Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][S:13]([C:16]1[C:21]2=[N:22][S:23][N:24]=[C:20]2[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].O[Li].O.Cl>C1COCC1.O>[N:24]1[S:23][N:22]=[C:21]2[C:16]([S:13]([NH:12][C:5]3[CH:6]=[C:7]([Cl:11])[C:8]([Cl:10])=[CH:9][C:4]=3[C:3]([OH:25])=[O:2])(=[O:15])=[O:14])=[CH:17][CH:18]=[CH:19][C:20]=12
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid methyl ester (0.95 g, 2.3 mmol) in THF (21 mL) and water (7 mL) was added LiOH.H2O (0.38 g, 9.1 mmol). The biphasic mixture was stirred overnight at rt. The mixture was acidified with conc. HCl and extracted with DCM (3×). The combined organic layers were dried (MgSO4) and concentrated to provide 0.80 g (88%) of the pure acid as a white solid. 1H NMR (500 MHz, CDCl3): 11.07 (s, 1H), 8.41 (dd, J=7.0, 1.0, 1H), 8.27 (dd, J=8.8, 1.0, 1H), 8.01 (s, 1H), 7.94 (s, 1H), 7.75 (dd, J=8.8, 7.0, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[C:7](Cl)([Cl:9])=[O:8].C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:9][C:7]([O:6][C@@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O=C(Cl)Cl
Reactant: O[C@@H]1CCOC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cl)O[C@@H]1CCOC1
Temperature: 25 °C
Yield: 85 %

Procedure:
A stirred solution of (R)-tetrahydrofuran-3-ol (7.9 g, 90 mmol) in anhydrous CH2Cl2 (50 mL) under an N2 atmosphere was cooled in an ice bath, and a 20% solution of phosgene in toluene (134 mL, 270 mmol) was slowly added. The reaction was allowed to warm to room temperature overnight, and the solvent was removed under vacuum to afford (R)-tetrahydrofuran-3-yl chloroformate (12.1 g, 85%) as a clear liquid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]2[C:3]=1[CH2:4][CH:5]([CH3:15])[CH2:6][C:7]2=[O:14].B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH2:4][CH:5]([CH3:15])[CH2:6][C:7]2=[O:14]
Reactant: COc1ccc(Br)c2c1C(=O)CC(C)C2
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC1CC(=O)c2c(O)ccc(Br)c2C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 5-bromo-8-methoxy-3-methyl-1,2,3,4-tetrahydronaphthalen-1-one (32.2 g 0.12 mol) in DCM (400 mL) at 0° C. was added boron tribromide (119 mL of a 1.0 M solution in DCM, 0.12 mol) dropwise. The mixture was stirred at 5° C. for 1 h then water (50 mL) was added cautiously. The mixture was washed with water (3×200 mL) then the organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with hexane: DCM (100:0-1:1), to afford the phenol (23.5 g, 77%). 1H NMR (250 MHz, CDCl3) δ 1.18 (3H, d, J=6.1 Hz), 2.22-2.55 (3H, m), 2.69-2.77 (1H, m), 3.14-3.23 (1H, m), 6.74 (1H, d, J=8.9 Hz), 7.59 (1H, d, J=8.9 Hz), 12.54 (1H, s)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][NH:14]3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[N+](C1C=C(C=CC=1)N)([O-])=O.[Cl:27][C:28]1[CH:41]=[CH:40][C:31]2[S:32][C:33]([S:36](Cl)(=[O:38])=[O:37])=[C:34]([CH3:35])[C:30]=2[CH:29]=1>>[Cl:27][C:28]1[CH:41]=[CH:40][C:31]2[S:32][C:33]([S:36]([N:14]3[C:15]4[C:11](=[CH:10][CH:9]=[C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH:16]=4)[CH2:12][CH2:13]3)(=[O:37])=[O:38])=[C:34]([CH3:35])[C:30]=2[CH:29]=1
Reactant: CN1CCN(c2ccc3c(c2)NCC3)CC1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Agent: Nc1cccc([N+](=O)[O-])c1
Product: Cc1c(S(=O)(=O)N2CCc3ccc(N4CCN(C)CC4)cc32)sc2ccc(Cl)cc12

Procedure:
The title compound (E123) was prepared from 6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole (prepared from 3-nitroaniline, using methodology of WO95/06637 Intermediate 3) (39 mg, 0.18 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (50 mg; 0.18 mmol) using the method of Example 1 (75 mg, 84%) MH+=462/464.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: NC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)Nc1cccc(OCCCCl)c1
Reaction time: 20 h
Yield: 83.1 %

Procedure:
A mixture of 45.6 g (0.3 mole) of 1-(3-hydroxyphenyl)urea, 94.5 g (0.6 mole) of 1-bromo-3-chloropropane, 124.4 g (0.9 mole) of anhydrous potassium carbonate and 1 liter of acetone was heated at reflux with mechanical stirring for 20 hr. The mixture was concentrated and the residue was slurried with 1.5 liters of water. The mixture was filtered and the filter cake was recrystallized from isopropanol to yield 57.0 g (83%) of off-white solid, m.p. 141°-143° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]2[C:15]([N:17]2[CH2:23][C:22]3[CH:24]=[C:25]([C:28]4[CH:29]=[C:30]5[N:36](C(OCC(C)C)=O)[CH:35]=[N:34][C:31]5=[N:32][CH:33]=4)[CH:26]=[CH:27][C:21]=3[O:20][CH2:19][CH2:18]2)=[O:16])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C.C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]2[C:15]([N:17]2[CH2:23][C:22]3[CH:24]=[C:25]([C:28]4[CH:29]=[C:30]5[N:36]=[CH:35][NH:34][C:31]5=[N:32][CH:33]=4)[CH:26]=[CH:27][C:21]=3[O:20][CH2:19][CH2:18]2)=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)COC(=O)n1cnc2ncc(-c3ccc4c(c3)CN(C(=O)N3CCC(=O)CC3c3cccc(F)c3)CCO4)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C1CCN(C(=O)N2CCOc3ccc(-c4cnc5[nH]cnc5c4)cc3C2)C(c2cccc(F)c2)C1
Yield: 289.6 %

Procedure:
2-methylpropyl 6-(4-{[2-(3-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate (0.19 g, 0.32 mmol) and potassium carbonate (0.20 g, 1.4 mmol) in methanol (10 mL) was stirred for 45 minutes at 25° C. The mixture was diluted with ethyl acetate (80 mL) washed with water (50 mL) and brine (25 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (methanol/ethyl acetate 1:10). Residue obtained by the concentration of product containing fractions was stirred 18 hours at 25° C. in diethyl ether (20 mL) and the solid product thus formed was isolated by filtration to give 2-(3-fluorophenyl)-1-{[7-(3H-imidazo[4,5-b]pyridin-6-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]carbonyl}piperidin-4-one (0.45 g, 27% yield). 1H NMR (400 MHz, d6-DMSO): 8.62 (s, 1H), 8.47 (s, 1H), 8.18 (s, 1H), 7.69 (d, 1H), 7.57 (d, 1H), 7.24 (q, 1H), 7.10-7.01 (m, 4H), 5.19 (t, 1H), 4.61 (m, 2H), 4.24 (m, 2H), 3.72 (m, 3H), 3.41 (m, 2H), 2.84 (m, 2H), 2.61 (m, 1H), 2.34 (d, 1H); MS (EI) for C27H24FN5O3: 486 (MH+).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([O:16]COC)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH3:3].Cl>O1CCOCC1.O.[Cl-].[Na+].O>[CH3:3][CH:2]([C:4]1[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([OH:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH3:1]
Reactant: COCOc1c(-c2ccccc2)c(C(C)C)cc2cc(OC)ccc12
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(O)c(-c3ccccc3)c(C(C)C)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
3-(1-Methylethyl)-6-(methyloxy)-1-{[(methyloxy)methyl]oxy}-2-phenyl naphthalene (71) (0.42 g, 1.24 mmol) was dissolved in dioxane (8 mL). 4 M HCl in dioxane (8 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with water (25 mL) and brine (25 mL) and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light yellow oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (20:1) to give 0.36 g (98%) of the title compound (72) as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.16 (d, J=6.8 Hz, 6H), 2.79 (sept, J=6.8 Hz, 1H), 3.93 (s, 3H), 5.08 (s, 1H), 7.05-7.12 (m, 2H), 7.30 (s, 1H), 7.32-7.38 (m, 2H), 7.42-7.50 (m, 1H), 7.50-7.58 (m, 2H), 8.07 (d, J=9.0 Hz, 1H). LCMS (APCI): m/z 293 (M+H)+.
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.C(N(CC)CC)C.[CH2:16]([O:23][C:24](=[O:34])[C@H:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCCC1>[CH2:16]([O:23][C:24](=[O:34])[C@H:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:26][C:5]([N:39]1[CH2:40][CH2:41][CH:36]([CH3:35])[CH2:37][CH2:38]1)=[O:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1CCN(C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trichloromethyl chloroformate (0.44 ml) was added to a solution of triethylamine (1.48 g) in dry tetrahydrofuran (15 ml) under ice-cooling and a solution of L-phenylalanine benzyl ester (1.27 g) in dry tetrahydrofuran (7.5 ml) was dropwise added slowly. Then, a solution of 4-methylpiperidine (1.15 ml) in dry tetrahydrofuran (7.5 ml) was dropwise added. The mixture was stirred at room temperature for 1 hour. The resulting salt was collected by filtration and washed with ethyl acetate (70 ml). The combined filtrate was washed twice with 0.1N hydrochloric acid, twice with a saturated aqueous solution of NaHCO3 and saturated brine, and dried over MgSO4. The solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (eluted with AcOEt/Hex=4/6 v/v) to give 1.86 g of the title compound as a colorless oil (see Table 11).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccccc1Cl
Product: O=C(Cl)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A mixture of 30.0 gm (0.176 mole) of o-chlorophenylacetic acid and 40.0 mL of thionyl chloride was stirred at ambient temperature for 18 hours. The volatiles were then removed in vacuo to give 32.76 gm (99.0%) of o-chlorophenylacetyl chloride as a transparent, pale yellow, mobile liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1.[H-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][C:12]2[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)cc(C)c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1N
Yield: 73.4 %

Procedure:
By using 1.10 g of 4-amino-3,5-dimethylphenol, 2.29 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 30 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 2.27 g of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24]O)[CH:19]=[CH:20][C:21]=1[CH2:22][CH3:23]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:24][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH:19]=[CH:20][C:21]=1[CH2:22][CH3:23]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1ccc(CO)cc1Cl
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)cc1Cl

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-ethylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.23 (3H, t, J=8.0 Hz), 2.76 (2H, t, J=8.0 Hz), 5.18 (2H, s), 5.74 (1H, d, J=0.8 Hz), 7.26 (2H, s), 7.40-7.44 (2H, m), 7.57 (1H, s), 8.03 (1H, s), 8.72 (1H, d, J=4.8 Hz). [M+H] Calc'd for C18H15ClN4O, 339; Found, 339.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.Br[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>O.CS(C)=O>[N:21]1[CH:22]=[CH:23][C:18]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:19][CH:20]=1
Reactant: Brc1ccncc1
Reactant: OCCCCCSc1nc2ccccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc2[nH]c(SCCCCCOc3ccncc3)nc2c1
Temperature: 150 °C
Yield: 31.9 %

Procedure:
0.47 g of the compound obtained in Example 13a, 0.30 g of 4-bromo-pyridine, 0.80 g of KOH and 0.20 g of 18-crown-6-ether were added to 20 ml of dimethyl sulfoxide and heated to 150° C. for 8 hours. The reaction mixture was cooled, then added with water and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 0.19 g of the title compound (yield: 30%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:6][NH:7][CH:8]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]([O:11][C:12](C)(C)[CH3:13])=[O:10])#[N:2].[NH2:24][OH:25]>C(O)C.O>[NH2:2][C:1](=[N:24][OH:25])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH2:6][NH:7][CH:8]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: NO
Reactant: CC(C)CC(NCc1cc(F)cc(C#N)c1)C(=O)OC(C)(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC(C)C)NCc1cc(F)cc(C(N)=NO)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
To tert-butyl 2-[(3-cyano-5-fluorobenzyl)amino]-4-methylpentanoate (3.0 g, 9.4 mmol) in ethanol (30 mL) was added hydroxylamine (1.2 mL, 0.019 mol) and it was stirred at 0° C. for 16 hrs. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried and concentrated. The crude product was purified by chromatography using petroleum ether/ethyl acetate as eluent, affording the title compound as a white solid (2.3 g, 70%). 1H NMR (DMSO-d6, 400 MHz): δ 9.73 (s, 1H), 7.46 (s, 1H), 7.30 (d, J=9.6 Hz, 1H), 7.13 (d, J=9.6 Hz, 1H), 5.84 (s, 2H), 3.75 (d, 1H), 3.55 (d, 1H), 2.98 (s, 1H), 2.38 (brs, 1H), 1.76-1.69 (m, 1H), 1.40 (s, 9H), 1.37 (dd, 2H), 0.96 (d, 3H), 0.87 (d, 3H). LC/MS (Method B) 354.3 (M+H)+. HPLC (Method A) Rt: 2.96 min (Purity 98.3%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CCO>[N:1]1([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2ncnc(Cl)c2c1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCO
Product: COc1ccc2ncnc(N3CCCc4ccccc43)c2c1
Yield: 59 %

Procedure:
Utilizing a procedure analogous to that described in Example 2, this product was prepared in 59% yield from 1,2,3,4-tetrahydroquinoline (2 eq.) and 4-chloro-6-methoxy-quinazoline (1.0 eq) in EtOH. (M.P. 98° C.; LC-MS: 292 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH3:28][N:29]([CH3:35])[S:30]([CH:33]=[CH2:34])(=[O:32])=[O:31]>>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:34][CH2:33][S:30]([N:29]([CH3:35])[CH3:28])(=[O:32])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: C=CS(=O)(=O)N(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CCS(=O)(=O)N(C)C)C3)cc1OCC2

Procedure:
Following the procedure of Example 152, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with N,N-dimethylethenesulfonamide to give 197 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.44 (1H, d, J=8.28 Hz), 7.84 (1H, d, J=0.67 Hz), 7.61 (1H, s), 7.05 (1H, dd, J=8.32, 1.83 Hz), 6.95 (1H, d, J=1.78 Hz), 6.00-5.90 (1H, m), 4.48-4.39 (4H, m), 3.80-3.72 (2H, m), 3.72-3.64 (1H, m), 3.27-3.19 (2H, m), 3.02-2.89 (4H, m), 2.87 (6H, s), 1.56 (6H, d, J=6.63 Hz). LCMS: RT=6.35 min, M+H+=486
Reaction SMILES: [CH3:1]N(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[H-].[Na+].CI>CCCCCC.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH3:1])(=[O:14])=[O:15])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(C(C)(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reaction time: 0.25 h
Yield: 93 %

Procedure:
An N,N-dimethylformamide (5 ml) solution of the 2-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-5-methylpyridine (52 mg, 0.132 mmol) obtained in Example 15 was added dropwise to an N,N-dimethylformamide (5 ml) suspension of sodium hydride (60% in oil) (30 mg, 0.75 mmol) under ice cooling. After the reaction mixture was stirred for 15 minutes under ice cooling, methyl iodide (12 μl, 0.198 mmol) was added thereto. After stirring at room temperature for 1 hour, water was added to the reaction mixture under ice cooling. The resulting mixture was concentrated under reduced pressure. To the residue was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=8:1 eluate was concentrated under reduced pressure. The residue thus obtained was solidified with hexane and collected by filtration to give the title compound (50 mg, 0.122 mmol, 93%) as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH3:10][O:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[CH3:10])(=[O:3])[CH3:2].[CH3:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([OH:14])(=[O:13])=[O:11])=[CH:16][CH:17]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)c1ccccn1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc[n+]1C
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
50.0 g (0.41 mol) of 2-acetylpyridine and 80.6 g (0.43 mol) of p-toluenesulfonic acid methyl ester were refluxed in 250 ml of toluene for 5 hours. After cooling, the light brown solid that had formed was filtered off, rinsed with toluene and dried under vacuum. Yield: 77.2 g (61%); 1H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.30 (s, 31-1); 2.81 (s, 3H); 4.35 (s, 3H); 7.10 (d, 2H); 7.47 (d, 2H); 8.26 (dd, 1H); 8.61 (d, 1H); 8.78 (dd, 1H); 9.18 (d, 1H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=C(C5C=CC=CC=5)C5C=CC=CC=5)[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.Cl.C(=O)(O)[O-]>O1CCCC1.CCOCC>[NH2:34][C:30]1[CH:29]=[C:28]([C:14]2[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[N:17]=3)=[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([NH:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:12]3[N:13]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(C(=Nc2cccc(-c3nn4c(NC5CCCC5)cccc4c3-c3ccnc(NC4CCCC4)n3)c2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reaction time: 0.08 h
Yield: 93 %

Procedure:
To a solution of N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-{3-[(diphenylmethylene)amino]phenyl}-pyrazolo[1,5-a]pyridin-7-amine (2.61 g, 4.22 mmol) in tetrahydrofuran (30 mL) at 0° C. was added 4N hydrochloric acid (20 mL) dropwise. Subsequently, the reaction mixture was stirred for 5 minutes. The reaction mixture was diluted with ether, then saturated aqueous bicarbonate was added slowly till the ether layer turned clear. The resulting mixture was stirred for 30 minutes. The phases were separated, the organic phase was washed with water, brine and dried (magnesium sulfate). Filtration and concentration of the filtrate to a solid, followed by recrystallization from ethyl acetate-hexanes, gave 2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (1.78 g, 93%) as a pale yellow solid. 1H NMR (CDCl3): δ 7.92 (d, 1H), 7.82 (d, 1H), 7.32 (t, 1H), 7.22 (m, 2H), 7.00–6.94 (m, 2H), 6.78 (m, 1H), 6.34 (d, 1H), 6.04 (m, 2H), 4.38 (m, 1H), 4.00 (m, 1H), 3.75 (broad, 2H), 2.14–2.05 (m, 4H), 1.83–1.54 (m, 12H); MS m/z 454 (M+1).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[I:12]Cl.O>CC(O)=O>[I:12][C:9]1[CH:10]=[C:4]([O:3][CH:2]([F:11])[F:1])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: ClI
Reactant: Nc1ccc(OC(F)F)cc1
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(OC(F)F)cc1I
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 22.3 %

Procedure:
A solution of 4-(difluoromethoxy)aniline (1.0 g, 6.30 mmol) in AcOH (6 mL) was heated to 60° C. and iodine monochloride (1.07 g, 6.6 mmol) in AcOH (15 mL) was added dropwise. The reaction mixture was then heated to 85° C. and stirred for 1.5 h. The reaction mixture was cooled to r.t. and poured into cold water and the resulting suspension filtered. The filtrate was concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 10-20% EtOAc/hexanes) gave the title compound (0.40 g, 22%) as a dark brown oil. δH (DMSO-d6) 7.38 (1H, d, J 2.7 Hz), 6.98-6.94 (1H, m), 6.97 (1H, t, J 74.8 Hz), 6.75 (1H, d, J 8.8 Hz), 5.20 (2H, br. s). LCMS (ES+) 286.0 (M+H)+, RT 3.28 minutes (Method 5).