Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][N:6]([C:10]([O-])=O)[CH2:5][C:4]=2[S:3][CH:2]=1.[N:13]([CH2:16][CH2:17][CH2:18][C:19]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23](C(=S)N)[N:22]=[C:21]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[S:20]1)=[N+]=[N-].BrC1C(=O)CCN(C(OC(C)(C)C)=O)C1.CCN(C(C)C)C(C)C>C(O)C>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:21]1[S:20][C:19]([CH2:18][CH2:17][CH2:16][NH2:13])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23]([C:2]2[S:3][C:4]3[CH2:5][N:6]([CH3:10])[CH2:7][CH2:8][C:9]=3[N:1]=2)[N:22]=1
Reactant: O=C([O-])N1CCc2ncsc2C1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Agent: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN)c3ccccc3)sc2C1
Reaction time: 8 h

Procedure:
Preparation of tert-butyl 24243-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate: To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.300 g, 0.717 mmol) in 10 mL of ethanol was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.239 g, 0.860 mmol) followed by DIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight at reflux, then treated with tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (100 mg) and stirred at reflux for a further 3 hours. The cooled mixture was partitioned between a saturated NaHCO3 solution (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a bright yellow foam, 0.313 g, 73%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][S:12][CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25].O.[CH:27]([OH:30])(C)C>CN(C)C=O>[CH:27]([C:10]1[O:6][C:7]([CH2:11][S:12][CH2:13][CH2:14][N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])=[CH:8][CH:9]=1)=[O:30]
Reactant: CC(C)O
Reactant: O=C1c2ccccc2C(=O)N1CCSCc1ccco1
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc(CSCCN2C(=O)c3ccccc3C2=O)o1
Reaction time: 5 h

Procedure:
A solution of phosphoryl chloride (21.4 g) in dry dimethylformamide (40 ml), cooled in ice, was added portionwise to a solution of N-[2-[(2-furanylmethyl)thio]ethyl]-1H-isoindole-1,3(2H)-dione (21.4 g) in dry dimethylformamide (70 ml). After 5 hours at room temperature, the solution was poured into iced water (1.7 l). Isopropyl alcohol (150 ml) was added and after 18 hours the solid which separated was filtered and crystallised from ethyl acetate-ether to give the title compound (22.3 g) m.p. 76°-77°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[O:21][C:22](=[O:24])[CH3:23])=[O:6]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C@@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=2)[CH2:11][CH2:10][C@H:9]1[O:21][C:22](=[O:24])[CH3:23])=[O:6]
Reactant: CC(=O)O[C@@H]1CCc2ccc([N+](=O)[O-])cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1CCc2ccc(N)cc2[C@H]1NC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 107.6 %

Procedure:
A solution of 114 (1.9 g) in DMF (100 mL) was treated with SnCl2-2H2O (4 g). After 4 h, additional SnCl22H2O (1 g) was added three times over three days. The solvent was then evaporated, the residue suspended in H2O-EtOAc, the mixture neutralized with 5N NaOH, and the mixture filtered. The. organics were separated, washed with brine, dried, and the solvent evaporated to give a brown foam (1.9 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][C@@H:12](OS(C)(=O)=O)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[N-:26]=[N+:27]=[N-:28].[Na+].CCN(CC)CC.N#N>O.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH2:11][C@H:12]([N:26]=[N+:27]=[N-:28])[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)Cc1c2n(c3c(F)cccc13)C[C@@H](OS(C)(=O)=O)CC2
Reactant: [N-]=[N+]=[N-]
Agent: N#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1c2n(c3c(F)cccc13)C[C@H](N=[N+]=[N-])CC2
Temperature: 68 °C
Reaction time: 18 h

Procedure:
A reaction mixture of the mesylate of Step 7 (1.67 kg, 4.32 mol), DMF (8.35 L), NaN3 (0.457 kg, 7.03 mol) and Et3N (65 ml, 0.466 mol) under a constant stream of N2 was maintained between 66-70° C. After 18 h, the mixture was cooled to room temperature and H2O (8.45 L) was slowly added with vigorous stirring. The reaction mixture was filtered; the crystals were washed with 1:1 DMF:H2O (16 L), 3:7 DMF:H2O (8.5 L), and water (14 L). The dark brown solid was dried under vacuum and nitrogen.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].C(O)(=O)C.[CH:13](=O)[C:14]([CH3:16])=[O:15].C([O-])(O)=O.[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][N:8]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: NNc1ccccn1
Reactant: CC(=O)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C=NNc1ccccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.9 %

Procedure:
To a solution of 2-pyridylhydrazine (10.0 g, 91.6 mmol) in water (30 mL) was added acetic acid (8.7 mL). This mixture was then added to a solution of pyruvaldehyde (16.5 g, 14.9 mL, 91.6 mmol) in water (400 mL). The mixture was stirred at room temperature for 3 days. The mixture was neutralized with NaHCO3 (solid) whereupon a yellow precipitate forms. The solid was isolated by filtration and then washed with water (30 mL). The solids were dried under high vacuum to afford 2-oxopropanal pyridin-2-ylhydrazone as a yellow solid (6.12 g, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH2:14].C([C:22]1[NH:23][CH:24]=CN=1)(C1NC=CN=1)=O.CN.C1C[O:32]CC1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:24]([NH:23][CH3:22])=[O:32]
Reactant: NCc1cc(-c2cc[nH]n2)ccc1Cl
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: C1CCOC1
Agent: CN
Solvent: ClCCl
Product: CNC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-5-(1H-pyrazol-3-yl)benzenemethanamine (i.e. the product of Step C of Synthesis Example 4) (2.4 g, 11.6 mmol) in THF (12 mL) and dichloromethane (12 mL) at 10° C. was added carbonyl diimidazole (2.8 g, 17.3 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then cooled to 0° C. A solution of methylamine in THF (2 M, 12.0 mL, 24 mmol) was added, and the reaction mixture was stirred at ambient temperature for 15 h. The reaction mixture was then diluted with dichloromethane, washed with water and brine, concentrated and purified by preparative TLC (2% methanol in chloroform as eluant) to provide the title product as a solid (1.0 g).
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[P:4]([OH:8])([O-:7])([O-:6])=[O:5].[Ca+2].P(OP(O)(O)=O)(O)(O)=[O:11]>>[OH2:5].[OH2:11].[P:4]([O-:8])([O-:7])([O-:6])=[O:5].[Ca+2:2].[Ca+2:2]
Reactant: O=P(O)(O)OP(=O)(O)O
Reactant: O=P([O-])([O-])O
Agent: [Ca+2]
Agent: [OH-]
Product: O
Product: O=P([O-])([O-])[O-]

Procedure:
A quantity of dicalcium phosphate dihydrate was prepared as in Examples 1 and 2 except that the slaked lime slurry was added to the monocalcium phosphate solution until the pH reached about 5.6 and then pyrophosphoric acid was added until the pH was reduced to about 5.3; no further slaked lime slurry was added.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.N1C=CC=CC=1.[Cl:19][C:20]1[S:21][C:22]([C:26](Cl)=[O:27])=[C:23]([CH3:25])[N:24]=1.O>O1CCCC1>[CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[C:6]([NH:11][C:26]([C:22]3[S:21][C:20]([Cl:19])=[N:24][C:23]=3[CH3:25])=[O:27])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2c(N)cccc21
Reactant: Cc1nc(Cl)sc1C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Cl)sc1C(=O)Nc1cccc2c1CCC2(C)C
Yield: 92.8 %

Procedure:
To a solution of 0.82 g (5.07 mmol) of 1,1-dimethyl-4-aminoindan and 0.48 g (6.08 mmol) of pyridine in 10 ml of tetrahydrofuran was added dropwise with stirring below 5° C. under ice cooling, a solution of 0.99 g (5.07 mmol) of 2-chloro-4-methylthiazole-5-carboxylic acid chloride in 3 ml of tetrahydrofuran, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% hydrochloric acid and then water and was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain crystals, which was washed with n-hexane and dried to obtain 1.51 g of N-(1,1-dimethyl-4-indanyl)-2-chloro-4-methylthiazole-5-carboxamide (yeild 93%).
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][O:17][CH2:18][C:19]#[C:20][C:21]([OH:23])=O.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][C:29]([C:35]#[N:36])=[C:28]2[NH:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Br:44])[CH:39]=1>O1CCCC1.N1C=CC=CC=1>[Br:44][C:40]1[CH:39]=[C:38]([NH:37][C:28]2[C:27]3[C:32](=[CH:33][CH:34]=[C:25]([NH:24][C:21](=[O:23])[C:20]#[C:19][CH2:18][O:17][CH3:16])[CH:26]=3)[N:31]=[CH:30][C:29]=2[C:35]#[N:36])[CH:43]=[CH:42][CH:41]=1
Reactant: COCC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: COCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
Isobutyl chloroformate(0.410 g, 3.0 mmol) and N-methylmorpholine(0.910 g, 9.0 mmol) were added to an ice cold solution of 0.680 g (6.0 mmol) of 4-methoxy-2-butynoic acid in 20 mL of tetrahydrofuran under N2. After stirring for 30 min, a solution of 0.500 g (01.47 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added and the mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice water, and then poured into saturated sodium bicarbonate and brine. The product was collected, washed with ethyl acetate, and dried in vacuo to give 0.200 g (35%) of yellow solid; ESMS m/z 435.1 (M+H+); mp 198-202° C.(dec).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34]O)=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.[CH3:38][S:39](Cl)(=O)=O.C[S-].[Na+]>C(N(CC)CC)C>[CH3:38][S:39][CH2:34][CH2:33][C:29]1[N:28]([CH2:27][CH2:26][CH2:25][CH2:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:14]3[N:15]=[C:11](/[CH:10]=[CH:9]/[C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:37])([F:36])[F:1])=[CH:4][CH:5]=4)[O:12][CH:13]=3)=[CH:19][CH:20]=2)[CH:32]=[CH:31][N:30]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: C[S-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CSCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1

Procedure:
Using 2-[1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazol-2-yl]-1-ethanol (1.00 g), triethylamine (0.544 ml), methanesulfonyl chloride (0.182 ml) and sodium thiomethoxide (288 mg), the same reaction as Reference Example 6-(iii) was carried out to yield the titled compound (761 mg) as a colorless amorphous form.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.N.[F:15][C:16](I)([F:18])[F:17]>C(OCC)(=O)C>[CH3:12][C:9]1([CH3:11])[CH:8]=[CH:7][C:6]2[CH:13]=[C:2]([S:1][C:16]([F:18])([F:17])[F:15])[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: CC1(C)C=Cc2cc(S)ccc2O1
Reactant: FC(F)(F)I
Agent: N
Solvent: CCOC(C)=O
Product: CC1(C)C=Cc2cc(SC(F)(F)F)ccc2O1
Reaction time: 2 h
Yield: 59.6 %

Procedure:
1.45 g of 6-mercapto-2,2-dimethyl-2H-1-benzopyran (prepared as described in Preparation 6) was suspended in 30 ml of liquid ammonia, and 8.23 g of trifluoromethyl iodide were then added to the suspension at -60° C. in an atmosphere of nitrogen. The resulting mixture was then irradiated at -65° C. for 2 hours and then at 25° C. for 2 hours, using a low pressure mercury lamp. At the end of this time, the reaction mixture was diluted with ethyl acetate and washed with dilute aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic layer was then dried over anhydrous sodium sulfate and concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 20:2:1 by volume mixture of cyclohexane, chloroform and ethyl acetate as the eluent, to afford 1.17 g of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1)[CH3:3].C[O:19]C1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:27]2)=CC=1.[C:40](=[O:43])([O-:42])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:9]([OH:19])(=[O:13])/[CH:8]=[CH:14]/[C:40]([OH:42])=[O:43].[CH3:1][N:2]([CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[S:27])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1)[CH3:3].[CH3:1][N:2]([CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[S:27])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1)[CH3:3]
Reactant: CN(C)CC1CN(C)C(=O)c2cccnc2O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(C)CC1CN(C)C(=S)c2cccnc2O1
Product: O=C(O)/C=C/C(=O)O

Procedure:
To a solution of 4.8 g of 2-[(dimethylamino)methyl]2,3-dihydro-4-methylpyrido[3,2-f][1,4]oxazepin-5(4H)-one in 50 ml of toluene was added 4.9 g of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide. The reaction mixture was kept at reflux for two hours. Concentrated potassium carbonate solution was added which caused separation to give a three-layer system: a toluene layer, an aqueous layer and a gummy layer. Only the toluene and aqueous layer contained the desired free base of the title compound. The layers were separated and the gummy layer was discarded. The aqueous layer was extracted three times with methylene chloride. The methylene chloride extracts after washing with saturated sodium chloride solution were combined with the toluene layer. This organic solution was dried over anhydrous sodium sulfate and evaporated to give 5.25 g of oil. The oil, the free base of the title compound, was dissolved in methanol to which solution was added 2.45 g of fumaric acid. The mixture was heated with stirring and isopropyl alcohol was added to the point of cloudiness and the mixture was stirred overnight. Yellow powder was obtained, 2.85 g, which was recrystallized from methanol, m.p. 178°-179° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](CCl)[CH:10]=1.[NH:17]1[CH2:19][CH2:18]1>CO>[CH:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:1][N:17]2[CH2:19][CH2:18]2)=[CH:13][CH:14]=1)=[CH2:7]
Reactant: O=C([O-])[O-]
Reactant: C1CN1
Reactant: C=Cc1cccc(CCl)c1
Agent: [K+]
Solvent: CO
Product: C=Cc1ccc(CN2CC2)cc1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Anhydrous methanol (200 ml.), anhydrous potassium carbonate (10.0 g.) and ar-vinylbenzyl chloride (approximately 95% para isomer; 0.05 mol.) were charged to a predried reaction vessel equipped with a stirring means and a drying tube. Aziridine (27.0 ml.; 0.5 mol.) was added dropwise to the stirred reaction mixture. Subsequently, the stirred mixture was maintained at room temperature for 24 hours. The work up comprised adding a diatomaceous earth filtering aid to the reaction mixture, filtering out the solids, removing the solvent from the filtrate under reduced pressure and recovering as the pot residue 7.7 g. of crude product as a yellow/orange liquid. The product was purified by distillative techniques under reduced pressure. The product was thus obtained as a water-white liquid boiling at 50°-52°C. at 0.15-0.20 mm. of Hg pressure. Vapor phase chromatography (VPC) of this fraction showed it to contain 85.7% of the desired product. The compound was obtained from the VPC fractionation and its structure confirmed by infrared (IR) analysis, nuclear magnetic resonance (NMR) and elemental analysis.
Reaction SMILES: [F:1]C(F)(F)C(O)=O.[CH3:8][S:9]([N:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1)(=[O:11])=[O:10].[NH2:19][C:20]1[C:25]([C:26]([C:28]2[C:36]3[O:35]C=C[C:32]=3[CH:31]=[C:30]([F:37])[CH:29]=2)=[O:27])=[CH:24][N:23]=[C:22](Cl)[N:21]=1.C(N(C(C)C)CC)(C)C>C(O)C>[NH2:19][C:20]1[C:25]([C:26]([C:28]2[C:36]([OH:35])=[CH:32][CH:31]=[C:30]([F:37])[C:29]=2[F:1])=[O:27])=[CH:24][N:23]=[C:22]([NH:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:17][CH2:16]2)[N:21]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1nc(Cl)ncc1C(=O)c1cc(F)cc2ccoc12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3c(O)ccc(F)c3F)c(N)n2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
trifluoroacetic acid salt (0.68 g, 2.3 mmol, Example 162), (4-amino-2-chloro-pyrimidin-5-yl)-(5-fluoro-benzofuran-7-yl)-methanone (0.5 g, 1.7 mmol, Step F), and diisopropylethylamine (1 mL, Aldrich) were combined with ethanol (20 mL) and refluxed for 12 hours. The reaction was cooled and diluted with ice water (˜60 mL). After 2 hours, the suspension was filtered and dried at 50° C. and high vacuum to give 0.35 g (57%) of [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-hydroxy-phenyl)-methanone as a white solid. HRMS, observed: 434.1297; Calcd for (M+H)+: 434.1293. CDK4 IC50=0.030 μM; CDK1 IC50=0.058 μM; CDK2 IC50=0.002 μM; HCT 116 IC90=3.300 μM.
Reaction SMILES: [F:1][C:2]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([F:7])[CH2:3][CH2:4][CH2:5]I.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:16]([CH2:5][CH2:4][CH2:3][C:2]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([F:7])[F:1])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOP(=O)(OCC)C(F)(F)CCCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)(F)CCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of diethyl 1,1-difluoro-4-iodobutylphosphonate (1 eq) in DMF (0.27 M) was added sodium azide (3 eq). The reaction mixture was stirred at room temperature for 90 minutes. The mixture was diluted with ethyl acetate and washed with water. The aqueous phase was back extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-50% EtOAc/Hex to give the product as a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])=[CH:10][C:5]2=[CH:4][C:3]=1[CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].[H-].[Na+].I[CH2:41][CH3:42].O>CN(C)C=O.C(OCC)(=O)C>[CH2:41]([N:8]1[C:6]2=[N:7][C:2]([CH3:1])=[C:3]([CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH:4]=[C:5]2[CH:10]=[C:9]1[C:11](=[O:28])[NH:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[C:14]([F:15])([F:16])[F:17])[CH3:42]
Reactant: Cc1nc2[nH]c(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2cc1CNC(=O)OC(C)(C)C
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(CNC(=O)OC(C)(C)C)c(C)nc21
Reaction time: 2 h

Procedure:
tert-Butyl {[6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}carbamate (410 g, 0.77 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (7.9 ml). Sodium hydride (60%; 37 mg, 0.92 mmol) was added and the mixture was stirred with ice cooling for 2 h. Iodoethane (145 g, 0.92 mmol) was added and the reaction mixture was thawed with stirring over 18 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (3/1) and gave 300 g (68% of theory) of tert-butyl a {[1-ethyl-6-methyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}carbamate. HPLC-MS: log P=4.67; mass (m/z): 559.2 (M+H)+; 1HNMR (D6-DMSO): δ 1.21 (t, 2H), 1.40 (s, 9H), 3.32 (s, 3H), 4.21 (m, 2H), 4.57 (q, 2H), 6.28-6.32 (m, 1H), 7.29 (s, 1H), 7.37 (m, 1H), 7.70-7.87 (m, 2H), 8.06 (d, 1H), 8.20 (s, 1H), 9.67 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([NH:12][OH:13])[CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N:18]=[C:19]=[S:20])(C)C.CO>C1COCC1>[OH:13][N:12]([C@H:10]1[CH2:11][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9]1)[C:19]([NH2:18])=[S:20]
Reactant: C[Si](C)(C)N=C=S
Reactant: ON[C@H]1C[C@@H](c2ccc(F)cc2)C1
Solvent: CO
Solvent: C1CCOC1
Product: NC(=S)N(O)[C@H]1C[C@@H](c2ccc(F)cc2)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
To a stirred solution of cis-3-(4-fluorophenyl)cyclobutylhydroxylamine (1.81 g, 10 mmol) in THF (30 ml) was added trimethylsilylisothiocyanate (1.58 g, 12 mmol) at room temperature. After stirring for 3 hours at 70° C., MeOH (20 ml) was added. Volatiles were removed in vacuo, and the residue recrystallized from ethyl acetate/n-hexane/EtOH to afford 1.34 g (55.8% yield) of the title compound, m.p. 156-158° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:20])([CH3:19])[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)[C:4](=[O:21])[N:3]1[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:24]=1.[OH-].[K+].Cl>CO.O>[CH3:1][C:2]1([CH3:36])[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:19])([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[C:4](=[O:21])[N:3]1[CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:24]=1
Reactant: COC(=O)C(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccnc4)c3)C(C)(C)C2=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(N2C(=O)N(Cc3ccnc(Nc4cccnc4)c3)C(C)(C)C2=O)cc1
Yield: 68.1 %

Procedure:
To a solution of 0.34 g of methyl 2-[4-(4,4-dimethyl-2,5-dioxo-3-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidin-1-yl)phenyl]-2-methylpropanoate obtained in stage e) below in 20 mL of methanol, at room temperature, are added 7 mL of 1N potassium hydroxide. The reaction medium is heated at reflux for two hours and concentrated under reduced pressure. The residue obtained is taken up in 10 mL of water and then acidified with 2N HCl to pH=5. The white solid formed is filtered off and then dried to give 0.225 g of 2-[4-(4,4-dimethyl-2,5-dioxo-3-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidin-1-yl)phenyl]-2-methylpropanoic acid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.N[C@H:14](C(O)=O)CCC(=O)O>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:14])[CH3:5]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Tyr 0.93 (1); Glu 1.04 (1); Arg 0.97 (1)