Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=O)[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:26][O:27][NH2:28]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=[N:28][O:27][CH3:26])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CON
Reactant: O=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of the 2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 43, 159.9 mg, 0.41 mmol) and methoxyamine hydrochloride (52.3 mg, 0.62 mmol) in methanol (1.2 mL) and pyridine (1.2 mL) was heated under reflux for 3.5 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (75 mL), washed with a 1N aqueous hydrochloric acid solution (75 mL) and a saturated aqueous sodium chloride solution (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-methoxyimino-cyclopentyl)-N-thiazol-2-yl-propionamide (168.2 mg, 98%) as a white foam: mp 69–72° C. (foam to gel); (ES)+-HRMS m/e calcd for C18H19Cl2N3O2S (M+H)+ 412.0648 found 412.0652.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>O1CCCC1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reactant: O=C=Nc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1Cl)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 35 °C

Procedure:
A mixture of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (800 mg, 3.34 mM) and triethylamine (0.6 mL) in dry tetrahydrofuran (THF, 5 ml) was stirred for half an hour under nitrogen atmosphere at room temperature (35° C.). To the stirred reaction mixture, 2-chiorophenyl isocyanate (604 mg/ml, 5.01 mM) was added at once and then the reaction mixture was further stirred for 62 hours under N2 atmosphere at RT. The reaction mixture was concentrated under vacuum and then was added distilled water (15 mL) followed by the extraction with ether (3×15 mL). The ether layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product, which was finally chromatographed using chloroform-hexane (1:9) to give 8e. Yield: 1.02 g, 77.66%.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:29]2[CH2:28][CH2:27][C:26]3([N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][NH:24][C:25]3=[O:32])[CH2:31][CH2:30]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=C(c1ccc(F)cc1[N+](=O)[O-])N1CC1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Solvent: c1ccccc1
Solvent: CO
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 15 parts of 1-(4-fluoro-2-nitrobenzoyl)-aziridine, 12 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 8.8 parts of methanol and 56 parts of benzene is stirred first for 1.50 hours at reflux and further overnight at room temperature. The reaction mixture is evaporated. The residue is dissolved in trichloromethane and the solution is washed with water. Then there are added 8 parts of methanol and silica gel and the whole is stirred for 10 minutes. The silica gel is filtered off and the filtrate is evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and crystallized from 4-methyl-2-pentanone. It is filtered off and dried, yielding 13 parts of 4-fluoro-2-nitro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5]dec-8-yl)ethyl]benzamide; mp. 160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:10][CH2:11][S:12][CH3:13])=[N:8][C:4]=2[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:38].ClCCl.C(O)C.ClCl>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C@@H:9]([NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28]4)=[O:23])=[C:18]([CH3:29])[CH:17]=3)[CH2:10][CH2:11][S:12]([CH3:13])=[O:38])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=O)N[C@@H](CCS(C)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 57 %

Procedure:
Prepared analogously to Example 85 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide and 3-chloroperoxybenzoic acid in dichloromethane/glacial acetic acid. Yield: 57%; Rf value: 0.15 (silica gel; dichloromethane/ethanol=9:1); C24H27ClN4O3S (487.02); mass spectrum: (M+H)+=487/489 (chlorine isotope).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[O:7]=[C:8]([CH3:15])[CH2:9]CCC(O)=O>>[CH3:6][O:5][C:1]([CH2:2][CH2:3][CH2:9][C:8](=[O:7])[CH3:15])=[O:4]
Reactant: C=CC(=O)OC
Reactant: CC(=O)CCCC(=O)O
Product: COC(=O)CCCC(C)=O

Procedure:
Subsequently, the tubes are cooled rapidly, following which the contents of the tubes is analyzed gaschromatographically, and the conversion of the methyl acrylate, as well as the efficiency in the methyl ester of 4-oxopentane-1-carboxylic acid product, referred to the converted methyl acrylate, is determined.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]([C@H:12]([CH3:29])[C@:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)=[N+:10]=[N-:11]>C1(C)C=CC=CC=1>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C@:13]([OH:20])([C@H:12]([N:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]=[N:10]1)[CH3:29])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: C#Cc1ccccc1
Reactant: C[C@@H](N=[N+]=[N-])[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: C[C@@H](n1cc(-c2ccccc2)nn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 130 °C

Procedure:
A mixture of toluene (80 ml), phenylacetylene (6.7 ml) and (2R,3R)-3-azido-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (2 g) was heated for 8 hours at 130° C. After cooling, toluene was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel 50 g, eluent: ethyl acetate) to give Compound 58 (0.85 g) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15](OS(C)(=O)=O)[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11].[NH3:22]>O.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]([CH2:14][CH:15]([NH2:22])[CH3:16])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: N
Reactant: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Solvent: CO
Solvent: O
Product: Cc1cccc(C)c1N(CC(C)N)S(C)(=O)=O

Procedure:
A mixture of 1.0 g (3 mmoles) of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-methanesulfonyloxy-propane, 10 ml of methanol and 5 ml of concentrated aqueous ammonia is heated at 110° C. for 6 hours in a steel bomb. The mixture is cooled, diluted with 30 ml of water, and methanol is evaporated under reduced pressure. The residue is extracted thrice with 20 ml of chloroform, each. The chloroform solutions are combined, washed thrice with 20 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is triturated with 3 ml of diisopropyl ether. 0.55 g of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-amino-propane are obtained; m.p.: 106°-109° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[N:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.C(O)C.[OH-].[Na+]>ClCCl>[C:2]([C:3](=[O:5])[CH:4]=[CH:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(=O)C(C)(C)C
Reactant: O=Cc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)C=Cc1ccncc1
Reaction time: 12 h

Procedure:
A mixture of 3,3-dimethyl-2-butanone (2.5 ml, 20.0 mmol), 4-pyridinecarboxaldehyde (2.15 ml, 22.3 mmol), ethanol (7.6 ml), and 4.5% aqueous sodium hydroxide (4.6 ml) was kept at room temperature for 12 h. It was diluted with dichloromethane, washed with aqueous hydrochloric acid and water, dried and evaporated. Subsequent column chromatography (hexane-ethyl acetate=3:1) provided the title compound. MS (m/z): 190.4 (M+H)+ ; C12H15NO requir.189.3.
Reaction SMILES: C[C@@:2]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1CCCBr.[N-]=[N+]=[N-].[Na+]>C1COCC1.O>[C:2]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@]1(S(N)(=O)=O)C=CC=CC1CCCBr
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccccc1
Temperature: 22 °C
Reaction time: 96 h
Yield: 94 %

Procedure:
To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-3-bromopropylbenzene-sulfonamide (1.188 g, 2.295 mmol) in THF/H2O (20/4, 24 mL) was added sodium azide (1.49 g, 22.9 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 4 days. The mixture was extracted with ether (3×60 mL). The combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 0.941 g of 4-chloro-N-(2,5-dichlorophenyl)-N-[(R)-1-methyl-3-azidopropyl]]benzenesulfonamide as a colorless oil in 94% yield.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>ClCCl>[C:18]([O:1][CH:2]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:20])[CH3:19]
Reactant: O=C(O)CCCCCCC(O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(CCCCCCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8-Hydroxy-8-phenyloctanoic acid (25 g) was dissolved in dichloromethane (100 ml), and acetic anhydride (12 ml), pyridine (25 ml) and dimethylaminopyridine (0.1 g) were added to the solution, followed by stirring at room temperature for 3 hours. The reaction solution was washed with water and then twice with 2N hydrochloric acid, and the organic layer was washed with water, dried and concentrated under reduced pressure to give 8-acetoxy-8-phenyloctanoic acid (21 g). Its typical physical properties and nuclear magnetic resonance spectrum are shown in Table 13.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([CH2:10]O)=[C:8]([CH3:12])[N:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:5]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:10][C:9]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:7][C:8]=1[CH3:12]
Reactant: O=S(Cl)Cl
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CO
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl

Procedure:
In analogy to the procedure described in example 113H], [4-methoxymethyl-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a light red oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:43])[CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:38](=[O:43])[CH2:39][CH2:40][CH2:41][CH3:42])=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(=O)Cl
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
80 mg (0.19 mmol)) of Compound 5050 was dissolved in 5 mL of dry methylene chloride. To this solution at 0° C. was added triethylamine (0.19 mmol, 25 μL) followed by pentanoyl chloride (0.19 mmol, 22 μL). Reaction mixture was stirred at 0° C. for 15 minutes. Reaction mixture was quenched using water and evaporated. It was redissolved in 5 mL of DMF and purified using reverse phase HPLC. MS: 507.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21](=[O:22])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[O:9][C:10]([F:11])([F:12])[F:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccc(Br)cc1OC(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 76 %

Procedure:
4-Bromo-2-(trifluoromethoxy)aniline (1.0 g, 3.9 mmol) was dissolved in dry toluene (25 mL), sodium carbonate (0.621 g, 5.86 mmol) and benzyl chloroformate (0.669 mL, 4.69 mmol) was added and the mixture stirred under nitrogen at room temperature for 22 hours. The reaction was then heated to 80° C. and stirred at this. temperature for 17 hours and then heated further to reflux and stirred for 22 hours. Water (100 mL) was added to the coiled mixture, the aqueous phase separated and washed with ethyl acetate (2×100 mL). The combined organic extracts were washed with 0.5 M aq. citric acid (70 mL), water (70 mL), brine (70 mL), dried (MgSO4), filtered and concentrated in vacuo to give a pink solid. The crude material was purified by silica gel chromatography (40 g Si cartridge, 0-20% EtOAc in 40-60° C. petroleum benzine) to give the title compound (I46) (1.153 g, 76% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.7 Hz, 1H), 7.44-7.36 (m, 7H), 6.95 (s, 1H), 5.22 (s, 2H). LCMS Method C: rt 6.67 min; m/z 389.9 [M−H]−.
Reaction SMILES: O[CH:2]([CH3:28])[CH2:3][NH:4][C:5](=[O:27])[CH2:6][N:7]1[C:25](=[O:26])[N:10]2[CH:11]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:13]=[CH:14][C:9]2=[N:8]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>C1COCC1>[CH3:28][C:2]1[O:27][C:5]([CH2:6][N:7]2[C:25](=[O:26])[N:10]3[CH:11]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=4)[CH:13]=[CH:14][C:9]3=[N:8]2)=[N:4][CH:3]=1
Reactant: CC(O)CNC(=O)Cn1nc2ccc(-c3ccc(C(F)(F)F)cc3)cn2c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(Cn2nc3ccc(-c4ccc(C(F)(F)F)cc4)cn3c2=O)o1
Reaction time: 1 h
Yield: 101.2 %

Procedure:
N-(2-Hydroxypropyl)-2-(3-oxo-6-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)acetamide (30.0 mg, 0.0761 mmol) was treated with Dess-Martin periodinane (64.6 mg, 0.1522 mmol, 2.0 equiv.) in THF (2 mL) at room temperature in a 50 mL round bottomed flask. After stirring for 1 h, water (30 mL) was added and the whole was extracted with EtOAc (30 mL×3). Combined organic layers were washed with sat. Na2S2O3 aq. solution (30 mL), sat. NaHCO3 aq. solution (30 mL) and brine (30 mL) successively. The organic layer was dried over Na2SO4. The solvent was removed under a reduced pressure to give the desired product as colorless crystals (2-(3-oxo-6-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-N-(2-oxopropyl)acetamide, 30.3 mg, 0.077 mmol, >99%). LCMS (EI: 70 eV) 415 (M++Na), 393 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:23][C:22]3[CH:25]=[CH:26][C:19]([CH2:18][OH:17])=[CH:20][CH:21]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(Cn2ccc3ncnc(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) was dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (304 mg) was added, and the mixture was stirred at room temperature for 30 min. 4-Hydroxymethylbenzyl chloride (377 mg) was added, and the mixture was stirred at room temperature for 16 hrs. After diluting with water (30 mL), the mixture was extracted with ethyl acetate/tetrahydrofuran (3:1, 80 mL×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (383 mg) as a powder.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[CH:19])[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br[C:22]1[S:26][C:25]([C:27]([NH:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:28])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Pd](Cl)Cl.C(#N)C>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:20])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:22]3[S:26][C:25]([C:27]([NH:29][C@H:30]([C:37]([O:39][CH3:40])=[O:38])[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:28])=[CH:24][CH:23]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C#Cc1cnc2nc(NC(=O)C(C)(C)C)nc(O)c2c1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(Br)s1)C(=O)OC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)s1)C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of 1.70 g. (6.32 mmol.) of 2-pivaloylamino-4-hydroxy-6-ethynylpyrido[2,3-d]pyrimidine, 2.30 g. (6.32 mmol.) of dimethyl N-(5-bromothien-2-ylcarbonyl)-L-glutamate, 44 mg. of palladium chloride, 130 mg. of triphenylphosphine, 25 mg. of cuprous iodide, and 1.13 mL. of triethylamine in 30 mL. of acetonitrile was heated at reflux for 3 hours and then cooled to ambient temperature. The solvent was removed under reduced pressure and the residue column chromatographed (Waters 500) eluting with 1:19 methanol:methylene chloride to yield dimethyl N-[5-(2-{2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6yl}ethynyl)thien-2ylcarbonyl]-L-glutamate, m.p. 228°-230° C. Anal. Calc. for C26H27N5O7S: C, 56.41; H, 4.92; N, 12.65; S, 5.79. Found: C, 56.64; H, 4.77; N, 12.88; S, 5.58.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9].Cl[C:36]([O:38][CH3:39])=[O:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:22][CH2:23][N:24]([C:36]([O:38][CH3:39])=[O:37])[CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[O:17])[C@H:13]([C:27](=[O:28])[NH:29][C:30]2([C:33]#[N:34])[CH2:31][CH2:32]2)[CH2:12]1)(=[O:10])=[O:9]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Reactant: COC(=O)Cl
Product: COC(=O)N1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperazin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (35.4 mg, 70 μmol) in methylenehloride (0.7 mL) was added under stirring ethyldiisopropyl amine (18.3 μL, 105 μmol) and methyl chloroformate (6.15 μL, 77.0 μmol). The reaction was stirred at room temperature over night. The reaction was purified by column chromatography on silica gel using a gradient from methylenechloride to a mixture of methylenechloride/methanol (v:v 19:1) as solvent to yield the title compound as a white solid (32 mg, 80%). MS ISP (m/e): 564.3/566.1 (100/40) [(M+H)]+.
Reaction SMILES: C1(N(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(C4C=CC=CC=4)CCCC3)N=2)=O)CC1.[Si]([O:44][CH2:45][CH2:46][N:47]([CH2:77][C:78]([CH3:81])([CH3:80])[CH3:79])[C:48]([C:50]1[C:55]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]2([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:70][CH2:69][CH2:68][CH2:67]2)[N:51]=1)=[O:49])(C(C)(C)C)(C)C>>[CH3:79][C:78]([CH3:81])([CH3:80])[CH2:77][N:47]([CH2:46][CH2:45][OH:44])[C:48]([C:50]1[C:55]([O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[C:54]([OH:64])[N:53]=[C:52]([CH2:65][C:66]2([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[CH2:70][CH2:69][CH2:68][CH2:67]2)[N:51]=1)=[O:49]
Reactant: CC(C)(C)CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Product: CC(C)(C)CN(CCO)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 94.8 %

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (285) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(2,2-dimethyl-propyl)-amide (300) (350 mg, 0.55 mmol). The product was obtained as a light yellow sticky solid (270 mg, 94.03%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:14]3[C:9]([C:10]([NH2:15])=[N:11][CH:12]=[N:13]3)=[C:8]([C:16]3[CH:17]=[CH:18][C:19]4[C:23]([CH:24]=3)=[N:22][N:21]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=4)[CH:7]=2)[CH2:2]1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:25]([N:21]1[CH:20]=[C:19]2[C:23]([CH:24]=[C:16]([C:8]3[CH:7]=[C:6]([CH2:5][CH:3]4[CH2:4][N:1]([C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])[CH2:2]4)[N:14]4[C:9]=3[C:10]([NH2:15])=[N:11][CH:12]=[N:13]4)[CH:17]=[CH:18]2)=[N:22]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ncnn2c(CC3CNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 21.2 %

Procedure:
A mixture of 7-(azetidin-3-ylmethyl)-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.20 mmol), N,N-dimethylglycine (24 mg, 0.23 mmol), EDCl (41 mg, 0.22 mmol), HOBt (29 mg, 0.22 mmol), and N,N-diisopropylethylamine (102 μL, 0.59 mmol) in DMF (1.8 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 30% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 21 mg (22%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.90 (s, 1 H), 7.79 (d, 1 H), 7.58 (s, 1 H), 7.26-7.39 (m, 5 H), 7.13 (dd, 1 H), 6.62 (s, 1 H), 5.65 (s, 2 H), 4.26 (t, 1 H), 4.00 (t, 1 H), 3.90 (dd, 1 H), 3.66 (dd, 1 H), 3.31-3.21 (m, 4 H), 2.99-3.11 (m, 1 H), 2.30 (s, 6 H); ES-MS m/z 495.47 [M+H]+, HPLC RT (min) 2.03.