]([C:10]5[CH:9]=[CH:8][C:7]([C:6]([OH:43])=[O:5])=[CH:12][CH:11]=5)[CH2:18][CH2:17]4)=[CH:24][CH:23]=3)=[O:27])[N:29]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N2CCC(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
The above 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-1-yl)-benzoic acid tert-butyl ester (40 mg) was dissolved in a mixture of methylene chloride (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 1 hr and solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was dried and solvents were evaporated. The residue was triturated with ethyl acetate to give a solid as 4-(4-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidin-1-yl)-benzoic acid (25 mg). LC-MS for C29H24F3N3O4 (m/e) calcd 535, obsd 536 (M+H). 1H-NMR is consistent with the desired structure.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Br:32][C:33]1[C:34]([N:57]2[CH2:62][CH2:61][CH:60]([O:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:59][CH2:58]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:56]=[CH:55][C:45]([CH2:46][NH:47]C(=O)OC(C)(C)C)=[CH:44][CH:43]=3)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:33]1[C:34]([N:57]2[CH2:62][CH2:61][CH:60]([O:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:59][CH2:58]2)=[C:35]2[N:41]=[C:40]([C:42]3[CH:43]=[CH:44][C:45]([CH2:46][NH2:47])=[CH:55][CH:56]=3)[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCC(Oc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(-c2nc3c(N4CCC(Oc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Yield: 93.7 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl 4-(6-bromo-7-(4-phenoxypiperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzylcarbamate (17 mg, 0.029 mmol), TFA (0.25 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (13 mg, 93%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.84-1.90 (m, 2H, 2× piperidine CHAHB), 2.17-2.19 (m, 2H, 2× piperidine CHAHB), 3.61 (ddd, J=12.4, 9.7, 1.8 Hz, 2× piperidine NCHAHA), 3.80 (s, 3H, OCH3), 3.86-3.91 (m, 2H, 2× piperidine NCHAHA), 4.70 (septet, J=4.0 Hz, 1H, piperidine CH), 6.94 (t, J=7.3 Hz, 1H, phenyl H-4), 7.04 (d, J=7.8 Hz, 2H, phenyl H-2 & H-6), 7.30 (dd, J=8.6, 7.4 Hz, 2H, phenyl H-3 & H-5), 7.50 (d, J=8.6 Hz, 2H, phenyl H-3′ & H-5′), 8.11 (d, J=8.4 Hz, 2H, phenyl H-2′ & H-6′), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5);
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:18]=[CH2:19])=[C:4]([NH:10][CH:11]([CH:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)#[N:21].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[C:3]([CH:18]=[CH2:19])=[C:4]([NH:10][CH:11]([CH:15]([OH:17])[CH3:16])[C:12]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:31][CH:30]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: C=Cc1c(NC(C(=O)O)C(C)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: C=Cc1c(NC(C(=O)NNC(=O)c2ccc(C#N)cc2)C(C)O)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
2-(3-Chloro-4-cyano-2-vinyl-phenylamino)-3-hydroxy-butyric acid (690 mg, 3.8 mmol) and 4-cyanobenzohydrazide (673 mg, 4.18 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (514 mg, 3.8 mmol), TEA (0.8 mL, 5.7 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (1.09 g, 5.7 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with 5% citric acid (2×60 mL), 5% NaHCO3 (2×60 mL) followed by water (60 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (0.79 g, 49%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.92 (br s, 1H), 9.49 (br s, 1H), 7.99 (d, J=9 Hz, 2H), 7.81 (d, J=9 Hz, 2H), 7.42 (d, J=9 Hz, 1H), 6.61 (d, J=9 Hz, 1H), 6.53 (dd, J=12 and 18 Hz), 5.99 (d, J=9 Hz, 1H), 5.73 (dd, J=2 and 12 Hz, 2H), 5.64 (dd, J=2 and 18 Hz), 4.29-4.22 (m, 1H), 4.01-3.99 (m, 1H) and 1.20 (d, J=7 Hz, 3H).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].Br[CH2:11][CH2:12][Cl:13].[OH-].[Na+]>>[Cl:13][CH2:12][CH2:11][O:3][C:2]1[C:1]([O:8][CH3:9])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCBr
Reactant: COc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccccc1OCCCl
Temperature: 100 °C
Yield: 96.4 %

Procedure:
Guaiacol (6.2 g, 50 mmol) and 1-bromo-2-chloro-ethane (8.4 mL, 100 mmol) were mixed thoroughly and heated at 100° C. for 30 minutes. Then, 31 ml of 1.6 N NaOH aqueous solution was added into the mixture to bring the pH to about 7.0. After cooling, the mixture was extracted with chloroform. The chloroform layer was partitioned with 20% NaOH aqueous solution, water and saturated NaCl aqueous solution in sequence. The organic portion was dried with anhydrous sodium sulfite and evaporated to dryness to obtain O-(2-chloroethyl)guaiacol (18) (9 g; yield 96%). Rf 0.67 (chloroform with saturated ammonia water); IR (KBr) νmax 2934 (m), 1593 (s), 1504 (s), 1455 (s), 1254 (s), 1224 (s), 1178 (s), 1125 (s), 1028 (m) cm−1; 1H NMR (CDCl3, 400MHz): δ 6.94 (4H, m), 4.26 (2H, t, J=6.3Hz), 3.85 (3H, s, 2-OMe), 3.81 (2H, t, J=6.3Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:52][O:53][C:54](=[O:61])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH2:60]>[Cl-].[Na+].O.CN(C=O)C>[CH3:52][O:53][C:54](=[O:61])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][NH:60][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([CH:12]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[CH:14]=1
Reactant: COC(=O)CCCCCN
Reactant: O=C1Nc2ccc(F)cc2C1=Cc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzoic acid (283 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 6-aminocaproic acid methyl ester hydrochloride (219 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (332 mg, 81% yield) as a brown solid. LC-MS (m/z) 411 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.[N:16]([Sn:19]([CH3:22])([CH3:21])[CH3:20])=[N+:17]=[N-:18]>>[C:10]1([C:3]2[CH:4]=[C:5]([C:6]3[N:16]([Sn:19]([CH3:22])([CH3:21])[CH3:20])[N:17]=[N:18][N:7]=3)[CH:8]=[CH:9][C:2]=2[NH2:1])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(N)c(C2=CCCCC2)c1
Product: C[Sn](C)(C)n1nnnc1-c1ccc(N)c(C2=CCCCC2)c1

Procedure:
The title compound was prepared from 4-amino-3-cyclohex-1-enyl-benzonitrile (as prepared in the previous step, 245 mg, 0.123 mmol) and azidotrimethylstannane (267 mg, 1.29 mmol) according to the procedure in Example 52, step (c) (320 mg, 64%). Mass spectrum (ESI, m/z): Calcd. for C13H15N5, 242.1 (M-SnMe3+2H), found 242.2 (M+H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]([S:23]([C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][N:30]=[CH:31]2)(=[O:25])=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)(C)(C)C.[ClH:36].CO>>[ClH:36].[CH:31]1[C:32]2[C:27](=[C:26]([S:23]([N:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:10][CH2:9][NH2:8])(=[O:24])=[O:25])[CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCc1ccccc1)S(=O)(=O)c1cccc2cnccc12
Agent: Cl
Solvent: CO
Product: NCCCN(CCCCc1ccccc1)S(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 6 (249 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (188 mg) as white powdery solid.