Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:25]([NH:27][C@@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:26])[N:23]=[C:19]3[N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[CH3:35][C@H:28]([NH:27][C:25]([NH:24][C:22]1[N:23]=[C:19]2[N:18]=[CH:17][CH:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[N:20]2[N:21]=1)=[O:26])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:33])[CH3:34]
Reactant: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(OCc4ccccc4)cc3)n2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(O)cc3)n2n1

Procedure:
(S)-1-[7-(4-benzyloxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]-3-(1,5-dimethylhexyl)urea (the compound obtained in Example 245; 7.1 g) and palladium carbon (50% water content; 2.0 g) were suspended in acetic acid (570 ml), and the obtained suspension was stirred in a hydrogen atmosphere at a room temperature for 5 days. Thereafter, the reaction solution was filtrated with a filter medium (Celite), and the collected product was then washed with methanol. The filtrate and the washing solution were mixed, and the obtained mixture was then concentrated under a reduced pressure. The obtained residue was dissolved in methylene chloride (150 ml), and the obtained solution was washed with a saturated saline solution (100 ml) twice. The saturated saline solution layer obtained after the second washing was extracted with methylene chloride (70 ml×3). The organic layers were gathered, and the obtained layer was then concentrated under a reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with 1% to 2% methanol-containing methylene chloride) to obtain the captioned compound (4.72 g).
Reaction SMILES: [CH2:1]([CH:8]([NH:31][C:32]([C:34]1[CH:43]=[N:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1)=[O:33])[CH:9]([O:23][Si](C(C)(C)C)(C)C)[CH2:10][CH:11]([C:18]1[O:19][CH2:20][CH2:21][N:22]=1)[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[CH2:1]([CH:8]([NH:31][C:32]([C:34]1[CH:43]=[N:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:35]=1)=[O:33])[CH:9]([OH:23])[CH2:10][CH:11]([C:18]1[O:19][CH2:20][CH2:21][N:22]=1)[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C1=NCCO1
Solvent: C1CCOC1
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C1=NCCO1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid [1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-4-(4,5-dihydro-oxazol-2-yl)-7-fluoro-7-methyl-octyl]-amide (41 mg, 0.068 mmol) in tetrahydrofuran (0.70 mL) was added tris(dimethylamino)sulfur (trimethylsilyl)difluoride (56 mg, 0.203 mmol). The reaction was stirred for 1 hour then quenched with methanol and concentrated. Chromatography on silica gel gave the title compound (27.8 mg, 84%).
Reaction SMILES: [CH:1]1([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[C:13]([CH2:24][O:25][C:26]2[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=2)=[C:12]3[CH:36]=[O:37])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.[F:49][C:50]([F:56])([F:55])[S:51]([NH2:54])(=[O:53])=[O:52].C1COCC1>C(OCC)(=O)C.O>[CH:36]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([NH:8][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[CH:10]=2)[N:14]([CH2:18][CH2:19][CH2:20][C:21](=[O:22])[NH:54][S:51]([C:50]([F:56])([F:55])[F:49])(=[O:53])=[O:52])[C:13]=1[CH2:24][O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)=[O:37]
Reactant: O=Cc1c(COc2ccc3ccccc3c2)n(CCCC(=O)O)c2ccc(NC(=O)C3CCCC3)cc12
Reactant: NS(=O)(=O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1c(COc2ccc3ccccc3c2)n(CCCC(=O)NS(=O)(=O)C(F)(F)F)c2ccc(NC(=O)C3CCCC3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
The acid (1 eq) from step 1 of Example 53A was weighed into a flask and to this was added EDCI (1.35 eq) DMAP (1.1 eq), trifluoromethanesulfonamide (1.05 eq) followed by anhydrous THF (0.026 M) and the reaction mixture was stirred at 25° C., 3 h. Worked up with ethyl acetate/water followed by washing the organic layer with 0.05N HCl, saturated bicarbonate and brine. Chromatographic purification then afforded the desired product in 94% yield.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][CH2:24][CH2:25][CH3:26])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([N:8]([CH2:23][CH2:24][CH2:25][CH3:26])[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN(Cc1ccccc1)C(=O)Nc1ccc(C(=O)OCC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN(Cc1ccccc1)C(=O)Nc1ccc(C(=O)O)cc1

Procedure:
A solution of 5.30 g of 1-benzyl-1-(n-butyl)-3-(4-carboethoxyphenyl)urea in 100 ml of ethanol is treated with 25 ml of 1N aqueous sodium hydroxide, stirred under reflux for 16 hours, allowed to cool, acidified with 1N hydrochloric acid, and filtered. The solid is recrystallized from ethanol to yield 1-benzyl-1-(n-butyl)-3-(4-carboxyphenyl)urea as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13](=[S:15])[NH2:14])=[N:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:17][CH:18](OC)OC.C([O-])(O)=O.[Na+]>COCCOC.Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[S:15][CH:17]=[CH:18][N:14]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(CBr)OC
Reactant: NC(=S)CCCc1ccc([N+](=O)[O-])cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(CCCc2nccs2)nc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
To a solution of the compound 137 (2.1 g, 9.3 mmol) and 2-bromo-1,1-dimethoxyethane (6.31 g, 37.3 mmol) in DME (100 mL) was added dropwise 10 drops of the concentrated HCl at room temperature. The reaction mixture was stirred at 90° C. for 5 h, treated aq. NaHCO3 and extracted with DCM. The combined organic layers was washed with brine (30 mL), dried over Na2SO4, concentrated and purified with silica gel column chromatography (PE:EtOAc=3:1) to give compound 138 (1.8 g, 76%) as a white solid. 1H NMR (400 MHz, CDCl3) δ9.33-9.38 (m, 1H), 8.34-8.40 (m, 1H), 7.65-7.70 (m, 1H), 7.32-7.36 (m, 1H), 7.18-7.23 (m, 1H), 3.12 (t, 2H, J=7.6 Hz), 3.03 (d, 2H, J=7.2 Hz), 2.25-2.35 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:30])([F:29])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21]1)[OH:13].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([O:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21]2)[C:11]([F:30])([F:29])[F:10])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: OC(c1ccccc1-n1ccc(C(F)(F)F)n1)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OC(c2ccccc2-n2ccc(C(F)(F)F)n2)C(F)(F)F)n1
Temperature: 42.5 °C
Reaction time: 6 h
Yield: 106.6 %

Procedure:
2-Amino-4,6-dichloro pyrimidine (0.074 g, 0.45 mmol), 2,2,2-trifluoro-1-[2-(3-trifluoro methyl-pyrazol-1-yl)-phenyl]-ethanol (0.140 g, 0.45 mmol), and NaH (0.022 g, 0.59 mmol) were added to anhydrous THF (10 ml) under nitrogen atmosphere. The reaction was stirred at 40-45° C. for 6 h, and then cooled to room temperature, and quenched with water (0.2 ml). The reaction mixture was concentrated to give crude 4-chloro-6-[2,2,2-trifluoro-1-[2-(3-trifluoromethyl-pyrazol-1-yl)phenyl]-ethoxy]-pyrimidine-2-ylamine (0.21 g, >90% pure by LCMS), which was directly used in the next step.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>CN(C=O)C.[Cl-].[Na+].O>[I:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=1
Reactant: Clc1ncccn1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1ccc(Oc2ncccn2)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
Under an argon atmosphere, potassium carbonate (207 mg) was added to a solution of 4-iodophenol (220 mg) and 2-chloropyrimidine (114 mg) in DMF (1 ml), and the resulting mixture was stirred at 120° C. for 3 hours. The reaction solution was cooled to room temperature and saturated brine was added thereto, followed by extracting the resulting mixture with chloroform. Organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:hexane/ethyl acetate=3/1) to obtain 2-(4-iodophenoxy)pyrimidine (288 mg). NMR (H1, CDCl3): δ 6.97-7.00 (2H, m), 7.06 (1H, t, J=4.6 Hz), 7.73-7.75 (2H, m), 8.57 (2H, d, J=4.6 Hz)
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br-].[Li+].Cl[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[CH3:24][N:25]1[C:30](=[O:31])[C:29]2[CH2:32][NH:33][CH2:34][CH2:35][C:28]=2[NH:27][C:26]1=[O:36]>CN(C)C=O>[CH3:24][N:25]1[C:30](=[O:31])[C:29]2[CH2:32][N:33]([CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH2:34][CH2:35][C:28]=2[NH:27][C:26]1=[O:36]
Reactant: ClCCCCOC1CCCCO1
Reactant: Cn1c(=O)[nH]c2c(c1=O)CNCC2
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)[nH]c2c(c1=O)CN(CCCCOC1CCCCO1)CC2
Yield: 51 %

Procedure:
27 g of ethyldiisopropylamine, 18 g of lithium bromide and 46 g of 2-(4-chlorobutoxy) tetrahydropyran (86.3% pure according to GC) were added to 36.3 g of 3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione in 1 l of dimethylformamide, with stirring, and the mixture was stirred for 5 h at 70° C. It was concentrated under reduced pressure and 34.5 g of crude 3-methyl-6-[4-(tetrahydropyran-2-yloxy)butyl]-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione were obtained after working-up of the residue by extraction with dichloromethane and water and after drying and concentration of the combined dichloromethane phases, and this crude product was purified by column chromatography on aluminum oxide (actiVity grade III) and elution with dichloromethane/ethanol (volume ratio 90:10).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([C:21]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=1)[C:8]1[CH:13]=[C:12]([C:14]#[C:15][Si](C)(C)C)[CH:11]=[CH:10][C:9]=1[OH:20])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5]/[N:6]=[C:7](\[C:21]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][N:22]=1)/[C:8]1[CH:13]=[C:12]([C:14]#[CH:15])[CH:11]=[CH:10][C:9]=1[OH:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=C(c1cc(C#C[Si](C)(C)C)ccc1O)c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(O)c(/C(=N/OC(C)(C)C)c2ncccc2O)c1
Yield: 37 %

Procedure:
In methanol (50 ml) was dissolved 2-[2-hydroxy-5-(2-trimethylsilylethynyl)benzoyl]-3-hydroxypyridine O-t-butyl oxime (0.70 g). To the solution was added potassium carbonate (0.1 g) at room temperature, followed by heating for 3 hours under reflux. The reaction mixture was cooled by aeration, then the solvent was distilled off. To the residue were added chloroform and water for extraction. The organic layer was dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give (Z)-2-(5-ethynyl-2-hydroxybenzoyl)-3-hydroxypyridine O-t-butyloxime (0.21 g) (Compound 115).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH2:22][C:23](=[O:25])[CH3:24])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:14][CH2:13]1>O1CCCC1>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:12]1[CH2:18][N:17]2[C:19]([CH2:22][C:23]([OH:25])([CH3:1])[CH3:24])=[CH:20][N:21]=[C:16]2[C@H:15]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:14][CH2:13]1
Reactant: C[Mg]Br
Reactant: CC(=O)Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(O)Cc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 57 %

Procedure:
Methylmagnesium bromide (3.0 M in ether; 0.49 mL, 1.45 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-oxopropyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (61 mg, 0.145 mmol) in tetrahydrofuran (5 mL). After 2 h, the reaction was quenched with saturated aqueous ammonium chloride. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→96% dichloromethane/methanol) gave the title compound (36 mg). MS 436.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:16])([CH3:15])[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.C(#N)C.C(=O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:16])([CH3:15])[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)nc1
Agent: O=C=O
Agent: [Al+3]
Agent: [H-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(CO)Oc1ccc(Cl)nc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
A solution of ethyl 2-(6-chloropyridin-3-yloxy)-2-methylpropanoate (6.093 g, 25.0 mmol) in dry tetrahydrofuran (80 mL) is cooled to −20° C. (acetonitrile/dry ice bath) under nitrogen atmosphere. A solution of lithium aluminum hydride (1.0 M in THF, 35 ml) was added via drop-wise addition over 10 minutes. The mixture was stirred at −20° C. for 1 hour. The reaction was carefully quenched via addition of water (0.73 ml). The mixture was stirred for 10 minutes and then an aqueous solution of 5% sodium hydroxide (1.34 ml) was added with stirring for 10 minutes. Finally water (1.34 ml) was added and the mixture was stirred for 10 additional minutes. Magnesium sulfate was added and the material was filtered through a plug of celite, rinsing well with tetrahydrofuran. (Note that subsequent stirring of the aluminum salts in dichloromethane (50 ml) and filtering through celite provides additional product). The filtrates were stripped on the rotary evaporator, providing the desired product as a semi-viscous brown oil (4.843 g). (M+H)+=202 m/e.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][C:51]=1[F:52])[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:29]=[C:30]([O:31][C:32]2[CH:46]=[CH:45][C:35]3[N:36]=[C:37]([NH:39][C:40]([CH:42]4[CH2:44][CH2:43]4)=[O:41])[S:38][C:34]=3[C:33]=2[C:47]#[N:48])[CH:49]=[CH:50][C:51]=1[F:52])=[O:6]
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Reactant: N#Cc1c(Oc2ccc(F)c(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)c3cccc(C4(C#N)CC4)c3Cl)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (60 mg, 0.272 mmol) in tetrahydrofuran (1.5 mL) were added oxalyl chloride (29 μL, 0.340 mmol) and N,N-dimethylformamide (15 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (84 mg, 0.227 mmol) was added to the solution, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→480/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (92 mg, 59%) as a white powder.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17](S(C)(=O)=O)[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH2:44][NH2:45].C(N(CC)CC)C>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17]([NH:45][CH2:44][C:40]4[NH:39][CH:43]=[CH:42][N:41]=4)[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCc1ncc[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 60 °C

Procedure:
N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide (0.1 g, 0.2 mmol) is dissolved in DMF (10 mL) and (1H-imidazol-2-ylmethyl)amine dihydrochloride (0.053 g, 0.4 mmol) is added followed by triethylamine (0.167 mL, 1.2 mmol). The mixture is heated to about 60° C. for about 3 h. The reaction is judged to be complete by LCMS and the crude mixture is purified via reversed-phase HPLC. HPLC indicates 95% pure (254 nm) and the desired product is obtained as a white powder (54 mg, 50%): LC-MS m/z 528 (M+H)+, 1.45 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([C:22]2[N:23]=[CH:24][N:25]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:26]=2)(C(OC)=O)[C:10]([O:12]C2CCCC2)=[O:11])=[CH:4][CH:3]=1.Cl>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:22]2[N:23]=[CH:24][N:25]([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:26]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccc(N)nc1)(C(=O)OC1CCCC1)c1cn(C2CCCC2)cn1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(CC(C(=O)O)c2cn(C3CCCC3)cn2)cn1
Temperature: 180 °C
Reaction time: 48 h

Procedure:
Cyclopentyl methyl 2-(6-aminopyridin-3-ylmethyl)-2-(1-cyclopentyl-1H-imidazol-4-yl)malonate (0.30 g; 0.57 mmol) was dissolved in absolute ethanol (5 ml). At 0° C., ethanolic HCl was added. The reaction solution was left to stand at 10° C. for 48 h. It was then concentrated under reduced pressure and the residue was taken up in 2N HCl. It was heated in a microwave (3×4 min; 180° C.). This was followed by washing with EA, and the aqueous phase was neutralized with 1N NaOH and then freeze-dried. The residue was taken up in methanol and filtered twice through a cartridge (C18). Concentration of the filtrate under reduced pressure resulted in 0.10 g of 3-(6-aminopyridin-3-yl)-2-(1-cyclopentyl-1H-imidazol-4-yl)-propionic acid.
Reaction SMILES: CON(C)[C:4]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)=[O:5].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[F:10][C:9]([F:12])([F:11])[C:6]1([CH:4]=[O:5])[CH2:8][CH2:7]1
Reactant: CON(C)C(=O)C1(C(F)(F)F)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=CC1(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of compound A103-1 (164 mg, 0.832 mmol) in DCM (2 mL) was added diisobutylaluminum hydride (1 M in hexane, 1.0 mL, 1.0 mmol) at −78° C. under nitrogen atmosphere. After 0.5 h, the mixture was allowed to warm to 0° C. and stirred for 0.5 h. The reaction mixture was quenched with sat. KHSO4 aq. (10 mL) and extracted with DCM (2×4 mL). The combined organic layers were directly used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C@@H:7]([CH:30]([CH3:32])[CH3:31])[C:8]([N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)=[O:9].CCN(C(C)C)C(C)C>ClCCl>[CH2:26]([N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)[C:8](=[O:9])[C@@H:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:30]([CH3:31])[CH3:32])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)[C@@H](N)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)[C@@H](NS(C)(=O)=O)C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 0.75 g (6.5 mmol) of methanesulfonic acid chloride in 5 ml of dichloromethane is added dropwise, with stirring, to a solution of 1.8 g (5 mmol) of 2-(S)-amino-N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-3-methyl-butanoic acid amide and 1.4 ml (8 mmol) of Hunig base in 10 ml of dichloromethane. The reaction mixture is stirred at room temperature for a further 5 hours, diluted with 50 ml of dichloromethane and extracted with 20 ml of 4N hydrochloric acid. The dichloromethane phase is separated, washed in succession with water, 10 ml of bicarbonate solution and brine, dried and concentrated by evaporation to yield crude N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-2-(S)-methanesulfonylamino-3-methylbutanoic acid amide in the form of a yellowish oil of Rf value 0.56 [toluene/isopropanol/glacial acetic acid (170:30:2)]that can be used in the next step without being further purified.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])[NH:28][C:27]=1[C:37]([OH:39])=O.[NH2:40][CH2:41][C:42]1[C:43]([F:59])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:53]#[N:54])[C:45]([Cl:48])=[CH:46][CH:47]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:30]=[C:29]([C:31]([NH:33][CH:34]2[CH2:35][CH2:36]2)=[O:32])[NH:28][C:27]=1[C:37]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([O:49][C:50]2[CH:51]=[C:52]([C:53]#[N:54])[CH:55]=[C:56]([Cl:58])[CH:57]=2)[C:43]=1[F:59])=[O:39]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(NC1CC1)c1cc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C(=O)NC4CC4)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a solution of 3-chloro-5-[(cyclopropylamino)carbonyl]-1H-pyrrole-2-carboxylic acid (0.037 g, 0.161 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol) in DMF (2 mL). This solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% solution of Na2CO3, dried over MgSO4, filtered and evaporated. The residue was subjected to silica gel column chromatography (EtOAc/hexanes) to afford an impure solid. A second purification by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) afforded the title compound (0.0098 g, 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.10-8.26 (m, 1H), 7.82 (br. s., 1H), 7.39-7.62 (m, 5H), 7.33 (d, 1H), 6.35 (br. s., 1H), 4.42 (br. s., 2H), 2.62-2.79 (m, 1H), 0.61 (d, 2H), 0.45 (br. s., 2H). LCMS: m/z 521.2 (M+1).