Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][S:5]([C:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:18]=2)[C:11]([OH:16])=[C:12]([CH:14]=O)[CH:13]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[NH2:37])[C:31]([NH2:33])=[NH:32].C1(=O)C=CC(=O)C=C1>CO>[C:1]([NH:4][S:5]([C:8]1[CH:13]=[C:12]([C:14]2[NH:37][C:36]3[CH:35]=[CH:34][C:30]([C:31]([NH2:33])=[NH:32])=[CH:29][C:28]=3[N:27]=2)[C:11]([OH:16])=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23](=[O:25])(=[O:24])[NH2:26])[CH:18]=2)[CH:9]=1)(=[O:7])=[O:6])(=[O:3])[CH3:2]
Reactant: N=C(N)c1ccc(N)c(N)c1
Reactant: CC(=O)NS(=O)(=O)c1cc(C=O)c(O)c(-c2cccc(S(N)(=O)=O)c2)c1
Agent: O=C1C=CC(=O)C=C1
Solvent: CO
Product: CC(=O)NS(=O)(=O)c1cc(-c2cccc(S(N)(=O)=O)c2)c(O)c(-c2nc3cc(C(=N)N)ccc3[nH]2)c1
Temperature: 25 °C
Yield: 14 %

Procedure:
N-acetyl 5-formyl-6-hydroxy-biphenyl-3,3′-disulfonamide (74 mg, 0.19 mmol) was dissolved in methanol (10 mL) and stirred at room temperature. 3,4-Diaminobenzamidine (39 mg, 0.21 mmol) and 1,4-benzoquinone (20 mg, 0.2 mmol) were added to the solution and the mixture was refluxed for 1 hour. The solvent was removed by rotary evaporation under reduced pressure and the residue was dissolved in water and acetonitrile and purified by reverse phase HPLC (0.02N HCl/ACN) to give 2-(5-acetylsulfamoyl-2-hydroxy-3′-sulfamoyl-biphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine (14.1 mg) as a yellow amorphous powder. MS m/z: 527.4 (M−H+) and 529.3 (M+H+). 1H NMR (400 MHz, DMSO-d6): δ 9.36 (bs, 2H), 8.94 (bs, 2H), 8.08 (d, J=2.2 Hz, 1H), 8.22 (bs, 1H), 8.10 (t, J=1.5 Hz, 1H), 7.96 (d, J=2.2 Hz, 1H) 7.89 (d, J=1.8 Hz, 1H), 7.87-7.85 (m, 2H), 7.76 (dd, J=10, 1.5 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.46 (s, 2H) and 1.96 (s, 3H).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OCC)(=[O:18])[CH:15]([CH3:17])[OH:16]>>[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:18])[CH:15]([CH3:17])[OH:16]
Reactant: CCCCCCCCCCCCO
Reactant: CCOC(=O)C(C)O
Product: CCCCCCCCCCCCOC(=O)C(C)O
Temperature: 60 °C
Reaction time: 28 h
Yield: 80 %

Procedure:
A mixture of Novozym® 435 (500 g), 1-dodecanol (2000 mL), and ethyl lactate (2000 mL) in a 5 L reactor was stirred (˜200 rpm) at 60±5° C. for 28 hours. Upon work-up, 2000 g of lauryl lactate (>80% yield) was obtained as a pale yellow liquid. The purity of the product was >95% as assessed by GC-FID.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18](O)=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>O1CCCC1>[CH2:1]([N:8]1[C:17]([CH2:18][OH:19])=[C:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1c2ccc(Br)cc2c(-c2ccccc2)c(CO)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a solution of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg) in tetrahydrofuran (THF) (5 ml) were added oxalyl chloride (60 μl) and DMF (0.1 ml), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure. A solution of the residue in THF (3 ml) was added dropwise to a suspension of sodium borohydride (39 mg) in 1,2-dimethoxyethane. The mixture was stirred under ice-cooling for 1 hr. and poured into 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound (33 mg, 23%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[CH3:12][CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][CH2:25][CH3:26])=[O:15])[C:5]=2[CH:6]=[N:7]1)[CH3:13]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Reactant: OB(O)c1cncnc1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cncnc2)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 75 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (100 mg, 0.225 mmol) and 5-pyrimidinylboronic acid (42 mg, 0.337 mmol). The final product was collected as a white solid (77 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H) 9.35 (s, 2H) 9.21-9.26 (m, 1H) 8.63 (t, J=4.93 Hz, 1H) 8.45 (s, 1H) 8.38 (s, 1H) 7.99 (d, J=1.26 Hz, 1H) 5.92 (s, 1H) 5.18 (quin, J=6.57 Hz, 1H) 4.44 (s, 1H) 4.42 (s, 1H) 2.52-2.56 (m, 2H) 2.13 (s, 3H) 1.52-1.56 (m, 4H) 1.48-1.52 (m, 4H) 0.88 (t, J=7.33 Hz, 3H). LC-MS (ES) m/z=445.2
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl[CH2:15][CH:16]([OH:25])[CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>C(O)C.O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:15][CH:16]([OH:25])[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)OCCO2
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc2c(c1)OCCO2
Yield: 33.7 %

Procedure:
A solution of benzo-1,4-dioxan-6-ol (0.15 g; Tetrahedron, 1995, 3197) in ethanol (20 ml) at room temperature was treated with a solution of sodium hydroxide (0.044 g) in water (5 ml) and was then heated at reflux. A solution of (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g) in ethanol (5 ml) was added dropwise to the latter and the resulting mixture heated at reflux for 1 hour. The reaction mixture was cooled and then water was added. The organic component was extracted with dichloromethane, the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with ethyl acetate to give an oil (0.100 g).
Reaction SMILES: CO[C:3]1[C:4]2[N:5]([CH:14]=[N:15][N:16]=2)[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][N:8]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:3]1[C:4]2[N:5]([CH:14]=[N:15][N:16]=2)[C:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:7][N:8]=1
Reactant: COc1ncc(-c2cccs2)n2cnnc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncc(-c2cccs2)n2cnnc12
Temperature: 130 °C
Yield: 75 %

Procedure:
A 50 mL round bottom flask was charged with 8-methoxy-5-(thiophen-2-yl)-[1,2,4]triazolo[4,3-a]pyrazine (0.30 g, 1.3 mmol) and POCl3 (3 mL). The mixture was heated at 130° C. overnight. TLC indicated a complete conversion. Work-up: the reaction mixture was concentrated in vacuo. The residue was carefully poured into ice and extracted with EtOAc (10 mL). The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with a 1:5 EtOAc/petroleum ether, to afford 0.23 g (75%) of the product as a white solid. MS m/z: 237 (M+H+).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.O>C1COCC1>[NH2:3][C:4]1[C:9]([Br:1])=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1
Reactant: BrBr
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc([N+](=O)[O-])cc1Br
Reaction time: 1 h
Yield: 81.1 %

Procedure:
Bromine (62.6 mλ; 1.2 mole) was dropwise added to 2-amino-5-nitropyridine (154.1 g; 1.1 mole) in THF (300 mλ) at room temperature. The resulting mixture was stirred for one hour and then poured into water (3 λ). The crystals thus formed were recrystallized from acetonitrile (500 mλ) to give 2-amino-3-bromo-5-nitropyridine (A) (194.4 g; 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Na].[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])(=[O:29])[CH2:27][CH3:28]>C1C=CC=CC=1>[C:26]([CH:30]([C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:23]=[CH:24][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:14][CH:15]=1)[CH3:22])[C:31]([O:33][CH3:34])=[O:32])(=[O:29])[CH2:27][CH3:28]
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Reactant: CCC(=O)CC(=O)OC
Agent: [Na]
Solvent: c1ccccc1
Product: CCC(=O)C(C(=O)OC)C(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
Following the procedure of Example 4, 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]propionic acid chloride is added to the sodium salt of methyl propionylacetate in benzene to give methyl 2-propionyl-4-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-oxopentanoate (cpd. 27, Table C). This pentanoate is then heated with sodium chloride and DMSO to give 2-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-3,5-heptanedione (cpd. 27, Table D).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]=1I)[CH3:7])[CH3:2].C(N(CCC)CCC)CC.C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=2)[NH:8][C:6]=1[CH3:7])=[O:22])[CH3:2]
Reactant: CCOC(=O)C=C(C)Nc1ccc(CC(=O)OCC)cc1I
Agent: CCCN(CCC)CCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc2[nH]c(C)c(C(=O)OCC)c2c1
Temperature: 120 °C
Yield: 38 %

Procedure:
To a solution of 3-(4-ethoxycarbonylmethyl-2-iodo-phenylamino)but-2-enoic acid ethyl ester (12.5 g, 30 mmol) in DMF (30 mL), tripropylamine (4.3 g, 30 mmol), and Pd(II)acetate (0.33 g, 1.5 mmol) are added, and the reaction mixture is heated at 120° C. for 1 hour. After cooling to room temperature, ethyl acetate (150 mL) is added. The organic layer is washed with water (2×100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material is recrystallized from hexane/ethyl acetate to give a yellow-orange solid (3.3 g, 38%). MS: 290 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O.C(Cl)Cl>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:25]([C:24]1[CH:23]=[CH:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:20][CH2:19]3)=[CH:28][CH:27]=1)=[N:1]2
Reactant: NC(=O)c1c(N)cccc1Cl
Reactant: CC(C)N1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(C)N1CCN(c2ccc(-c3nc4cccc(Cl)c4c(=O)[nH]3)cc2)CC1
Temperature: 140 °C

Procedure:
A solution of 2-amino-6-chlorobenzamide (0.314 g, 1.85 mmol) and 4-(4-isopropylpiperazin-1-yl)benzaldehyde (0.430 g, 1.85 mmol) in DMA (25 mL) were treated with p-TsOH (0.035 g, 0.185 mmol) and NaHSO3 (0.212 g, 2.04 mmol), and the mixture was heated at 140° C. for 18 hours. Then, the mixture was cooled, diluted with CH2Cl2 (200 mL), and washed with saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous MgSO4, filtered, concentrated, and purified by silica gel chromatography, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 6:3:1 CHCl3/MeOH/concentrated NH4OH. The resulting solids were rechromatographed with 9:1 CH2Cl2/MeOH to afford the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 12.24 (br s, 1H), 8.11 (d, J=8.8 Hz, 2H), 7.66-7.71 (m, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 3.28-3.34 (m, 4H), 2.64-2.73 (m, 1H), 2.55-2.59 (m, 4H), 1.01 (d, J=6.4 Hz, 6H). ESI MS m/z 383 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:34]=[CH:33][C:9]2[C:10](=[O:32])[CH2:11][CH:12]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[C:21]([OH:28])[C:20]=3[CH2:29][CH2:30][CH3:31])[O:13][C:8]=2[C:7]=1[CH2:35][CH2:36][CH3:37].O.[OH-].[Li+]>O.O1CCCC1.O>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:12]2[CH2:11][C:10](=[O:32])[C:9]3[CH:33]=[CH:34][C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])=[C:7]([CH2:35][CH2:36][CH3:37])[C:8]=3[O:13]2)=[C:20]([CH2:29][CH2:30][CH3:31])[C:21]=1[OH:28])(=[O:27])[CH3:26]
Reactant: CCCc1c(OCCCCC2CC(=O)c3ccc(OCC(=O)OC)c(CCC)c3O2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCCCCC2CC(=O)c3ccc(OCC(=O)O)c(CCC)c3O2)ccc(C(C)=O)c1O

Procedure:
A solution of 0.3 g of the ester product from Example 17 and 0.48 g of lithium hydroxide monohydrate in 10 ml of 1:1 water-tetrahydrofuran was stirred at room temperature for 24 hours then diluted with water and extracted with ether (the ether extract was discarded). The aqueous solution was acidified with 1N hydrochloric acid and extracted 3 times with ether. The ether extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo giving a solid residue which was chromatographed on 12 g of silica gel. Elution with tetrahydrofuran gave the acid which was recrystallized from methanol yielding rac.-[[2-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl]-3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl]oxy]acetic acid as an off-white solid, m.p. 163.5°-167.0° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[C:11]([NH2:23])=[CH:10][C:9]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=23)[CH:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][C:35]=34)[CH:28]=[CH:27][N:26]=2)=[CH:10][C:11]([NH:23][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:15][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:17]2)[CH:13]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A solution of acryloyl chloride (42 μL, 0.52 mmol) in CH2Cl2 (1 mL) was added dropwise to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 141, 240 mg, 0.52 mmol) and DIPEA (0.099 mL, 0.57 mmol) in CH2Cl2 (10 mL), which was cooled in an ice/water bath. The mixture was stirred for 1 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (135 mg, 50%) as a yellow solid after trituration with CH3CN; 1H NMR: 1.61-1.74 (2H, m), 1.73-1.85 (2H, m), 1.87-1.99 (2H, m), 2.03 (2H, t), 2.35 (3H, s), 2.61 (2H, t), 3.01 (2H, t), 3.60 (2H, d), 3.84 (3H, s), 3.89 (2H, d), 4.09 (2H, t), 5.70 (1H, d), 6.14-6.30 (2H, m), 6.47 (1H, dd), 6.95 (1H, d), 7.73 (1H, s), 7.83 (1H, s), 8.05 (1H, s), 8.26 (1H, d), 9.26 (1H, s); m/z: ES+ MH+ 515.7.
Reaction SMILES: F[C:2]1[C:22]([F:23])=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C=O>[F:23][C:22]1[C:2]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:3][C:4]2[N:13]=[CH:12][C:11]3[N:10]([CH3:14])[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=3[C:5]=2[CH:21]=1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(F)cc3c2c1=O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2cnc3cc(N4CCCC4)c(F)cc3c2c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
A suspension of 2 g of ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 1.1 g of pyrrolidine in 40 cm3 of dimethylformamide was heated, with stirring, at a temperature of 70° C. for 8 hours. After cooling to 20° C., the mixture was poured into 150 cm3 of ice-cold water. The insoluble material was dewatered, washed 3 times with 30 cm3 of water, and dissolved in 300 cm3 of dichloromethane; the residual water was decanted off. The organic extracts were dried over sodium sulphate; after filtration and concentration under reduced pressure (5.2 kPa), the compound obtained was purified by chromatography on 180 g of silica gel (0.06-0.20 mm). Elution was carried out with 3.6 liters of a dichloromethane-ethanol mixture (97-3 by volume) and with 6 liters of a dichloromethane-ethanol mixture (94-6 by volume), 150 cm3 fractions were collected. The fractions obtained from the latter mixture were concentrated to dryness under reduced pressure. 0.85 g of ethyl 9-fluoro-4-methyl-1-oxo-8-pyrrolidinyl-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of a yellow compound, which melted at 270° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1>>[O:38]1[C:42]2([CH2:47][CH2:46][N:45]([C:21]3[N:20]=[C:19]([O:18][C:11]4[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:29]=[C:30]([N:32]6[CH2:37][CH2:36][O:35][CH2:34][CH2:33]6)[CH:31]=[C:2]([F:1])[CH:3]=5)=[CH:9][CH:10]=4)[CH:24]=[CH:23][N:22]=3)[CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC4(CC3)OCCO4)n2)c2ccccc12)c1cc(F)cc(N2CCOCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 1,4-dioxa-8-aza-spiro[4.5]decane according to conditions described in general procedure C. Mp: 115-117° C.; 1H NMR (400 MHz, CDCl3) δ 1.64 (t, J=5.0 Hz, 4 H), 3.26 (t, J=4.3 Hz, 4 H), 3.77 (s, 4 H), 3.88 (t, J=4.7 Hz, 4 H), 3.96 (s, 4 H), 5.98-5.99 (m, 1 H), 6.77 (d, J=11.7 Hz, 1H), 7.07 (d, J=7.8 Hz, 1 H), 7.32-7.34 (m, 2 H), 7.50-7.60 (m, 3 H), 7.90 (d, J=8.2 Hz, 1 H), 8.00 (d, J=8.6 Hz, 1 H), 8.10 (s, 2 H), 8.15-8.17 (m, 1 H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:32][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Oc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(Oc2ccc(-c3nn4c(NC5CCCC5)cccc4c3-c3ccnc(NC4CCCC4)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
To a solution of 4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (100 mg, 0.22 mmol) in dichloromethane (5 mL) was added copper (II) acetate (40 mg, 0.22 mmol), phenylboronic acid (80 mg, 0.66 mmol), triethylamine (92 μL, 0.66 mmol) and molecular sieves. The mixture was stirred at room temperature for 24 hours. Solids were removed by filtration and the filtrate was concentrated, followed by purification by flash chromatography (2:3 ethyl acetate:hexanes) to give N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-phenoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (14 mg, 12%) as a yellow foam. 1H NMR (CDCl3): δ 8.05–6.85 (m, 12 H), 6.40 (d, 1H), 6.06 (m, 2H), 5.12 (d, 1H), 4.40 (m, 1H) 4.01 (m, 1H), 2.20–2.09 (m, 4H), 1.82–1.59 (m, 12H); MS m/z 531 (M+1).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]2[CH3:16])=[CH:6][C:5]=1[CH3:17].C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:3][C:4]1[C:5]([CH3:17])=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]2[CH3:16])=[CH:8][C:9]=1[Br:1]
Reactant: Cc1cn(-c2ccc(N)c(C)c2)c(C)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cn(-c2cc(C)c(N)c(Br)c2)c(C)n1
Reaction time: 0.5 h

Procedure:
A solution of bromine (5.6 cm3) in glacial acetic acid (50 cm3) was added dropwise over 0.5 hours to a stirred solution of 1-(4-amino-3-methylphenyl)-2,4-dimethylimidazole (20.3 g) and sodium acetate (9.02 g) in glacial acetic acid (200 cm3). After a further 0.5 hours, volatile material was removed in vacuo, and the residue was partitioned between chloroform (200 cm3) and 10% aqueous sodium hydroxide solution (to pH 10). The aqueous phase was further extracted with chloroform (2×100 cm3) and the combined and dried (MgSO4) organic extracts were evaporated in vacuo to afford a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 19:1. Combination and evaporation of the appropriate fractions gave an oil which was triturated with ether to afford the title compound, m.p. 176°-180.5°. The mother liquors were evaporated and the residue was rechromatographed on silica, as before, to give a further crop of material (total yield 17.3 g).
Reaction SMILES: [K+].[C:2]1(=[O:17])[N:6]([CH2:7][S:8]([O-])(=[O:10])=[O:9])[C:5](=[O:12])[C:4]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:3]12.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1C=CC=CC=1>[C:2]1(=[O:17])[N:6]([CH2:7][S:8]([Cl:19])(=[O:10])=[O:9])[C:5](=[O:12])[C:4]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CS(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [K+]
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CS(=O)(=O)Cl
Reaction time: 1.5 h

Procedure:
To 41.7 g. (0.15 mol.) of phthalimidomethanesulfonic acid potassium salt in 220 ml. of dry benzene is added 22.5 g. (0.132 mol.) of phosphorus pentachloride. The reaction mixture is refluxed on a steam bath for one hour, then an additional 22.5 g. of phosphorus pentachloride is added and heating is continued for 1.5 hours. The reaction mixture is evaporated to dryness, crushed ice is added to the residue and the slurry is filtered. The product is washed with water to give phthalimidomethanesulfonyl chloride.