Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH2:28])[C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH2:28])[C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1ncc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1ncc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cc1N
Yield: 17.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxypyridin-3-amine (80 mg, 0.14 mmol) was hydrolyzed with lithium hydroxide (12 mg, 0.28 mmol) in THF/methanol/water (2/2/1 mL) to yield 10 mg (17.1% yield) after purification by preparative TLC(Silicagel-1000 micron) using 5% methanol in chloroform as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.37 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.717-7.712 (d, 1H), 7.61 (s, 1H), 7.36-7.29 (m, 2H), 7.10-6.98 (m, 3H), 5.41 (s, 2H), 4.00 (s, 3H). MS: m/z=415.2 (M+1), HPLC: 88.73% in method B.
Reaction SMILES: ClC1CCCCC1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:12]([O:13][CH3:14])[CH:11]=1.[Li].[B:19](OC)([O:22]C)[O:20]C.Cl>C1COCC1.C1CCCCC1.O>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:12]([O:13][CH3:14])[C:11]=1[B:19]([OH:22])[OH:20]
Reactant: COB(OC)OC
Reactant: COc1cccc(OC)c1
Agent: Cl
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1cccc(OC)c1B(O)O
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
A mixture of 20.88 g of chlorocyclohexane (0.176 mol) and 22.1 g of resorcinol dimethyl ether (0.16 mol) is added dropwise to a suspension of 2.35 g of lithium granules (0.34 mol) in 300 g of THF at −50° C., with an addition time of 2 hours being selected. After a conversion of the chlorocyclohexane of >97% determined by GC (total of 9 h), 16.6 g of trimethyl borate (0.16 mol) are added dropwise at the same temperature over a period of 15 minutes. After stirring for another 30 minutes at −50° C., the reaction mixture is poured into 120 g of water, the pH is adjusted to 6.3 by means of 37% HCl, and THF and cyclohexane are distilled off at 35° C. under reduced pressure. 25 ml of methylcyclohexane are added to the product suspension, the colorless product is filtered off with suction and is washed once with 25 ml of cold methylcyclohexane and once with 25 ml of cold water. After drying, 26.5 g of 2,6-dimethoxyphenylboronic acid (0.146 mol, 91%, melting point: 104–107° C.) are obtained in the form of colorless crystals, HPLC purity >99% a/a.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:48]=[CH:47][C:20]([C:21]([N:23]([CH3:46])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([O:39]C4C=CC=CC=4)=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:23]([CH3:46])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([N:53]4[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]4)=[O:39])=[O:22])=[CH:47][CH:48]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCNC(=O)Oc3ccccc3)cc2)cc1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCNC(=O)N3CCN(C)CC3)cc2)cc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 64.9 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-phenoxycarbonylaminopentyloxy)phenyl]benzamide (290 mg) in N,N-dimethylformamide (15 ml) was added 1-methylpiperazine (271 mg) at ambient temperature. The reaction mixture was stirred at 80° C. for 10 hours. The reaction mixture was cooled and extracted with ethyl acetate and washed with saturated sodium hydrogen carbonate and brine. The organic solution was dried over sodium sulfate. The solvent was removed by evaporation and subjected to silica gel column chromatography (SiO2; 30 g, 5% methanol in chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-[5-(4-methylpiperazin-1-carbonylamino)pentyloxy]phenyl]benzamide (190 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])=[C:6]2[C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34])[CH2:12][CH2:11][CH:10]=[C:9]3B1OC(C)(C)C(C)(C)O1.I[C:36]1[S:37][CH:38]=[C:39]([CH3:41])[N:40]=1.[OH-].[Ba+2].[OH-]>C(#N)C.O.Cl.[Pd+2].ClC1C=C[C-](P(C(C)(C)C)C(C)(C)C)C=1Cl.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH3:1][N:2]1[C:7]2=[C:8]3[N:13]([C:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#[N:19])=[C:6]2[C:5](=[O:32])[N:4]([CH3:33])[C:3]1=[O:34])[CH2:12][CH2:11][CH:10]=[C:9]3[C:36]1[S:37][CH:38]=[C:39]([CH3:41])[N:40]=1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(B1OC(C)(C)C(C)(C)O1)=CCC3
Reactant: Cc1csc(I)n1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P([c-]1ccc(Cl)c1Cl)C(C)(C)C
Solvent: O
Solvent: CC#N
Product: Cc1csc(C2=CCCn3c(-c4cccc(C#N)c4)c4c(=O)n(C)c(=O)n(C)c4c32)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(1,3-dimethyl-2,4-dioxo-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,7,8-hexahydropyrimido[4,5-a]indolizin-5-yl)benzonitrile (step 9) (202 mg, 0.44 mmol), 2-iodo-4-methylthiazole (Intermediate O) (90 mg, 0.40 mmol), dichloro[1,1′ bis(di-tert-butylphosphino)]ferrocene palladium (11) (13 mg, 0.02 mmol) and barium hydroxide (137 mg, 0.80 mmol) in acetonitrile/water (1:1, 2 mL) was stirred at room temperature for 45 minutes and at 80° C. for 1 hour. The reaction mixture was diluted with 1M HCl (10 mL) and was extracted with DCM (3×10 mL). The combined organic layers were filtered through a hydrophobic frit and the solvent removed under vacuum. Purified by chromatography on silica, eluting with 0.5% MeOH/DCM, 1% MeOH/DCM, 1.5-2.0% MeOH afforded the title product:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F-:11].[K+]>S1(CCCC1)(=O)=O.[Cl-].C([N+]1C=CC(N(CCCC)CCCC)=CC=1)C(C)(C)C>[F:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: CCCCN(CCCC)c1cc[n+](CC(C)(C)C)cc1
Agent: [Cl-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)cc1
Reaction time: 9 h
Yield: 96.3 %

Procedure:
A reaction mixture of 85.3 g of 4-chloronitrobenzene (CNB), 45.3 g of potassium fluoride, 1.4 g of the N-neopentyl-4-(N',-N'-di-n-butylamino)pyridinium chloride (NPDBAPC) obtained in Example lII in 109.6 g of sulfolane was heated with stirring for 9 hours at 205°-215° C. At the end of this period, HPLC assay of a sample of the reaction mixture indicated less than 1% residual CNB. Simple distillation of the reaction mixture under vacuum gave 73.6 g of 4-fluoronitrobenzene (FNB) for a 96.3% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.[CH:27](N1C2C=CC=CC=2N=N1)=[O:28]>O1CCCC1.ClCCl>[CH3:26][C:21]1[CH:20]=[C:19]([NH:18][C:16]([C:15]2[C:10]([S:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH:27]=[O:28])[CH:7]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH:24]=[C:23]([CH3:25])[CH:22]=1
Reactant: O=Cn1nnc2ccccc21
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)c2)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(NC=O)c2)c1

Procedure:
2-(2-Aminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (the free base of Compound No. 3-1, 50 mg, 0.14 mmol) was dissolved in anhydrous tetrahydrofuran (0.20 mL), a solution of N-formylbenzotriazole (19 mg, 0.13 mmol) in anhydrous tetrahydrofuran (0.2 mL) was added thereto, and then the mixture was refluxed for 16 hours. The mixture was diluted with dichloromethane (15 mL), and then the whole was washed with 2 N aqueous sodium hydroxide solution (4.0 mL) twice and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 60 mg of the target compound quantitatively as a colorless solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:19])[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1)=O>O1CCCC1>[CH3:19][N:8]([CH2:9][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:17][CH:18]=1)[CH3:7]
Reactant: CN(C)C(=O)c1ccc(CN)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(CN)cc1

Procedure:
Into a suspension of 0.95 g of lithium aluminum hydride and 100 ml of tetrahydrofuran, a solution obtained by dissolving 1.77 g of 4-dimethylaminocarbonylbenzylamine prepared in Reference Example 5 in 50 ml of tetrahydrofuran, was dropwise added under stirring, and the reaction solution was refluxed for 3 hours. After cooling, the reaction solution was cooled with ice, and ice pieces were gradually added to decompose the excessive reducing agent. Tetrahydrofuran was distilled off, and the residue thereby obtained was extracted with dichloromethane. The extract was washed with water and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off to obtain 1.13 g of the above identified compound as a pale yellow oily substance.
Reaction SMILES: S([O-])([O-])(=O)=O.[NH2:6][OH:7].Cl[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10].[OH-].[Na+]>>[OH:7][NH:6][C:9](=[O:10])[O:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCOC(=O)Cl
Reactant: NO
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCOC(=O)NO

Procedure:
With respect to butyl N,O-dimethylcarbamate, a process disclosed in the specification of West German Patent Application Laid-open No. 3,245,503 is known. This process comprises reacting sulfate of hydroxylamine as a starting material with butyl chloroformate in the presence of sodium hydroxide, extracting the reaction product with dichloromethane, drying the extract, distilling the solvent away from the dried extract to obtain butyl hydroxycarbamate and dimethylating this product using dimethyl sulfate and a sodium hydroxide solution to obtain ethyl N,O-dimethylhydroxycarbamate in the total yield of 65%.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:19]([NH2:21])=[O:20])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C([Sn]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(CCCC)CCCC)CCC.C(N1C2C(=CC=C(C3ON=CC=3)C=2)C(=O)C(C(N)=O)=C1)C>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:11]=3)[C:6](=[O:22])[C:7]([C:19]([NH2:21])=[O:20])=[CH:8]2)=[CH:13][CH:14]=1
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(Cl)ccc2c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: CCn1cc(C(N)=O)c(=O)c2ccc(-c3ccno3)cc21
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccccc3)ccc2c1=O

Procedure:
1,4-Dihydro-1-(4-fluorophenyl)-4-oxo-7-phenyl-3-quinolinecarboxamide [I; R=H, R1 =4-FC6H4, R2 =H, R6 =H, R7C6H5 ] was prepared from 2.22 g 1,4-dihydro-7-chloro1-(4-fluorophenyl)-4-oxo-3-quinolinecarboxamide (Example 42c), 3.30 g tributylstannylbenzene (prepared from tributyltin chloride and bromobenzene) and 2.50 g dichlorobis-triphenylphosphine palladium according to the procedure of Example 37, part (c), and was obtained (1.4 g) as colorless crystals, m.p. 289-292° C. when recrystallized from acetonitrile.
Reaction SMILES: [Si](O[C@@H]1[C@@](CI)(CO)O[C@@H]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])C1)(C(C)(C)C)(C)C.[Si](O[C@@H]1[C@@](C)(CO)O[C@@H](N2C=C(C)C(=O)NC2=O)C1)(C(C)(C)C)(C)C>[OH-].[Na+].CO.[Pd]>[NH:18]1[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]1=[O:20]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@](CO)(CI)O2)c(=O)[nH]c1=O
Agent: [Pd]
Agent: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@](C)(CO)O2)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: CO
Product: Cc1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A solution of the 4'-α and 4'-β isomers of 3'-O-t-butyldimethylsilyl-4'-iodomethylthymidine (26 mg, 0.05 mM), prepared, e.g., as described in Preparation 6, 10% Pd-C (palladium on carbon) (15 mg), 1 N NaOH (2 drops) in CH3OH was stirred under hydrogen atmosphere at 25° C. for 66 hours. The solvent was removed by evaporation under vacuum pressure. The residue was purified by flash silica gel chromatography. The column was eluted with CH2Cl2 +5% CH3OH, yielding a mixture of the 4'-α and 4'-β isomers of 3'-O-t-butyldimethylsilyl-4'-methylthymidine (13 mg, 0.035 mM) as a colorless oil. MS 371 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][C:13]([NH2:17])=[N:14][CH:15]=3)[N:10]([CH3:18])[N:9]=2)=[CH:4][CH:3]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>>[NH2:17][C:13]1[N:12]=[C:11]2[N:10]([CH3:18])[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:20]([Cl:19])(=[O:22])=[O:21])[CH:4]=3)[C:16]2=[CH:15][N:14]=1
Reactant: Cn1nc(-c2ccc(Cl)cc2)c2cnc(N)nc21
Reactant: O=S(=O)(O)Cl
Product: Cn1nc(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)c2cnc(N)nc21
Temperature: 120 °C

Procedure:
3-(4-Chloro-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (559 mg, 2.15 mmol) is dissolved in chlorosulfonic acid (6.45 ml, 96.84 mmol) and the reaction mixture is heated to 120° C. for 24 hours. After cooling to room temperature the reaction mixture is used crude as a solution for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[CH:29]1([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1.C[Al](C)C>C1(C)C=CC=CC=1>[CH:29]1([C:32]2[CH:38]=[CH:37][C:35]([NH:36][C:22]([C:20]3[C:19]4[O:18][C:17]([CH3:26])([CH3:27])[CH2:16][C:15]=4[C:12]4[N:13]([CH3:14])[C:9]([NH:8][C:7]5[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=5[Cl:28])=[N:10][C:11]=4[CH:21]=3)=[O:24])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3ccc(C4CC4)cc3)c3c(c21)CC(C)(C)O3
Yield: 35.2 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.245 mmol), 4-cyclopropylaniline (Intermediate-50, 0.047 g, 0.356 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.045 g of the desired product. 1HNMR (DMSO-d6): δ 0.63 (m, 2H), 0.91 (d, J=6.6 Hz, 2H), 1.60 (s, 6H), 1.89 (m, 1H), 3.48 (s, 2H), 3.59 (s, 3H), 7.05 (d, J=7.8 Hz, 2H), 7.26 (s, 1H), 7.54 (d, J=8.1 Hz, 2H), 8.46 (s, 2H), 9.61 (br s, 1H), 10.88 (br s, 1H); MS [M−H]−: 520.06.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10]>>[N:6]1[CH:7]=[CH:8][C:3]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[CH:4][CH:5]=1
Reactant: Brc1ccncc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl
Product: N#Cc1ccc(-c2ccncc2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 11 using 4-bromopyridine hydrochloride instead of 1-bromo-3-pentyloxybenzene and 4-cyanophenylboronic acid instead of tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-benzyl]carbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[CH:12][N:11]3[C:25]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.CN(C=O)C.[CH3:35][C:36]([NH2:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO>[C:36]([NH:39][C:19]([C:18]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]3[N:11]([C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:12]=2)[CH:24]=[CH:23][CH:22]=1)=[O:20])([CH3:38])([CH3:37])[CH3:35]
Reactant: CC(C)(C)N
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)O)c3)cn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(-c3cccc(C(=O)NC(C)(C)C)c3)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
3-(2-(4-Fluorophenyl)-3-(methylcarbamoyl)imidazo[1,2-a]pyridin-6-yl)benzoic acid (40 mg, 0.10 mmol) was slurried into DMF (0.7 mL) and TEA (0.1 mL). To this slurry was added 2-methylpropan-2-amine (11.27 mg, 0.154 mmol) and then HATU (59 mg, 0.15 mmol) (solution became yellow). The reaction was stirred at rt overnight (complete by LCMS). The reaction was diluted with MeOH (0.7 mL), filtered and purified by prep HPLC (acetonitrile/water, with 10 mM ammonium acetate buffer) to yield 6-(3-(tert-butylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (19.6 mg, 0.042 mmol, 41% yield) as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 9.25 (br s, 1H), 8.08 (t, J=1.8 Hz, 1H), 7.90 (dd, J=9.2, 1.8 Hz, 1H), 7.88-7.85 (m, 1H), 7.84-7.82 (m, 1H), 7.81-7.78 (m, 2H), 7.77 (br d, J=9.2 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.29 (t, J=8.9 Hz, 2H), 2.69 (s, 3H), 1.52 (s, 9H). LC-MS retention time 1.39 min; m/z 443 (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 mM where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.C(N)C1C=CC=CC=1.[CH2:19]1[CH2:24][CH2:23][CH:22]([N:25]=[C:26]=[N:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:21][CH2:20]1>C(#N)C>[C:26]([NH:25][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:24][CH2:23]1)([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:10]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Solvent: NCc1ccccc1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 16 h

Procedure:
Fmoc-arginine(PMC)—OH AA3 (3.83 g, 5.0 mmol) and HOBT (0.76 g, 5.0 mmol) were combined in acetonitrile (100 mL) and benzylamine (0.54 g, 5.0 mmol) was added dropwise at about rt, followed by DCC (2.06 g, 10.0 mmol) and stirred for about 16 h. A solid was filtered and the filtrate was evaporated in vacuo to an oil, which was then dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO3 (2×), brine (2×), then dried (Na2SO4) and evaporated in vacuo to a solid, which was triturated with hexane (2×) to give a solid (impure with dicyclohexylurea). A portion of this solid (1.17 g, 1.25 mmol) was dissolved in acetonitrile (30 mL), diethyl amine (1.5 mL) was added and the reaction was stirred at about rt for about 1 h. The solution was then evaporated in vacuo to a solid, which was triturated with hexane (2×). The solution was then evaporated in vacuo to a solid, which was then combined in ACN (25 mL) with Fmoc-3,4-difluorophenylalanine (0.53 g, 1.25 mmol) and HOBT (0.19 g, 1.25 mmol). DIC (0.32 g, 2.5 mmol) was added and the reaction was stirred at about rt for about 16 h. Fmoc-protected dipeptide was filtered (0.77 g) and stirred in ACN (30 mL) with diethyl amine (1.5 mL) for about 2.5 h. The reaction was evaporated in vacuo to an oil, which was triturated with hexane (3×) to the white solid AA4.
Reaction SMILES: [C@H:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:16]1[N:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:20][CH:21]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:22]1([C:19]2[N:18]=[N:17][C:16]([N:5]3[CH2:6][CH:1]4[CH2:7][C@H:4]3[CH2:3][N:2]4[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: CC(C)(C)OC(=O)N1CC2C[C@H]1CN2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC1CN2c1ccc(-c2ccccc2)nn1

Procedure:
1.0 g (5.0 mmol) of 1,1-dimethylethyl (1S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, 1.14 g (6.0 mmol) of 3-chloro-6-phenylpyridazine and 0.84 ml (6.0 mmol) of triethylamine in 45 ml of toluene are introduced into a 100 ml three-necked round-bottomed flask and the mixture is refluxed for 72 h.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1.[Cl:33][Si](C)(C)C>CC(CC)=O>[ClH:33].[CH3:32][N:2]([CH3:1])[C:3]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)N2CCC(c3c[nH]c4ccccc34)C2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-dimethylamino-4-phenylcyclohexylidene)-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]ethanone (200 mg, 0.47 mmole) was dissolved in ethyl methyl ketone (10 ml) and chlorotrimethylsilane (0.09 ml, 0.7 mmole) was added. After 1.5 hours the hydrochloride was obtained as a diastereoisomer mixture in the form of a colourless compound with an m.p. of 220°-223° C. in a yield of 96% (210 mg) (Example 11).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=3)[N:8]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[N:8]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1ccc(Nc2nccc(-c3ccncc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(Nc2nccc(-c3ccncc3)n2)cc1
Reaction time: 2 h

Procedure:
An 800 mg portion of [4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenoxy]acetic acid, ethyl ester was dissolved in 100 ml of ethanol and 10.7 ml of 1N sodium hydroxide was added. The mixture was stirred for 2 hours, the solvent removed and the residue dissolved in 5 ml of water. The pH was adjusted to 7.0 with 1N hydrochloric acid and the solid collected, washed with water and dried. The solid was recrystallized from dimethylformamide-ethanol, giving 600 mg of the desired product as yellow crystals, mp 308°-310° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](CC(O)=O)[CH:8]=1>C(Cl)Cl.CN(C=O)C>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:1][C:2]([Cl:4])=[O:3])[CH:8]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (211 μl; 2.23 mmol; 1.2 eq.) was added to a suspension of 3-pyridineacetic acid (255 mg; 1.86 mmol; 1.0 eq.) in DCM/DMF (5 mL:3 μL) maintained at 0° C. under nitrogen atmosphere. The reaction mixture was then stirred at rt for 1 h. It was then concentrated under reduced pressure. The solid obtained was used as such in amidation reactions.