Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[N:21]=2)[C:17]#[N:18])[CH2:9][CH2:8]1)=[O:6].C[O-].[Na+].CO.[CH:37]([NH:39][NH2:40])=O>CO>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:21]=[C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[CH:19]=[C:16]([C:17]3[NH:40][N:39]=[CH:37][N:18]=3)[CH:15]=2)[CH2:9][CH2:8]1)=[O:6]
Reactant: NNC=O
Reactant: N#Cc1cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)nc(Nc2nccs2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(c1cccc(Cl)c1F)N1CCN(Cc2cc(-c3ncn[nH]3)cc(Nc3nccs3)n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 25.2 mg of 2-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-6-(thiazol-2-ylamino)isonicotinonitrile obtained in Example 104 and 1 ml of methanol was added 0.3 ml of a 28% sodium methoxide-methanol solution, followed by stirring at room temperature for 5 hours. To the reaction solution was added a solution of 3.3 mg of formohydrazide in 1 ml of methanol. The reaction mixture was stirred at room temperature for 17 hours, and then heated under reflux for 24 hours. To the reaction solution was added a solution of 16.6 mg of formohydrazide in 1.5 ml of methanol, and further heated under reflux for 22 hours. The reaction solution was cooled to room temperature, and then concentrated. The resulting residue was purified by a thin-layer chromatography for fractionation (eluent: chloroform/methanol=7/1) to give the title compound.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:24]=[CH:23][C:11]3[NH:12][C:13]([C:15]4[C:19]([N+:20]([O-])=O)=[CH:18][NH:17][N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>[Pd].CN(C=O)C>[N:1]1([CH2:7][C:8]2[CH:24]=[CH:23][C:11]3[NH:12][C:13]([C:15]4[C:19]([NH2:20])=[CH:18][NH:17][N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Reaction time: 4 h
Yield: 71.1 %

Procedure:
Palladium on carbon (10%, 0.08 g) was added to solution of 5-morpholin-4-ylmethyl-2-(4-nitro-1H-pyrazol-3-yl)1H-benzimidazole (0.82 g, 2.5 mmol) in DMF (30 ml) under an atmosphere of nitrogen. The mixture was shaken under a hydrogen atmosphere for 4 h then filtered through celite, washing with methanol. The filtrate was concentrated in vacuo to give 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine as a brown solid (530 mg, 71%). (LC/MS: Rt 1.94, [M+H]+ 299).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH2:12][OH:13])[O:8][N:7]=1)=[O:5].[OH:19]S(O)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][C:12]([OH:19])=[O:13])[O:8][N:7]=1)=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=C(c1cc(CCO)on1)c1ccc(Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(O)Cc1cc(C(=O)c2ccc(Cl)cc2Cl)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 12.8 g of 2-[3-(2,4-dichlorobenzoyl)-isoxazol-5-yl]ethanol and a few crystals of tetra-n-butylammonium hydrogen sulfate in 1000 ml of CH2Cl2 was added 150 ml of 9M H2SO4. To this was added 13.2 g of pulverized K2Cr2O7 and the mixture was stirred at room temperature for 1 hour. The organic phase was separated from the aqueous phase and washed with water. The acid product was extracted from the organic phase using 40 ml of 4% NaHCO3. The alkaline solution was washed with CH2Cl2 several times, until all the neutral impurities were removed, and the solution was then acidified slowly with 5% HCl until all the acid precipitated. The solid was filtered, washed with water, and dried to yield 3.9 g of a powder. Recrystallization from 100 ml of 50% toluene/hexane gave 3.5 g (26%) of crystals, m.p. 108°-109° .
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1
Reactant: CN1CCN(C2CCN(c3ccc([N+](=O)[O-])cc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C2CCN(c3ccc(N)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102 %

Procedure:
A suspension of 1-Methyl-4-[1-(4-nitro-phenyl)-piperidin-4-yl]-piperazine-(46 mg, 0.15 mmol) and Pd/C (10%, 8 mg) in MeOH (2 mL) is stirred at room temperature under H2 (balloon pressure) for 16 hours, then filtered through celite, washed with EtOAc, concentrated under reduced pressure to give 42 mg of the title compound as a light grey solid.
Reaction SMILES: [N:1]1([C:8]2[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]CCCC)=[O:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[Na+]>O>[N:1]1([C:8]2[C:9]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCCCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCCC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCCC3)nc2c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed butyl 3-(azepan-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.36 mmol, 1.00 equiv), methanol (15 mL), sodium hydroxide (71 mg, 1.77 mmol, 4.98 equiv), water (2 mL). The resulting solution was stirred for 2 hrs at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with aq hydrogen chloride (1 mol/L). The resulting solids were collected by filtration. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, XbridgePrep Shield RP 18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (60% CH3CN up to 90% in 8 min, up to 100% in 1.5 min); Detector, UV 220 254 nm. This resulted in 80 mg (61%) of 3-(azepan-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]=O)[N:3]=1.Cl.[NH2:20][OH:21]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])=[C:4]([CH:17]=[N:20][OH:21])[N:3]=1
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C=O)n1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(C=NO)n1

Procedure:
This compound was made from the compound of Example 46 by reaction with hydroxylamine hydrochloride in ethanol, mp. 260°-5° C.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[C:35]([O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=[CH:32][C:16]=1[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](O)=[O:28])=[CH:24][CH:25]=2)[C:20]([CH3:30])=[C:19]1[CH3:31]>>[Cl:14][C:15]1[C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27](=[O:28])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:24][CH:25]=3)[C:20]([CH3:30])=[C:19]2[CH3:31])=[CH:32][CH:33]=[CH:34][C:35]=1[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1Cl
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(2-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[O:12][CH3:13])=[C:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([O:19]CC)=[O:18])[C:6]2=[O:22].C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:32][N:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)[CH3:34]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(OCC)(=O)C>[CH:14]1([C:9]2[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6](=[O:22])[N:5]3[C:10]=2[C:11]([O:12][CH3:13])=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[CH2:35][N:33]([CH3:34])[CH3:32])[CH:3]=[CH:4]3)[CH2:15][CH2:16]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(OC)c(Cl)ccn2c1=O
Reactant: CN(C)Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1c(-c2ccccc2CN(C)C)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Yield: 48.4 %

Procedure:
100 mg of ethyl 8-chloro-1-cyclopropyl-9-methoxy-4-oxo-4H-quinolizine-3-carboxylate was suspended in 1 ml of toluene. 0.5 ml of ethanol, 0.25 ml of 2 M aqueous sodium carbonate solution, 61 mg of 2-(N,N-dimethylaminomethyl)phenylboronic acid and 10 mg of bis(triphenylphosphine)palladium (II) chloride were added to the obtained solution, and they were heated under reflux in argon atmosphere for 38 hours. Ethyl acetate was added to the reaction mixture. The organic layer was taken, washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resultant residue was purified by the silica gel column chromatography (eluent: chloroform/acetone=4/1) to obtain 59 mg of 1-cyclopropyl-8-(2-dimethylaminomethylphenyl)-9-methoxy-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH:5]1[CH2:8][NH:7][CH2:6]1.C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1>C(O)(C)C>[Cl:23][C:24]1[N:29]=[C:28]([N:7]2[CH2:8][CH:5]([O:4][C:3]3[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=3[Cl:1])[CH2:6]2)[CH:27]=[CH:26][N:25]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Clc1ccc(OC2CNC2)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Clc1ccc(OC2CN(c3ccnc(Cl)n3)C2)c(Cl)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of 3-(2,4-dichlorophenoxy)azetidine (1.0 g, 4.6 mmol) in isopropanol (14 mL) was added N,N-diisopropylethylamine (DIPEA) (1.0 mL, 6.9 mmol) and 2,4-dichloropyrimidine (0.686 g, 4.6 mmol and the reaction mixture was heated at 80° C. for 7 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×20 mL) and water (2×20 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(3-(2,4-dichlorophenoxy)azetidin-1-yl)pyrimidine (0.600 g, 40%) as a solid. Observed mass (M+1): 330.0
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][C:10](OC)([O:12]C)[CH2:9]2)=[CH:4][CH:3]=1.Cl>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:9][C:10](=[O:12])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: COC1(OC)CC(c2ccc(Br)cc2)(N2C(=O)c3ccccc3C2=O)C1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CC(c2ccc(Br)cc2)(N2C(=O)c3ccccc3C2=O)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A solution of 2-(1-(4-bromophenyl)-3,3-dimethoxycyclobutyl)isoindoline-1,3-dione (0.3 g, 0.72 mmol) in Acetone (30 ml) was added 6M HCl (3 ml) and the resulting solution was stirred at 50° C. for 2 h. The reaction mixture was concentrated to give product 0.26 g.).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:36])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:29])[CH:22]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:12]=[CH:11][C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:36])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:29])[CH:22]=1
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Yield: 87 %

Procedure:
In a manner similar to that of Example (18e), by reaction of 400 mg (26% by mass) of 10% palladium-on-charcoal, 1.54 g (3.16 mmol, 1 eq) of methyl (E)-3-[2-benzyloxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]acrylate in 20 ml of methanol and 5 mL of ethyl acetate, and after crystallization from pentane, 1.1 g of methyl 3-[2-hydroxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate are obtained in solid form. Yield=87%
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([CH3:16])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])[N:3]=1.[Cl-].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Zn+])=[CH:21][CH:20]=1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:5]=[C:4]([C:9]([CH3:16])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])[N:3]=1
Reactant: Clc1ccc(C[Zn+])cc1
Reactant: CC(C)(O[Si](C)(C)C)c1cc(Cl)nc(Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O[Si](C)(C)C)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Temperature: 50 °C
Yield: 71 %

Procedure:
To a solution of 2,4-dichloro-6-(1-methyl-1-trimethylsilanyloxy-ethyl)-pyrimidine (5.02 g, 18.0 mmol) in THF (60 mL) was added Pd(TPP)4 (0.83 g, 0.72 mmol). The solution was flushed with argon, and subsequently, a 0.5 M solution of 4-chloro-benzylzinc chloride in tetrahydrofuran (36 mL, 18.0 mmol) was added at 20° C. over 1-3 minutes. The reaction mixture was heated to 50° C. for 3 h under an atmosphere of argon. After cooling the mixture to 20° C., saturated aqueous ammonium chloride solution (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (2×30 mL) and the organic layers were washed with brine (2×30 mL), dried over sodium sulfate, and evaporated under reduced pressure. The residual oil was purified by chromatography on silica gel using heptane/0-30% ethyl acetate as eluent to afford the title compound (4.72 g, 71%) as a colorless oil.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.CN1CCOCC1.C(Cl)(=O)OCC.C(O)(C(F)(F)F)=O.[NH2:38][C@H:39]([C:57]([NH2:59])=[O:58])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:56])[NH:45][S:46]([C:49]1[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=1)(=[O:48])=[O:47]>CN(C)C=O>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([NH:38][C@H:39]([C:57]([NH2:59])=[O:58])[CH2:40][CH2:41][CH2:42][NH:43][C:44](=[NH:56])[NH:45][S:46]([C:49]1[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=1)(=[O:48])=[O:47])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](N)C(N)=O)cc1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C)C(N)=O)cc1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
2.493 g of Boc-D-Leu-OH.H2O was dissolved in 10 ml of dimethylformamide. The solution was cooled to -20° C. 1.1 ml of N-methylmorpholine and 0.96 ml of ethyl chlorocarbonate were added to the solution. After 5 min, a solution of 4.414 g of CF3COOH.H-Arg(Tos)-NH2 and 1.65 ml of N-methylmorpholine in 20 ml of dimethylformamide was added thereto and the mixture was stirred at about -5° C. for 2 h. After concentration, the residue was dissolved in ethyl acetate and washed with NaHCO3 and water successively. After concentration, ether was added thereto to solidify the product. Thus, 4.96 g of Boc-D-Leu-Arg(Tos)-NH2 was obtained.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7](B(O)O)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[C:22]1[CH:33]=[CH:32][C:25]([CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[N:27]1([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:7]3[CH:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:9][C:8]=3[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:33][CH:32]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: Brc1ccc(Cn2ccnc2)cc1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Yield: 63.4 %

Procedure:
5-iso-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (200.5 mg, 0.628 mmol, see Example 1(c) above), 1-(4-bromobenzyl)-1H-imidazole (98.8 mg, 0.416 mmol, see step (a) above), toluene (15 mL), ethanol (15 mL), NaOH (1.0M, 1.5 mL, 1.5 mmol) and Pd(PPh3)4 (14.5 mg, 0.125 mmol) were mixed under N2. The mixture was warmed to reflux for 2 hours. The mixture was diluted with EtOAc (50 mL), washed with water and brine, and dried over MgSO4. The solvent was removed and the residue was separated by column chromatography with chloroform:methanol (20:1) as eluent to give 113.9 mg of the sub-title compound (yield: 63.27%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH:30]([N:33]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:35]=[N:34]2)[CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:16]2[CH:17]=[C:12]([N:8]3[CH:7]([CH3:26])[CH2:6][C:5]4[C:10](=[CH:11][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH:30]6[CH2:31][CH2:32][O:27][CH2:28][CH2:29]6)[CH:37]=5)=[CH:3][CH:4]=4)[CH2:9]3)[N:13]=[C:14]([NH2:25])[N:15]=2)[CH2:23][CH2:22]1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC1(C)OB(c2cnn(C3CCOCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3cnn(C4CCOCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.3 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol) and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling, it was diluted with methanol. The solid was filtered off. The filtrate was purified with RP-HPLC (pH=10) to afford 0.9 mg of the desired product. LCMS (M+H)+: m/z=489.4.
Reaction SMILES: C([O:3][C:4](=[O:38])[C@H:5]([CH2:14][C:15]1[C:20]([I:21])=[CH:19][C:18]([O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:17]([O:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:16]=1)[NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.[OH-].[Li+].C(O)(=O)C>C1COCC1.O>[C:10]([O:9][C:7]([NH:6][C@H:5]([C:4]([OH:38])=[O:3])[CH2:14][C:15]1[C:20]([I:21])=[CH:19][C:18]([O:22][C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[C:17]([O:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:16]=1)=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1I)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1I)C(=O)O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The iodo derivative 17 (3.5 mmol) (prepared as shown in FIG. 6) was dissolved in 40 mL of THF and cooled in an ice bath (0° C.) and a solution of lithium hydroxide (7.0 mmol) in 12 mL of water was added dropwise under argon. The resulting mixture was stirred at 0° C. for 4 h and then 2 h at room temperature. The reaction mixture was then neutralized with acetic acid to pH 5 and extracted with ethyl acetate. The organic phase was dried using Na2SO4, filtered and evaporated to dryness to provide an oil which was purified by silical gel column chromatography resulting in N-(tert-butoxycarbonyl)-3,4-di(tert-butoxycarbonyloxy)-6-iodo-L-phenylalanine (23).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:11]2[CH2:10][CH2:9][N:8]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Br)cc1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(N2CCN=C2c2ccccc2)cc1
Yield: 25 %

Procedure:
A mixture of 28.8 parts of 2-phenyl-1H-imidazole, 37.4 parts of 1-bromo-4-methoxybenzene, 20 of potassium carbonate and 180 parts of N,N-dimethylacetamide is stirred for one week at reflux temperature. The reaction mixture is cooled, poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are dried, filtered and evaporated, yielding 10 parts (25%) of 1-(4-methoxyphenyl)-2-phenyl-4H-imidazole as a residue.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>C(#N)C>[O:21]=[C:19]([CH3:20])[CH2:18][O:1][C:2]1[C:3]([C:8]([NH2:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncccc1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)COc1cccnc1C(N)=O

Procedure:
A mixture of 27.6 g of 3-hydroxy-2-pyridinecarboxylic acid amide and 31 g of potassium carbonate in 600 ml of acetonitrile is heated to the boil for 2 hours, while stirring well. 22.2 g of chloroacetone are added dropwise to the resulting thick paste in the course of 30 minutes. The reaction mixture is stirred for 20 hours whilst boiling under reflux. The undissolved material is filtered off after cooling and the filtrate is evaporated under reduced pressure. The residue is stirred with water, whereupon unconverted 3-hydroxy-2-pyridinecarboxylic acid amide remains as an undissolved residue. The aqueous solution is evaporated under reduced pressure and the residue is extracted with methylene chloride. The organic solution, after evaporation under reduced pressure, gives crude 3-(2-oxo-propoxy)-2-pyridinecarboxylic acid amide which melts at 135°-140° C. after crystallisation from ethanol.