Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]([OH:16])=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[C:19]([Cl:24])(=O)[C:20](Cl)=O>ClCCl.CN(C=O)C>[Cl:24][C:19]1[CH:20]=[CH:3][CH:4]=[CH:5][C:6]=1[NH:7][C:14]([C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([Br:1])[CH:18]=[CH:17][C:5]=3[C:6]=2[N:7]=1)=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1Cl)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 3 h

Procedure:
To a suspension of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (396 mg) in dry dichloromethane (20 mL) was added oxalyl chloride (180 μL) and DMF (1 drop). After 3 hours the solvent was removed in vacuo and to the residue was added acetonitrile (20 mL), 2-chloroaniline (140 μL) and sodium bicarbonate (111 mg). After 3 hours, water was added to the reaction mixture and the resulting precipitate was collected by filtration to yield 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-chloro-phenyl)-amide (467 mg).
Reaction SMILES: [CH2:1]([C@@H:5]([C:11]([OH:13])=[O:12])[C@H:6]([OH:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH3:4].[C:14]1(C)[CH:19]=CC(S(O)(=O)=O)=C[CH:15]=1>COC(OC)(C)C.ClCCl>[CH3:15][C:14]1([CH3:19])[O:8][C:7](=[O:9])[CH:6]([CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:11]([OH:13])=[O:12])[O:10]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCC[C@@H](C(=O)O)[C@H](O)C(=O)O
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S, 3R)-3-(n-butyl)-2-hydroxysuccinic acid F-4 (300 mg, 1.58 mmol) in 2,2-dimethoxypropane (10 mL) was added p-toluenesulfonic acid (20 mg) and the reaction was stirred at room temperature for 16 h. The solution was diluted with dichloromethane and washed with brine, dried (Na2SO4) and then purified by silica gel chromatography to afford 1.2 mmol 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid F-5 (78%).
Reaction SMILES: [OH:1][CH:2]([C:5]([O:18][CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].C([O-])([O-])=O.[K+].[K+].CS([C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[N:31]=1)(=O)=O.O>CN(C=O)C>[CH3:39][O:38][C:32]1[CH:33]=[C:34]([O:36][CH3:37])[N:35]=[C:30]([O:1][CH:2]([C:5]([O:18][CH3:19])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]#[N:4])[N:31]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(c1ccccc1)(c1ccccc1)C(O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OC(C#N)C(OC)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7.3 g (28.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionitrile were dissolved in 90 ml of DMF, and 4 g (28.8 mmol) of K2CO3 and 6.3 g (28 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. The mixture was stirred at room temperature for about 12 h., then poured into water and extracted with ethyl acetate. The combined organic phases were washed again with H2O, dried and concentrated. The residue obtained in this way was then purified by chromatography on silica gel (n-heptane/ethyl acetate).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH3:30][C@H:31]([NH:40][CH3:41])[C@@H:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:40]([CH:31]([CH3:30])[CH:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:41])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C(O)c1ccccc1)N(C)C(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a dry round-bottomed flask equipped with a magnetic stirrer and an argon inlet was dissolved N (benzyloxycarbonyl)-glycine (5.00 g, 23.9 mmol, 1.0 equiv) in dichloromethane (25 mL). Triethylamine (3.66 mL, 26.3 mmol, 1.1 equiv) was added and the resulting mixture was cooled to 0° C. To the reaction was added dropwise trimethylacetylchloride (2.94 mL, 23.9 mmol, 1.0 equiv). A white precipitate formed and dichloromethane (25 mL) was added to allow efficient stirring. The reaction was stirred for 30 min at 0° C. and then a solution of (+)-pseudoephedrine (4.15 g, 25.1 mmol, 1.05 eq) and triethylamine (3.66 mL, 26.3 mmol, 1.1 eq) in dichloromethane (40 mL) was added via cannula. The reaction was stirred for 30 min at 0° C. Most of the solvent was removed under reduced pressure and water and saturated sodium bicarbonate were added. The product was extracted with two portions of ethyl acetate and the organic extracts were washed with saturated ammonium chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel with ethyl acetate/hexanes as the eluent (30%-80% gradient) gave [S-(R*,R*)-N2-(benzyloxycarbonyl)-N1-(2-hydroxy-1-methyl-2-phenylethyl)-N1-methyl glycinamide (6.67g, 78%) as a white foam (1:1 mixture of rotamers): 1H NMR (CDCl3, 300 MHz) δ7.25-7.40 (m, 10H), 6.04 (m, 1H), 5.09 (28, 4H), 4.67 (m, 0.5H), 4.51 (d, 0.5H, J=4.5 Hz), 4.49 (d, 0.5H, J=4.7 Hz), 4.23 (dd, 0.5H, J1 =16.7 Hz, J2=3.8 Hz), 4.15 (s(br), 1H), 4.04 (dd, 0.5H, J1=16.5 Hz, J2=5.1 Hz), 3.92 (d, 1H, J=4.3 Hz), 3.77 (m, 0.5H), 2.88 (s, 1.5H), 2.77 (s, 1.5H), 0.94 (d, 1.5H, J =6.4 Hz), 0.92 (d, 1.5H, J=6.3 Hz); 13C NMR (CDCl3, 75.5 MHz) δ169.3, 169.0, 156.2, 141.4, 141.1, 136.30, 136.26, 128.4, 128.2, 128.02, 127.95, 127.7, 126.6, 126.5, 75.2, 74.6, 66.5, 57.4, 56.1, 42.9, 42.6, 29.3, 26.8, 14.9, 13.9; FTIR (neat film) cm-1 3405, 3323, 3031, 2980, 1719, 1638.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([N:13]([CH2:21][C:22]#[CH:23])C(=O)OC(C)(C)C)[C:10]([CH3:24])=[N:9]2)[CH:5]=[N:6][CH:7]=1.[ClH:25]>O1CCOCC1.C(OCC)C>[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([NH:13][CH2:21][C:22]#[CH:23])[C:10]([CH3:24])=[N:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: C#CCN(C(=O)OC(C)(C)C)c1cn(-c2cncc(F)c2)nc1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: C#CCNc1cn(-c2cncc(F)c2)nc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl 1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-yl(prop-2-ynyl)carbamate (1.03 g, 3.11 mmol) in dioxane (5 mL) was added 4 molar (M) hydrogen chloride (HCl; 3.9 mL, 15.5 mmol) in diethyl ether (Et2O). The mixture was stirred at room temperature for 48 h and the resulting white solid was filtered, washed with Et2O and dried under vacuum to give the title compound as a white solid (741 mg, 89%): mp 167-168° C.; 1H NMR (400 MHz, DMSO d6) δ 8.92-8.85 (m, 1H), 8.42 (d, J=2.5 Hz, 1H), 8.15 (s, 1H), 8.12-8.02 (m, 1H), 3.85 (d, J=2.5 Hz, 2H), 3.27-3.19 (m, 1H), 2.22 (s, 3H); ESIMS m/z 230.4 ([M]+).
Reaction SMILES: N1C=CC=CC=1.C1C([N+]([O-])=[O:14])=CC=C(O)C=1.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCOCC1>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:14])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 3 h

Procedure:
The succinylated 2-azetidinone is dissolved in dioxane (10 ml). Anhydrous pyridine (1 ml) and p-nitrophenol (0.2 g) are added followed by dicyclohexylcarbodiimide (0.6 g, 2.5 mmole). Stirring is continued for 3 hours. The dicyclohexyl-urea formed is filtered and the filtrate is added to controlled pore glass (5 g) suspended in dimethylformamide (5 ml). Triethylamine (2 ml) is added and briefly shaken. After leaving it overnight, the CPG is filtered, washed with methanol, ether and air dried.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].P(Br)(Br)[Br:16]>>[Br:16][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14]
Reactant: BrP(Br)Br
Reactant: O=C1c2ccccc2C(=O)N1CCO
Product: O=C1c2ccccc2C(=O)N1CCBr
Temperature: 0 °C

Procedure:
A mixture of 5.35 g (0.028 mol) of N-(2-hydroxyethyl)phthalimide and 7.7 g (0.028 mol) of phosphorus tribromide is warmed until solution is obtained. The reaction mixture is then cooled and poured into ice water. The resulting solid is collected by filtration and washed with water to give N-(2-bromoethyl)phthalimide.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12]/[C:13](/[CH3:17])=[CH:14]\[C:15]#[N:16]>C(O)(=O)C>[C:4]([C:3]1[CH:6]=[C:7]([CH:10]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[NH:12][C:2]([CH3:9])=[C:3]2[C:4]#[N:5])[CH:8]=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: C/C(N)=C/C#N
Reactant: N#Cc1cc(C=O)ccc1F
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc(F)c(C#N)c2)C(C#N)=C(C)N1
Temperature: 90 °C
Reaction time: 4 h
Yield: 160.7 %

Procedure:
30 g (201.2 mmol) 2-fluoro-5-formylbenzonitrile and 35 g (431.6 mmol) 3-aminocrotononitrile were dissolved in acetic acid (500 ml) and heated to 90° C. After 4 h, the reaction mixture was cooled to rt, concentrated, neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The remaining solid was dissolved in ethyl acetate, and hexane was added. The precipitate was filtered off to afford the title compound (45 g, 80% of th.) as a pale yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[O:21]1[CH:28]2[CH:24]([CH2:25][NH:26][CH2:27]2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:25][CH:24]4[CH2:23][CH2:22][O:21][CH:28]4[CH2:27]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1CC2CNCC2O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CC2CCOC2C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with hexahydro-2H-furo[3,2-c]pyrrole (1214875-23-6) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=380.5 [MH+].
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]([N+:22]([O-])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=S)=[CH:30][CH:29]=1)(=[O:27])[CH3:26]>C(OCC)(=O)C.C(O)C.[Pd].O1CCCC1>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]2[N:12]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:35]([NH:34][C:31]3[CH:32]=[CH:33][C:28]([C:25](=[O:27])[CH3:26])=[CH:29][CH:30]=3)=[N:22][C:9]2=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)c1ccc(N=C=S)cc1
Reactant: CCCCNc1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)n1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCNc1ccc2nc(Nc3ccc(C(C)=O)cc3)n(CCCN3CCCCC3)c2n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
N6-butyl-3-nitro-N2-(3-piperidin-1-ylpropyl)pyridine-2,6-diamine (500 mg) in solution in a mixture of ethyl acetate/ethanol 3:1 (10 ml), and 10% palladium on carbon (50 mg) are introduced into an autoclave. After stirring for 3 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the mixture is filtered on celite in a flask containing a solution of 4-acetylphenyl-isothiocyanate (270 mg, 1 eq) in tetrahydrofuran (10 ml). N-cyclohexylcarbodiimide-N-methyl-polystyrene resin (acquired from Novabiochem; load 1.9 mmol/g; 2.63 g, 3 eq) is added to the filtrate thus obtained. The mixture is heated to reflux for 15 hours, cooled down to ambient temperature then filtered on frit and the filtrate is concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound (230 mg; 34% yield).
Reaction SMILES: C(OC([N:8]([CH2:17][CH:18]([NH:25][CH2:26][C:27]([O:29]C)=O)[CH2:19][CH2:20][N:21]([O:23][CH3:24])[CH3:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[CH2:17][CH:18]([CH2:19][CH2:20][N:21]([O:23][CH3:24])[CH3:22])[NH:25][CH2:26][C:27]2=[O:29])=[CH:15][CH:14]=1
Reactant: COC(=O)CNC(CCN(C)OC)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(C)CCC1CN(Cc2ccc(F)cc2)C(=O)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl N-{1-{[(tert-butoxycarbonyl)-(4-fluorobenzyl)amino]methyl}-3-[methoxy(methyl)amino]propyl}glycinate (1.63 g, 3.82 mmol) in CH2Cl2 (41 mL) was treated with TFA (12.6 mL) at 0° C. The mixture was stirred at ambient temperature under inert atmosphere for 2 h and then concentrated in vacuo. The resulting oil was suspended in water (46 mL) and treated, portion-wise, with solid K2CO3 (3.1 g). The reaction was heated to 100° C. for 30 min. After cooling to ambient temperature, the mixture was saturated with NaCl and extracted into CH2Cl2 three times. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield the title compound as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.29-7.23 (m, 2H), 7.05-6.99 (m, 2H), 4.63 (d, J=14.8 Hz, 1H), 4.47 (d, J=14.8 Hz, 1H), 3.62 (dt, J=17.2, 38.8 Hz, 2H), 3.47 (s, 3H), 3.12-3.10 (m, 1H), 3.08-2.94 (m, 2H), 2.71-2.62 (m, 2H), 2.55 (s, 3H), 1.82 (br s, 1H), 1.63 (dd, J=6.4, 12.4 Hz, 2H). ES MS (M+1)=296.4.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:10]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH2:22]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[N:10]1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCn1nc(-c2ccc(OC)cc2)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCCCn1nc(-c2ccc(O)cc2)c2cccc(C(F)(F)F)c21
Yield: 48.3 %

Procedure:
Prepared according to Method D step C from 3-(4-methoxyphenyl)-1-pentyl-7-trifluoromethyl-1H-indazole (0.068 g, 0.19 mmol), boron tribromide (0.094 mL, 1.0 mmol) and 0.3 mL of cyclohexene to give the product (0.032 g) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([CH2:31][CH2:32][CH2:33]Cl)(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8](=[O:19])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[C:10]=2[F:18])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][S:28]([CH2:31][CH2:32][CH2:33][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)(=[O:30])=[O:29])[CH2:23][CH2:22]2)[N:3]=1
Reactant: C1COCCN1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCCl)CC2)nc1N
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NS(=O)(=O)CCCN3CCOCC3)CC2)nc1N

Procedure:
To a stirred solution of 3-chloro-propane-1-sulfonic acid [4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-amide (104 mg, 0.20 mmol, Example 293) in tetrahydrofuran (5 mL), morpholine (100 mg, 1.15 mmol, Aldrich) was added and the mixture was heated at reflux for 24 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3×5 mL). The extracts were combined and dried with sodium sulfate and concentrated. The residue was chromatographed (8% 9N ammonia in methanol/dichloromethane) to give a pale yellow solid. 57 mg, 50%. MS (ES) MH+=569. CDK4 IC50=0.015 μM; CDK1 IC50=0.008 μM; CDK2 IC50=0.005 μM; HCT 116 IC90=0.374 μM.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[C:11]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20](F)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1>CC(N(C)C)=O>[Cl:9][C:10]1[C:11]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([N:5]3[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 286.2 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (126 mg, 1.11 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 87, 215 mg, 0.50 mmol) in DMA (5 mL) and the mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was then concentrated in vacuo and combined with material from the reaction below for work up. (3R)—N,N-dimethylpyrrolidin-3-amine (276 mg, 2.42 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 87, 470 mg, 1.10 mmol) in DMA (10 mL) and the mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was concentrated in vacuo and combined with the material from the first procedure described above, for work-up. The combined residues were dissolved in CH2Cl2 (100 mL), and the resulting solution was washed with water (2×100 mL) and sat. brine (100 mL), and then dried (MgSO4) and concentrated in vacuo, Purification by FCC, eluting with 1-10% CH3OH in CH2Cl2 gave the title compound (747 mg, 89%) as an orange gum; m/z: ES+ M+ 522.30.
Reaction SMILES: Cl[CH:2]1[S:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13].C(=O)(O)[O-:15].[Na+]>O1CCCC1>[OH:15][CH:2]1[S:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13]
Reactant: O=C1C(Cl)SCN1c1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C(O)SCN1c1ccccc1

Procedure:
By a procedure similar to that described in Preparative Example 2, Step 3 above, but using 5-chloro-3-phenyl-4-thiazolidinone (prepared as in Step 2 above), tetrahydrofuran (10 ml) and saturated aqueous sodium bicarbonate (15 ml), the title compound was obtained as an oily solid, yield 0.24 g.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[C:28]([NH:29]C(=O)OCC3C=CC=CC=3)=[CH:27][C:26]3[C:21](=[CH:22][C:23]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[C:42](=[O:47])[CH2:41]4)=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:29][C:28]1[C:19]([C:17]([NH:16][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:4]2[CH2:5][C@H:6]([CH3:9])[C@@H:7]([OH:8])[C@H:2]([NH2:1])[CH2:3]2)=[O:18])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[C:42](=[O:47])[CH2:41]1)[CH:22]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](N)[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)C(=O)C4)ccc3cc2N)C[C@@H](N)[C@@H]1O

Procedure:
A mixture of benzyl [2-[({4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(4-methyl-3-oxopiperazin-1-yl)quinolin-3-yl]carbamate (0.0070 g, 0.011 mmol) in 3.0 mL of MeOH was hydrogenated in the presence of 8 mg of 10% Pd on carbon under a balloon of hydrogen at room temperature for 1 h. The mixture was then filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H33N8O3 [M+H]+: m/z=505.3. found: 505.3.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[N:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F-].[K+]>CO.[Pd]>[C:16]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:18][C:13]([N:4]2[N:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])=[CH:14][CH:15]=1
Reactant: O=c1c2ccccc2c(O)nn1-c1ccc(I)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: O=c1c2ccccc2c(O)nn1-c1ccc(-c2ccccc2)cc1
Yield: 74.2 %

Procedure:
4-Hydroxy-2-(4-iodophenyl)-2H-phthalazin-1-one (0.1 g, 0.3 mmol), phenyl boronic acid (0.04 g, 3 mmol), palladium black (0.02 g, 0.2 mmol) and KF (0.1 g, 18 mmol) were dissolved in MeOH (2 ml) and heated at reflux for 7 h. Removal of supernatant palladium by filtration, extraction with H2O and subsequent filtration of the precipitated solid yielded the desired title compound (0.07 g, 78% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO) 11.88 (1H, s), 8.33 (1H, d), 7.89-8.03 (3H, m), 7.78-7.86 (6H, m), 7.50 (2H, t), 7.39 (1H, t),; MS (ESI+)=315.3 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[N:10]2[C:11](=[O:20])[C:12]3[C:17]([C:18](=[O:19])[N:9]2[CH2:8][CH2:7][CH2:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:4].[OH-].[K+]>CO>[O:19]=[C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:20])[N:10]2[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][N:9]12
Reactant: COC(=O)[C@@H]1CCCn2c(=O)c3ccccc3c(=O)n21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1CCCn2c(=O)c3ccccc3c(=O)n21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of (S)-6,11-dioxo-1,2,3,4-tetrahydro-pyridazino[1,2-b]phthalazin-1-carboxylic acid methyl ester (1.078 g, 3.93 mmol) in MeOH (35 mL) was added KOH (232 mg, 4.12 mmol) in MeOH (11 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 hours, then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was extracted with water. The aqueous phase was acidified with 2.0-M HCl then extracted several times with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was crystallized from diethyl ether and the title compound was obtained as a white solid (744 mg, 73%): 1H NMR (400 MHz, CD3OD) δ 1.80 (1H, m), 1.97 (1H, m), 2.16 (1H, m), 2.56 (1H, m), 3.36 (1H, m), 4.83-4.88 (2H, m), 5.71 (1H, m), 7.90 (2H, m), 8.26 (2H, m).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[O:1][CH2:16][CH2:15][CH2:14]1
Reactant: BrCCCBr
Reactant: COC(=O)c1cccc(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1OCCCO2

Procedure:
Methyl 2,3-dihydroxybenzoate (1.870 g, 11.12 mmol), 1,3-dibromopropane (2.25 g, 11.1 mmol) and potassium carbonate (6.15 g, 44.5 mmol) were stirred in N,N-dimethylformamide (20 ml) overnight at 60° C. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.