Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:14]([C:15]3[C:16]([CH3:22])=[N:17][O:18][C:19]=3[CH2:20][OH:21])=[CH:13][N:12]([CH3:23])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:31][S:32]([O:21][CH2:20][C:19]1[O:18][N:17]=[C:16]([CH3:22])[C:15]=1[C:14]1[C:10]([C:8](=[O:9])[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:11][N:12]([CH3:23])[CH:13]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1noc(CO)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(COS(C)(=O)=O)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of (4-chlorophenyl)(4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)methanone (0.05 g, 0.15 mmol) in DCM (10 mL), was added triethylamine (0.1 mL) and methane sulfonyl chloride (0.05 mL) at room temperature. The mixture was stirred for 2 h at room temperature. DCM (50 mL) and saturated sodium bicarbonate solution (20 mL) were added. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the titled product as yellow oil (0.035 g, 56%). LC/MS m/z 409 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[CH3:13]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([O:9][CH3:13])=[O:8]
Reactant: O=C(O)C=Cc1cccc(Br)c1
Reactant: CO
Product: COC(=O)C=Cc1cccc(Br)c1
Yield: 81 %

Procedure:
Reaction of 3-bromocinnamic acid (22.72 g) with methyl lodide (21.3 g) as described in Example 1 gave the title ester (19.5 g, 81%) as a white solid mp (methanol) 62°-65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][C:34]([CH3:45])([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35](Cl)=[O:36]>N1C=CC=CC=1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[C:34]([CH3:33])([CH3:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: CC(C)(Cc1ccccc1)C(=O)Cl
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)C(C)(C)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.250 g, 0.573 mmol) in pyridine (3 mL) at 0° C. was treated with 2,2-dimethyl-3-phenylpropanoyl chloride (0.304 g, 1.55 mmol). The reaction mixture was stirred for 10 min at 0° C. The ice bath was removed and the reaction mixture was stirred at room temperature for 5 h. Solvent was removed under reduced pressure to dryness. Dichloromethane (15 mL) and saturated sodium bicarbonate solution (5 mL) were added to the solid. The layers were separated using an Empore extraction cartridge. The organic solvent was removed under reduced pressure. The crude solid was purified by flash chromatography using 10% methanol in dichloromethane, then 15% (methanol with 5% ammonium hydroxide) in dichloromethane as eluent. The crude solid from the previous purification was recrystallized using ethyl acetate and heptane. The precipitate was filtered to give 0.201 g (59%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide. A hot solution of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide (0.201, 0.337 mmol) in ethyl acetate was treated with a hot solution of maleic acid (0.117 g, 1.011 mmol) in ethyl acetate. The precipitate was filtered under nitrogen, and dried under high vacuum to give 0.265 g of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2,2-dimethyl-3-phenylpropanamide tri-maleate. 1H NMR (DMSO-d6, 400 MHz) δ 8.46 (s, 1H), 8.241 (s, 1H), 8.107-8.086 (d, 1H, J=8.4 Hz), 7.248-7.183 (m, 7H), 6.170 (s, 6H), 4.697 (m, 1H), 3.883 (s, 3H), 2.931 (s, 3H), 2.9-2.75 (br, s, 4H), 2.671 (s, 3H), 2.104-1.990 (m, 7H), 1.588-1.5632 (m, 2H), 1.226 (s, 7H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 5.413 min (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:10])=[O:11]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a solution of 3-(2,5-dichlorophenylsulfonyloxy)-5-methylphenol (642 mg, 2.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl) dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (700 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.56 (s, 2H), 6.63 (s, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.82 (m, 2H), 2.26 (s, 3H), 2.00 (m, 2H), 1.58 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH2:13][CH3:14])([O-:12])=[O:11].N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:13](/[N+:10]([O-:12])=[O:11])\[CH3:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC[N+](=O)[O-]
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C/C(=C\c1ccc(Cl)cc1)[N+](=O)[O-]
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of 4-chlorobenzaldehyde (28.57 g, 203 mmol), nitroethane (44.0 mL, 610 mmol) and piperidine (4.01 mL, 40.6 mmol) in toluene (200 mL) was stirred at reflux (Dean-Stark) for 6 h and the mixture was stored at room temperature overnight. The solvent was removed under reduced pressure and the product was recrystallised from absolute EtOH. The crystals were filtered off, washed with a small amount of absolute EtOH and dried to give 23.25 g of the desired product. The mother liquor was concentrated, heated, cooled. Another batch of crystals was filtered off, washed with a small amount of absolute EtOH and dried in vacuo, to afford 3.95 g of the desired product. Total yield: 27.20 g (68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=S)[NH:10][NH2:11])=[CH:4][CH:3]=1.Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)Nc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccc(Cl)cc2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
A suspension of 20.1 g (0.10 mole) of 4-(4-chlorophenyl)-3-thiosemicarbazide in 80 mL of absolute ethanol was treated with 16.5 g (0.10 mole) of ethyl 2-chloroacetoacetate and the mixture stirred for 1.0 hr at room temperature. Alcoholic hydrogen chloride (2N, 60 mL) was added and the dark precipitate dissolved while heating the mixture at reflux for 1.0 hr. The solution was filtered while hot, and the filter cake washed with absolute ethanol. The filtrate was evaporated under reduced pressure and the residue triturated in cold absolute ethanol and filtered. Both filter cakes were found to be the same compound by TLC (10% methanol in benzene on silica gel). The two were combined, dissolved in hot absolute ethanol (the hydrochloride salt was water insoluble), partially neutralized with saturated aqueous sodium bicarbonate, and the solid filtered (10.4 g, mp 212°-226° C.). A second crop was obtained by treating the filtrate with saturated aqueous sodium bicarbonate (11.5 g, mp 220°-225° C.). The second crop was recrystallized from absolute ethanol to give 3.8 g of product, mp 223°-225° C. This solid was dried at 100° C./0.1 mmHg/3 hr; then for ~16 hr at RT/0.1 mmHg.
Reaction SMILES: COC1C=CC([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=CC=1.C(Br)C>CC(C)=O>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][NH2:9]
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Solvent: CC(C)=O
Solvent: CCBr
Product: NCCCOc1ccc2ccccc2c1

Procedure:
A mixture of N-(4-methoxyphenyl)-[3-(naphthalen-2-yloxy)propyl]amine (0.5 gm, 0.002 mole) and ethyl bromide(0.52 ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 12 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get oily compound which was further crystallized by benzene hexane mixture to get N-(4 methoxyphenyl)-N-ethyl [3-(naphthalen-2-yloxy)propylamine, crystallized as yellow oil, (yield 0.64 gm, 94.6%).
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=1.[Na+].[C:9]1([S:15]([O-:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH:7]1([S:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: BrC1=CCCCC1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)C1C=CCCC1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
Bromocyclohexene (35.9 ml, 310.5 mmol) is dissolved in 1 l of DMF, cooled down to 0° C. and after addition of benzenesulfinic acid sodium salt (86.6 g, 527.8 mmol) the mixture is stirred for 17 h at room temperature. Then the mixture is evaporated under high vacuum. The residue is diluted with ether, washed with water, dried over Na2SO4 and evaporated under reduced pressure. The crude product is purified by Flash-chromatography (ethyl acetate/hexanes (1:9), 1 kg silicagel).
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C:18](=[N:22][O:23][CH3:24])[CH2:17][CH2:16]3)[CH:12]=1)=[O:7])(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:24][O:23][N:22]=[C:18]1[C:19]2[C:15](=[CH:14][C:13]([C:11]3[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=3[C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CON=C1CCc2cc(-c3cc(C(=O)OC(C)(C)C)oc3-c3ccncc3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON=C1CCc2cc(-c3cc(C(=O)O)oc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The product from Step 2 (4.74 g, 11.7 mmol) was dissolved in trifluoroacetic acid (50 ml) and dichloromethane (50 ml). The solution was stirred at room temperature for 3 hours and then evaporated in vacuo, azeotroping three times with dichloromethane. The resulting solid was triturated with diethyl ether, filtered and dried to afford the title product (5.46 g), which was used without further purification; MS (AP−) m/e 347 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c(=O)c3ccccc3oc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c2ccccc2oc2c(CBr)cccc12
Yield: 70.3 %

Procedure:
A well-stirred mixture of the above 4-methylxanthenone (6.5 g, 31 mmol), N-bromosuccinimide (5.5 g, 31 mmol) and benzoyl peroxide (30 mg) in dry CCl4 (250 mL) was heated under reflux with powerful illumination for 3 h. The hot mixture was filtered, the filtrate was evaporated and the residue was crystallized from the minimum volume of boiling petroleum ether (ca. 1800 mL) to give 4-bromomethylxanthenone (VII: R1 =H, Z=CH2Br) (6.3 g, 71%) as colourless needles, mp 191°-192° C. Anal. (C14H9BrO2) C,H,N,Br.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC.C1C=CC=CC=1>[C:11]1([C:7]2[S:6][CH:10]=[CH:9][CH:8]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=C1CCCCC1
Reactant: c1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: c1ccccc1
Product: C1=C(c2cccs2)CCCC1
Reaction time: 16 h

Procedure:
n-Butyllithium (40.7 ml, 1.5 M) was added dropwise to a stirred solution of thiophene (5 g) in dry ether (50 ml) and the mixture heated under reflux for 30 min. After cooling to -78°, cyclohexanone (6.21 ml) in dry ether (30 ml) was added dropwise and the temperature allowed to rise to ambient. After 1h 2N hydrochloric acid (80 ml) was added and stirring continued for 16h. The organic layer was separated and the aqueous layer extracted with ether (2×40 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to give an oil, which was dissolved in benzene (50 ml) and heated under reflux in the presence of PTSA for 0.75h. the cooled solution was washed twice with 8% NaHCO3 solution and the aqueous solution extracted with ether (2×40 ml), dried (MgSO4) filteed and evaporated to give the title compound as an oil (9.83 g). TLC(F) Rf 0.73
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.[CH3:18]CCCCC>>[CH3:18][N:8]1[C:7]2[C:15](=[CH:16][CH:17]=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]3=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CCCCCC
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Product: Cn1c2ccccc2c2ccc3ccccc3c21
Yield: 97.3 %

Procedure:
Using the procedure outlined in Example 34A, 11H-benzo[a]carbazole (Cambridge Chemicals, Inc.) gave a 97.3% yield of 11-methyl-11H-benzo[a]carbazole, mp 167°-169°, (hexane), (C,H,N).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Product: CCOC(=O)c1nc(-c2cccc(OC)c2)c2snc(-c3ccc(Cl)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-Bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 3-methoxyphenylboronic acid: MS (m/z) 441.1 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[C:20]3=[CH:21][N:22]([C:24]4[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[N:23]=[C:19]3[C:18]([Br:32])=[CH:17][N:16]=2)[N:11]=[CH:10][N:9]=1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:32][C:18]1[C:19]2[C:20](=[CH:21][N:22]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[N:23]=2)[C:15]([NH:14][C:12]2[CH:13]=[C:8]([NH2:7])[N:9]=[CH:10][N:11]=2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Nc2ncc(Br)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Nc2ncc(Br)c3nn(-c4c(Cl)cccc4Cl)cc23)ncn1
Yield: 28.3 %

Procedure:
A solution of {6-[7-bromo-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-ylamino]-pyrimidin-4-yl}-carbamic acid tert-butyl ester (95 mg, 0.18 mmol) in DCM (2 mL) and TFA (1 mL) was stirred at room temperature for 3 hours. The solvent was removed and the residue partitioned between DCM and NaHCO3 (sat. aq.). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (70-90% ethyl acetate in cyclohexane), to afford the title compound as a white solid (23 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.22 (s, 1H), 9.29 (s, 1H), 8.15 (d, J=0.9 Hz, 1H), 8.04 (s, 1H), 7.84 (d, J=1.2 Hz, 1H), 7.82 (s, 1H), 7.73 (dd, J=7.1 and 9.0 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 6.74 (br s, 2H). LCMS (Method B): RT=3.25 min, m/z: 450 [M+H+].
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32]([CH:29]5[CH2:30][CH2:31][O:26][CH2:27][CH2:28]5)=[O:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CCOCC1

Procedure:
The title compound, white solid (22.3 mg, 74%), MS (ISP) m/z=443.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and tetrahydro-2H-pyran-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)(O)[C:4]([F:7])([F:6])[Cl:5].S(Cl)([Cl:22])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:19])([F:18])[C:3]([Cl:22])([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)[C:4]([F:7])([F:6])[Cl:5]
Reactant: CCOc1ccc(C(O)(C(F)(F)F)C(F)(F)Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccc(C(Cl)(C(F)(F)F)C(F)(F)Cl)cc1

Procedure:
A mixture of 1,1,1,3,3-pentafluoro-2-(4-ethoxyphenyl)-3-chloropropan-2-ol (28 g), thionyl chloride (45 cm3) and pyridine (3 cm3) was heated at the reflux temperature for 4 hours, diluted with toluene and the volatile components removed by evaporation under reduced pressure. The residual oil was dissolved in chloroform, washed with water and dried over anhydrous magnesium sulphate. Removal of the solvent by evaporation under reduced pressure yielded 1,1,1,3,3-pentafluoro-2,3-dichloro-2-(4-ethoxyphenyl)propane (29.5 g) as a residual oil.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:6]=[C:7]([CH:11]2[NH:23][C:21]3[C:22]4[C:13](=[N:14][NH:15][C:16](=[O:24])[C:17]=4[CH:18]=[CH:19][CH:20]=3)[CH:12]2[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31](OCC)[O:32]CC)[CH:26]=2)[CH:8]=[CH:9][CH:10]=1)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[O:24]=[C:16]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[NH:23][CH:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[CH:4]=[O:3])[CH:12]([C:25]4[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=4)[CH:31]=[O:32])[C:13]([C:22]=23)=[N:14][NH:15]1
Reactant: CCOC(OCC)c1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C(OCC)OCC)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2cccc(C=O)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 8,9-bis(3-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, 0.46 mmol) in 3N hydrochloric acid (5 mL) was stirred at room temperature for 3 hr. The mixture was then adjusted to pH=8 with potassium carbonate. The resulting suspension was filtered to give 3,3′-(3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8,9-diyl)dibenzaldehyde (160 mg, yield 88%) as a light yellow solid. LC-MS (ESI) m/z: 396(M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23](F)=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15].O>CS(C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
2-methoxyethanol (152 mg, 2 mmol) was dissolved in 30 mL of dimethyl sulfoxide in an ice-water bath, followed by addition of 60% sodium hydride (80 mg, 2 mmol). The mixture was warmed up to 40° C. and stirred for 2 hours, then N-(3-chloro-4-fluoro-phenyl)-7-fluoro-6-nitro-quinazolin-4-amine 8a (336 mg, 1 mmol) was added. The reaction mixture was stirred for 4 hours at 40° C., then warmed up to 50° C. and stirred for 12 hours. The reaction mixture was added with water (20 mL), filtered and the filter cake was washed with water (50 mL), dried under vacuum to obtain the title compound N-(3-chloro-4-fluoro-phenyl)-7-(2-methoxyethoxy)-6-nitro-quinazolin-4-amine 8b (392 mg, yield 100%) as a yellow solid, which was directly used in the next step.
Reaction SMILES: [CH2:1]([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:29])(=[O:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:12][CH:11]=1)[C:6](Cl)=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[NH:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][CH2:41][CH2:40]1>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:29])(=[O:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:12][CH:11]=1)[C:6]([N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:42][CH2:41][CH2:40]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)N1CCCc2ccccc21

Procedure:
The title compound was prepared from N-butyl-N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]carbamoyl chloride (from Example 4, Step A), N,N-diisopropylethylamine, and 1,2,3,4-tetrahydroquinoline in toluene, according to the procedure of Example 4, Step A, to give 93% yield of the desired material after flash chromatography as a foam, homogeneous by TLC in 4:1 hexane-EtOAc; FAB-MS m/e 534 (M+1)+.