Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[C:13](O)([C:14]([O:16][CH3:17])=[O:15])[CH2:12][C:11]([CH2:19][OH:20])=[N:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1>CO>[Cl:2][C:3]1[C:4]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([CH2:19][OH:20])=[N:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1(O)CC(CO)=NN1c1ncccc1Cl
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(CO)nn1-c1ncccc1Cl
Reaction time: 0.75 h

Procedure:
The solution of HCl (9.1 g, 4% solution in methanol) was added to the suspension of (28.5 g, 0.1 mol) of methyl 1-(3-chloropyridin-2-yl)-5-hydroxy-3-(hydroxymethyl)-4,5-dihydro-1H-pyrazole-5-carboxylate in 100 ml of methanol. After ca. 30-60 min at 25-30° C., the clear yellow solution had formed. Methanol was removed in vacuo and the precipitate was washed with water. Yield 26.7 g, 100%. M.p. 104° C.
Reaction SMILES: C[O:2][C:3](=[O:16])[C@@H:4]([NH2:15])[CH2:5]/[CH:6]=[CH:7]\[CH2:8][C@H:9]([NH2:14])[C:10]([O:12]C)=[O:11].[ClH:17]>O1CCOCC1>[ClH:17].[ClH:17].[NH2:15][C@@H:4]([CH2:5]/[CH:6]=[CH:7]\[CH2:8][C@H:9]([NH2:14])[C:10]([OH:12])=[O:11])[C:3]([OH:16])=[O:2]
Reactant: COC(=O)[C@@H](N)C/C=C\C[C@H](N)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](C/C=C\C[C@H](N)C(=O)O)C(=O)O

Procedure:
To a mixture of (S,S)-2,7-diamino-(Z)-oct-4-ene-1,8-dioic acid dimethyl ester (0.6 g, 1.3 mmol), conc HCl (1 ml) and dioxane (10 ml) were added and the solution was refluxed for 2 hours, and then evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([N+:21]([O-])=O)[CH:15]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1>CCO.C1COCC1.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[CH:18][CH:19]=3)=[N:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nnc(-c3ccc(N)c([N+](=O)[O-])c3)o2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-c2nnc(-c3ccc(N)c(N)c3)o2)cc1

Procedure:
A solution of 4-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-yl]-2-nitrophenylamine (1.0 g, 3.21 mmol) in 80 mL of EtOH/THF (1:1) was hydrogenated over PtO2 (100 mg) at one atm for 2-4 h. The catalyst was filtered through Celite and washed with EtOH and THF. The solvent was removed under reduced pressure to give the title compound as a yellow solid. MS: m/z 283 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.C(N(CC)CC)C.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[NH:59]1[CH2:64][CH2:63][CH:62]([N:65]2[CH2:70][C:69]3[CH:71]=[CH:72][N:73]=[CH:74][C:68]=3[NH:67][C:66]2=[O:75])[CH2:61][CH2:60]1>O1CCCC1>[O:75]=[C:66]1[NH:67][C:68]2[CH:74]=[N:73][CH:72]=[CH:71][C:69]=2[CH2:70][N:65]1[CH:62]1[CH2:61][CH2:60][N:59]([C:35]([NH:1][C@@H:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]2=[O:24])=[O:36])[CH2:64][CH2:63]1
Reactant: O=C1Nc2cnccc2CN1C1CCNCC1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(N2Cc3ccncc3NC2=O)CC1
Reaction time: 1 h
Yield: 26.3 %

Procedure:
A solution of (3R) 3-amino-2-oxo-5-phenyl-1-(2,2,2-trifluorethyl)-2,3-dihydro-1H-1,4-benzodiazepine (0.030 g, 0.090 mmol) and 4-nitrophenylchloroformate (0.018 g, 0.090 mmol) in dry tetrahydrofuran (2 mL) was cooled to 0° C. under argon. Triethylamine (0.013 mL, 0.090 mmol) was added and the reaction stirred for 1 h. Solid 3-piperidin4-yl-3,4-dihydropyrido[3,4-d]pyrimidin-2(1H)-one bisTFA salt (0.90 mmol) followed by triethylamine (0.065 mL) were added. The reaction was allowed to come to room temperature and stirred for 1 h. The reaction was quenched with 1N NaOH and concentrated. The crude product was purified by chromatography (silica gel, 0 to 10% methanol in methylene chloride gradient elution), to give the title compound (0.014 g, 27% yield). MS 592.2276 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][NH2:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:18]>>[Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][NH:15][C:28](=[O:29])[CH2:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][S:17]([CH3:16])(=[O:18])=[O:19])[CH:22]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: NC[C@@H]1CN(Cc2ccc(Cl)s2)CCO1
Reactant: CS(=O)(=O)Nc1cccc(CC(=O)O)c1
Product: CS(=O)(=O)Nc1cccc(CC(=O)NC[C@@H]2CN(Cc3ccc(Cl)s3)CCO2)c1
Yield: 45.8 %

Procedure:
Example 50 was prepared in an analogous manner to Example 44 using a mixture of Intermediate 14A (0.1 g) and Intermediate 18(0.1 g) to give the title compound (0.085 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([O:19]C)=[O:18])[N:12]=[C:11]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O>CO>[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([OH:19])=[O:18])[N:12]=[C:11]1[C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCCC(=O)OC(C)(C)C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CCCn1c(-c2ccc(Cl)cc2)nn(CC(=O)O)c1=O
Reaction time: 1 h

Procedure:
A solution of 48 mg (117 μmol) of the compound from Example 223A in 2 ml methanol is treated with a 1 N lithium hydroxide solution in water (470 μl, 470 μmol). After 1 hr at RT, the methanol is removed on the rotary evaporator. The residue is dissolved in DMSO and purified by preparative HPLC. 41 mg (88% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([NH:15][C:16]1([CH2:20][C:21]([NH2:23])=O)[CH2:19][CH2:18][CH2:17]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1COCC1>[CH2:7]([NH:15][C:16]1([CH2:20][CH2:21][NH2:23])[CH2:19][CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC(=O)CC1(NC(=O)c2ccccc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCC1(NCc2ccccc2)CCC1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
LiAlH4 (570 mg, 15.0 mmol) was added portionwise to a solution of [1-(benzoylamino)cyclobutyl]acetamide (687 mg, 3.00 mmol) in THF (30 mL) at room temperature over the course of 30 minutes, and the mixture was heated to reflux for 5 hours. The mixture was cooled in an ice-water bath, aqueous THF and few drops of water were added, and the mixture was allowed to stand overnight. The mixture was filtered through celite and the solution was dried over anhydrous Na2SO4. The solution was concentrated in vacuo to give the title compound as a pale yellow oil (609 mg, 99%). 1H-NMR (400 MHz, CDCl3) δ 1.65-1.80 (2H, m), 1.82 (2H, t, J=7.3 Hz), 1.86-2.02 (4H, m), 2.82 (2H, t, J=7.3 Hz), 3.65 (2H, s), 7.20-7.38 (5H, m).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8](Cl)[N:9]=[C:10]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[C:5]=2[S:4][CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].O>CN1CCCC1=O>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([NH:20][CH2:19][CH2:17][OH:18])[N:9]=[C:10]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[C:5]=2[S:4][CH:3]=1
Reactant: Clc1nc(-c2ccco2)c2scc(Br)c2n1
Reactant: NCCO
Solvent: CN1CCCC1=O
Solvent: O
Product: OCCNc1nc(-c2ccco2)c2scc(Br)c2n1
Temperature: 90 °C
Yield: 37.8 %

Procedure:
A solution of 7-bromo-2-chloro-4-(2-furyl)thieno[3,2-d]pyrimidine (110 mg, 0.35 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was treated with ethanolamine (32 μL, 0.52 mmol), heated at 90° C. for 16 h, cooled, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2: EtOAc:Heptane, 1:1) to give the title compound (45 mg, 38%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:2]=1.[CH3:20][N:21]=[C:22]=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:20][NH:21][C:22](=[O:23])[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:14]=1
Reactant: CN=C=O
Reactant: Oc1cccc(C2CCCN2Cc2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2Cc2cccnc2)c1
Reaction time: 13 h
Yield: 85 %

Procedure:
To a solution of 3-[1-(3-pyridinylmethyl)-2-pyrrolidinyl]phenol (0.92 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.22 ml) followed by milled potassium carbonate (0.65 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 13 hrs, filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, ethyl acetate). The appropriate fractions were collected and concentrated to give 0.94 g (85%) of product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:21])[C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O.[Fe]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([N:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH3:21])=[O:20])=[CH:16][CH:15]=1
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C(=O)c1ccc(N)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 105.5 %

Procedure:
A solution of 4 ml (ca 40 mmol) of concentrated hydrochloric acid in 50 ml of ethanol and 50 ml of water was added dropwise over 2 hours to a refluxing suspension of 6.34 g 114 mmol, 3 equiv) of iron filings and 11.0 g (37.8 mmol) of N-(4-chlorophenyl)-N-methyl-4-nitrobenzamide in 200 ml of ethanol and 200 ml of water. The mixture was refluxed for 1 hour and allowed to cool to room temperature and then adjusted to a pH of 11 with 10% aqueous sodium hydroxide. The suspension was filtered and the residue washed 3 times with 200 ml of hot ethyl acetate. The solution was evaporated to remove the organics and the aqueous liquid was extracted 3 times with 200 ml of EtOAc. The combined organics were washed twice with 250 ml of water and 100 ml of brine, then dried over MgSO4, filtered and evaporated to obtain 10.4 g of the desired product as an orange solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl>N1C=CC=CC=1>[S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=1)([O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:14])=[O:13]
Reactant: COCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 86.1 %

Procedure:
To a solution of 38 g of 2-methoxyethanol in 12 ml of pyridine was added portionwise, over two hours, 95.3 g of p-toluenesulfonyl chloride at 0° C. The reaction mixture was stirred for 20 hours, poured into 200 ml of concentrated hydrochloric acid and 1 liter of ice cubes, extracted with methylene chloride and washed successively with methylene chloride, water and a saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and stripped to yield 99 g of 2-methoxyethyl tosylate as a yellow oil.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH:10]=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[BH4-].[Na+].Cl>CO>[OH:11][CH2:10][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=Cc1cnc2ccccn12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnc2ccccn12
Yield: 47.7 %

Procedure:
A mixture of 9.4 g (0.1 mole) of 2-aminopyridine and 19.2 g (0.11 mole) of 45% aqueous chloroacetaldehyde was stirred, during which spontaneous heating occurred. When the exothermic reaction subsided, the mixture was dissolved in methanol containing 15 ml of concentrated aqueous ammonia and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Distillation at 80-83° and 0.2 mm Hg pressure yielded 10.5 g of imidazo[1,2-a]pyridine as an oil. A solution of 9.5 g (80.5 mmole) of imidazo[1,2-a]pyridine in 60 ml of dimethylformamide was heated to 90°. Phosphorus oxychloride (9.27 ml, ca. 100 mmole) was added dropwise over a twenty minute period, and the mixture was stirred at 90° for two hours and at room temperature for an additional twenty hours. The mixture was diluted with 60 ml of water and made basic with 30% aqueous sodium hydroxide. The resultant solid was collected by filtration, washed with water, and air dried to yield 1.8 g of 3-imidazo[1,2-a]pyridinecarboxaldehyde as the analytically pure p hydrate. [Calcd. for C8H6N2O.H2O: C, 58.53; H, 3.68; N, 17.06. Found: C, 58.77; H, 3.68; N, 17.48.]To a solution of 1.6 g (10 mmole) of 3-imidazo[1,2-a]-pyridinecarboxaldehyde in 15 ml of methanol was added 204 mg (5.4 mmole) of sodium borohydride. After one hour the mixture was acidified with concentrated hydrochloric acid and then concentrated in vacuo. Recrystallization of the residue from ethanol yielded 707 mg of 3-hydroxymethylimidazo[1,2-a]pyridine as the hydrochloride salt. A 500 mg (2.7 mmole) portion of the hydroxymethyl compound was dissolved in 3.0 ml of concentrated hydrochloric acid and heated at 80° for one hour. The mixture was concentrated in vacuo and the residue was recrystallized from isopropyl alcohol to yield 465 mg of 3-chloromethylimidazo[1,2-a]pyridine as the hydrochloride salt. A mixture of 390 mg (1.92 mmole) of the chloromethyl compound and 288 mg (1.92 mmole) of 2-mercaptobenzimidazole in 7 ml of isopropyl alcohol was stirred for one hour. The precipitate that formed was collected and partitioned between 5% aqueous sodium hydroxide and dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue with diethyl ether yielded the title compound as an analytically pure solid. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](I)[CH3:16]>CN(C)C=O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:16]
Reactant: CCI
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-bromophenol (5.00 g) and potassium carbonate (5.99 g) in anhydrous dimethylformamide (25 ml) was added ethyl iodide (2.77 ml) under ice-water cooling and the mixture was stirred at 0° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with 2N aqueous sodium hydroxide solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo to give 4-ethoxybromobenzene as yellow oil (5.44 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(N(CC)CC)C.Br[CH2:36][CH2:37][OH:38]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][CH2:36][CH2:37][OH:38])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Reactant: OCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NCCO)CC2)nc1N

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (100 mg, 0.27 mmol, Example 120) and triethylamine (200 uL) in tetrahydrofuran (3 mL), 2-bromoethanol (20 uL, 0.28 mmol, Aldrich) was added and the mixture was stirred at reflux for 5 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3×10 mL) and the extracts were dried with sodium sulfate. Removal of solvent gave a yellow solid which was purified by reverse phase HPLC to give a pale yellow solid. 86 mg, 75%. MS (ES) MH+=422. CDK4 IC50=0.020 μM; CDK1 IC50=0.018 μM; CDK2 IC50=0.005 μM; HCT 116 IC90=0.179 μM.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:27]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:34])[C:18]([Cl:35])=[CH:17][N:16]=1>>[Cl:35][C:18]1[C:19]([NH:21][C:22]2[C:27]([S:28]([CH:31]([CH3:32])[CH3:33])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:34])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Product: CC(C)S(=O)(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 1221d. Product isolated as a light grey solid (50 mg, 37%). LCMS 506.11 (M+H), HPLC purity 94%, 1H-NMR (CDCl3, 400 MHz) δ 8.23 (s, 1H), 8.16 (s, 1H), 7.86 (d, J=7.7 Hz, 1H), 7.62-7.59 (m, 2H), 7.32-7.38 (m, 1H), 7.04 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.88 (s, 1H), 3.10-3.00 (m, 1H), 2.73 (dd, J=7.1 Hz, 2H), 2.34 (dd, J=7.2 Hz, 2H), 2.20 (dd, J=6.8 Hz, 2H), 1.23 (d, J=6.9 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[C:24]([F:34])=[CH:25][C:26]([F:33])=[C:27]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[C:24]([F:34])=[CH:25][C:26]([F:33])=[C:27]([S:29]([NH2:32])(=[O:30])=[O:31])[CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (68 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (91 mg, 75%). MS (ISP) 485.1 [(M+H)+]; mp 272-275° C.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[OH:23]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[O:23][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Oc1c(F)cccc1F
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1c(F)cccc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 2-fluoro-5-nitrobenzoate (J. Org. Chem. 1990, 55, 2034.) and 2,6-difluorophenol: 1H-NMR (CDCl3) δ 8.83 (1H, d, J=2.8 Hz), 8.25 (1H, dd, J=9.2, 2.8 Hz), 7.32–7.20 (1H, m), 7.12–7.02 (2H, m), 6.82 (1H, d, J=9.2 Hz), 3.98 (3H, s); MS (ESI) m/z 310 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=[CH:6][CH:5]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-:26].[K+].[K+].OO.C(=O)([O-])O.[Na+]>C(#N)C.CO>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:18])=[C:16]([CH3:17])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]2[O:26][C@@H:6]2[C@H:5]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1c2c(ccn3c(C)c(C)nc23)C=CC1c1ccccc1
Agent: O=C([O-])O
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CC(=O)N1c2c(ccn3c(C)c(C)nc23)[C@@H]2O[C@@H]2[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.64 g (2 mmol) of rac-10-acetyl-2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2-h][1,7]naphthyridine (racemic) are dissolved in 3 ml of acetonitrile and 1 ml of methanol and treated with 0.18 g (1.2 mmol) of potassium carbonate. 0.2 ml of hydrogen peroxide solution (30% in water) is then slowly added dropwise with ice cooling. The mixture is then allowed to warm to room temperature and is stirred for 16 h. After addition of saturated sodium hydrogencarbonate solution, it is extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel (eluent diethyl ether/triethylamine 9:1). After crystallization from diethyl ether, 80 mg (12%) of the title compound are isolated as a colorless solid (m.p. 222° C.).
Reaction SMILES: [Li+].[OH-:2].C([O:5][C:6](=[O:23])[CH2:7][NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)C>C1COCC1.CO.O>[O:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:23])=[O:2])=[CH:11][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [OH-]
Reactant: CCOC(=O)CNCc1ccc(Oc2ccccc2)cc1
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
LiOH (4.81 g, 114.63 mmol) was added to a stirred solution of (4-phenoxy-benzylamino)-acetic acid ethyl ester (5.72 g, 19.12 mmol) in THF:MeOH:H2O (3:1:1, 75 mL), and the resulting mixture was stirred at room temperature for 5 hrs. The MeOH and THF were evaporated, and the residue was acidified with cold 20% aqueous HCl. The resulting precipitate was filtered, washed with water and dried to afford 4.74 g (91.41% yield) of (4-phenoxy-benzoylamino)-acetic acid. 1H NMR (DMSO): δ 7.8 (d, 2H,), 7.75 (t, 1H), 7.4 (t, 2H), 7.15 (t, 1H), 7.05 (d, 2H), 7.0 (d, 2H).
Reaction SMILES: [CH:1]1([O:6][N:7]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.NN.[N+:20]([C:23]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:26][C:24]=1[NH2:25])([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>O1CCCC1.OS([O-])(=O)=O.[Na+].ClCCl>[NH2:25][C:24]1[CH:26]=[CH:27][C:28]([S:30]([NH:7][O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)(=[O:32])=[O:31])=[CH:29][C:23]=1[N+:20]([O-:22])=[O:21]
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Reactant: Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Agent: NN
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1ccc(S(=O)(=O)NOC2CCCC2)cc1[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 68.1 %

Procedure:
A solution of 2-(cyclopentyloxy)-1H-isoindole-1,3(2H)-dione (10.00 g, 43.30 mmol) in anhydrous tetrahydrofuran (100 mL) at ambient temperature under an Argon atmosphere was treated with anhydrous hydrazine (1.49 mL, 47.63 mmol). After stirring vigorously for 2.5 hours, the resulting slurry was filtered and washed with approximately 20 mL of anhydrous tetrahydrofuran. The filtrate was combined with o-nitroaniline-p-sulfonyl chloride (11.26 g, 47.63 mmol) and N,N-diisopropylethylamine (9.05 mL, 51.96 mmol) and stirred under an Argon atmosphere for 16 hrs. at ambient temperature. The reaction mixture was diluted with 1N NaHSO4 and dichloromethane and transferred to a separatory funnel. The organic phase was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with 5% aqueous potassium carbonate, dried over anhydrous magnesium sulfate, filtered through a pad of diatomaceous earth and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 1:1 ethyl acetate:hexane. Fractions containing the product were combined, evaporated in vacuo to a residue and triturated with hexane. The slurry was filtered and the product was dried under high vacuum to provide 4-amino-N-(cyclopentyloxy)-3-nitrobenzenesulfonamide (8.89 g, 68%) as a yellow solid. H1-NMR (chloroform-D3): 1.57 (m, 4H), 1.74 (m, 4H), 4.61 (m, 1H), 6.52 (b, 2H), 6.73 (s, H), 6.90 (d, 1H), 7.79 (m, 1H), 8.70 (d, 1H). MS(ESI): 324 (M+Na).