Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:23]=[C:11]3[N:12]=[C:13]([CH3:22])[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:15](Cl)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Na+].[I-:25]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:23]=[C:11]3[N:12]=[C:13]([CH3:22])[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:25])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)Cc1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Temperature: 80 °C
Yield: 81.3 %

Procedure:
Methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (1 g, 2.53 mmol) and NaI (1.519 g, 10.14 mmol) were suspended in acetonitrile (10 mL) and the resulting mixture was heated at 80° C. for 5 h. After cooling to room temp, mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL) and aqueous Na2S2O3 (25 mL), dried (Na2SO4), filtered and concentrated. Crude was then triturated with ethyl acetate/hexane to afford methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (1 g, 2.057 mmol, 81% yield) as off white solid. 1H NMR (400 MHz, CDCl3) δ: 8.20 (t, J=1.8 Hz, 1H), 7.95 (dt, J=7.8, 1.3 Hz, 1H), 7.55 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.08 (s, 1H), 4.02 (s, 2H), 3.79 (s, 3H), 2.66 (s, 3H). LCMS (M+H)=486.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][O:25]CC)[N:14]([CH2:15][CH2:16][NH:17][C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:24][OH:25])[N:14]([CH2:15][CH2:16][NH:17][C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCNC(=O)NC(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)NCCn1c(CO)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
A stirring solution of N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-isopropylurea (400 mg, 1.1 mmol) in dichloromethane (50 mL) was sealed with a septum and purged with nitrogen gas. The solution was cooled in an ice/water bath and a 1.0 M solution of boron tribromide in dichloromethane (2.2 mL) was added via syringe. The resulting mixture was stirred for 2 hours while warming to ambient temperature. The mixture was cooled back to 0° C. in an ice/water bath and the second portion of boron tribromide (1.0 M, 5.5 mL) was added. The reaction was stirred for 18 hours while warming to ambient temperature. Aqueous hydrochloric acid (6N, 10 ml) was added and the mixture was stirred for 1 hour. The layers were separated and the aqueous fraction was neutralized by the slow addition of solid sodium hydroxide until the pH reached 14. A fine precipitate formed. The aqueous mixture was extracted with chloroform (2×50 mL) and filtered. The resulting solid (filter cake) was combined with the organic extracts, methanol (50 mL), and silica gel (5 g). The mixture was concentrated under reduced pressure. The crude product absorbed on silica was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-35% CMA in chloroform over 2.6 L) followed by recrystallization from acetonitrile to provide 170 mg of N-{2-[4-amino-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl}-N′-isopropylurea as an off-white solid, mp>240° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.N1CCCCC1.[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.Cl[Pd]Cl.[Cu]I>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([C:36]#[C:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:3][N:4]=1
Reactant: C#Cc1ccccc1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C#Cc3ccccc3)c2c1
Reaction time: 20 h
Yield: 65 %

Procedure:
A solution of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.52 g, 1.5 mmoles), prepared as described in example 45, in dry DMF (10 ml) under N2 was added with piperidine (1 ml, 10 mmoles), phenylacetylene (0.15 g, 1.5 mmoles), PdCl2 (0.013 g, 0.075 mmole), triphenylphosphine (0.039 g, 0.15 mmole) and CuI (0.014 g, 0.075 mmole). The mixture was stirred for 20 hours, poured into saturated NHCl (10 volumes) and extracted twice with CH2Cl2, then washed with 5% HCl, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: CH2Cl2/ethyl ether 9:1). The resultant solid was triturated in ethyl ether to give 0.41 g of the title compound (yield: 52%). m.p.: 213.4-214.4° C. (dec.).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=3)C3C=CC=CC=3C(=O)O2)=[CH:4][CH:3]=1.[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>>[C:5]1([C:8]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:29][C:28]=2[C:27]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:25]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: ClCC1CO1
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Product: c1ccc(-c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
(A-1) 159 g of 3,3-bis(4-hydroxyphenyl)-2-benzofuran-1-on, 426.6 g of epichlorohydrin, and 160 g of a 50% alkali aqueous solution are mixed in a 1 L flask and then reacted together at 95° C. for 1 hour to form a bisphenylbenzofuran-type epoxy resin. 215 g of the bisphenylbenzofuran-type epoxy resin is mixed with 450 mg of triethylbenzylammoniumchloride, 100 mg of 2,6-diisobutylphenol, and 72 g of acrylic acid. The mixture is heated and completely dissolved at a temperature ranging from 90 to 120° C., while air is blown therein at a speed of 25 Ml per minute.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19].[Cl-].[Ca+2].[Cl-]>>[Cl:17][S:18]([C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[C:5](=[O:16])[C:6]=2[CH:7]=1)(=[O:20])=[O:19]
Reactant: O=c1c2ccccc2oc2ccc(Cl)cc12
Reactant: O=S(=O)(O)Cl
Agent: [Ca+2]
Agent: [Cl-]
Product: O=c1c2cc(Cl)ccc2oc2ccc(S(=O)(=O)Cl)cc12
Temperature: 120 °C
Yield: 98.1 %

Procedure:
80 g (0.347 moles) of 2-chloroxanthone (DHAR, J. Chem. Soc. 117, 1068) are suspended in 210 ml of chlorosulfonic acid (368.1 g; 3.16 moles) in a 500 ml one neck flask provided with refluxing coolant and calcium chloride valve. The mixture is slowly heated in an oil bath up to 120° C. under magnetic stirring. It is maintained at 120°-130° C. until the gas development ceases (2-3 h). The cool reaction mixture is carefully dropwise added to a becker containing ground ice under mechanical stirring. A heavy crystalline product is separated which is filtered on Buchner and washed with iced H2O. It is dried in air. There are obtained 112 g (98%) of raw 2-(chlorosulfonyl) 7-chloroxanthone. After TLC monitoring (silica gel F245 ; toluene, acetic acid 14:1, visualizer UV) the product is used as such for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:30][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCCCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCCC2)cn1
Yield: 100 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using cyclohexylamine instead of methylamine, to the title compound (126 mg, 100%) which was obtained as a white solid. MS: m/e=392.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:11]([CH2:12][CH3:13])[C:10]([C:14]3[C:15]([NH2:19])=[N:16][O:17][N:18]=3)=[N:9][C:4]=2[C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.B(OC)(OC)[O:26]C.C(=O)=O.CC(C)=O>C1COCC1>[NH2:19][C:15]1[C:14]([C:10]2[N:11]([CH2:12][CH3:13])[C:3]3[C:2]([OH:26])=[CH:7][N:6]=[C:5]([Cl:8])[C:4]=3[N:9]=2)=[N:18][O:17][N:16]=1
Reactant: COB(OC)OC
Reactant: CCn1c(-c2nonc2N)nc2c(Cl)ncc(Br)c21
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCn1c(-c2nonc2N)nc2c(Cl)ncc(O)c21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A suspension of 4-(7-bromo-4-chloro-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine (VI, 50 g, 0.14 mol) in THF (1 L) was cooled in a dry-ice/acetone bath until the internal temperature was below −75° C. Isopropyl magnesium chloride (225 mL, 2M in ether, 0.45 mol) was added slowly at a rate to keep the reaction temperature below −70° C. After an additional 10 min., trimethyl borate (54 mL, 0.48 mol) was added and the reaction was maintained in the dry-ice acetone bath for 1 h. The bath was removed and the reaction was allowed to reach ambient temperature. After 18 h., the resultant yellow suspension was cooled to 0° C. A solution of 30% hydrogen peroxide (250 mL) and 3N NaOH (100 mL) was added at a rate to keep the reaction temperature below 40° C. The ice bath was then removed and the reaction was stirred vigorously at ambient temperature for 2 h. The bulk of the organic solvent was removed under reduced pressure and the aqueous layer was acidified to pH 3 with 1N HCl. After stirring the resulting suspension for 30 min., ethyl acetate (200 mL) was added. After stirring for another 1 h, the solid was collected by filtration. The filter cake was washed sequentially with water, ethyl acetate, toluene and ethyl acetate. The solid was dried to a constant weight to give 35.9 g (88% yield) of the desired compound (VII) as a pale yellow solid. This was used without further purification. MS (ES+) m/z 281.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Mg+2].[Cl-].[CH2:15]=[O:16].C(N(CC)CC)C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:15]=[O:16])[C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cccc(C=O)c1O
Yield: 90 %

Procedure:
To a stirred suspension of 2-tert-butylphenol (3)(4.55 g, 30 mmol), magnesium chloride (5.71 g, 60 mmol) and paraformaldehyde (2.08 g, 66 mmol) in THF (120 mL) at room temperature, was added triethylamine (8.35 mL, 60 mmol) dropwise. The reaction was heated to reflux for 3 hours to give an orange suspension. This was extracted using EtOAc (3×50 mL). A small amount of diluted HCl can be added if a permanent emulsion is formed. The organic layers were dried over MgSO4 and the volatiles evaporated under low pressure to yield a pale yellow oil which did not need any further purification. It can become dark green on storage. Yield: 90%. Pale yellow oil. 1H-NMR δH: 1.44 (9H, s, 3×CH3), 6.97 (1H, t, J=7.5 Hz, HAr), 7.41 (1H, dd, J=1.5 Hz, J=7.5 Hz, HAr), 7.54 (1H, dd, J=1.2 Hz, J=7.5 Hz, HAr), 9.88 (1H, s, CHO), 11.82 (1H, s, OH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:13][N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].O[CH2:15][C@@H:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][N:12]([CH2:15][C@@H:16]([NH2:18])[CH3:17])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Clc1ccc(-c2ccn[nH]2)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](N)Cn1ccc(-c2ccc(Cl)c(Cl)c2)n1

Procedure:
Into a flask containing 5-(3,4-dichlorophenyl)-1H-pyrazole (1.5 g, 7.04 mmol), (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (1.357 g, 7.74 mmol) and triphenylphosphine (2.77 g, 10.56 mmol), dry THF (30 ml) was added under nitrogen atmosphere. After few minutes of stirring, DIAD (2.77 ml, 14.08 mmol) was added dropwise through a septum while using icebath to prevent the temperature from rising. The resulting mixture was stirred at RT overnight. The mixture was evaporated. The Boc-protection was removed by adding ethanol (7 ml), 10% HCl/EtOH (50 ml), concentrated HCl (5 ml) and stirring the mixture over the weekend. The mixture was evaporated, extracted with DCM/water. The pH of the water phase was adjusted to ˜12 using 2 M NaOH and extracting the phase again with DCM. The combined organic phases were dried with Na2SO4, filtered and evaporated. 1H-NMR (400 MHz; DMSO-d6): δ 1.00 (d, 3H), 4.70-4.87 (m, 3H), 6.84 (d, 1H), 7.65 (d, 1H), 7.76-7.84 (m, 2H), 8.02 (d, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[CH:31]([N:27]1[C:26]([C:20]2[S:21][C:22]3[CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:35]=[CH:34][C:17]=4[C:18]=3[N:19]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Reaction time: 18 h
Yield: 27.7 %

Procedure:
Alternatively, to a suspension of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (470 mg, 0.95 mmol) in MeOH (10 mL) was added 1M HCl in ether (1.9 mL, 1.90 mmol). The reaction mixture was stirred for 18 hours then the volatiles were removed in vacuo. The resultant residue was stirred in diethyl ether (20 mL) for 20 minutes then the solid was filtered off and further triturated with a mixture of MeOH and ether to give 375 as a white solid (104 mg, 28%). LCMS: RT=7.82 min, [M+H]+=396. 1H NMR δ (ppm) (DMSO-d6): 8.86 (2 H, s), 8.26 (1 H, d, J=8.20 Hz), 8.05 (1 H, s), 7.03 (1 H, dd, J=8.26, 1.83 Hz), 6.87 (1 H, d, J=1.78 Hz), 5.81-5.71 (1 H, m), 4.31 (2 H, t, J=5.01 Hz), 3.37 (2 H, t, J=5.01 Hz), 3.30 (2 H, d, J=12.46 Hz), 2.93 (2 H, d, J=11.52 Hz), 2.84-2.75 (1 H, m), 1.92-1.75 (4 H, m), 1.49 (6 H, d, J=6.59 Hz)
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]([CH3:13])([CH3:12])[CH2:4][C:5]1([CH3:11])[CH2:9][O:8][C:7](=[O:10])[NH:6]1.C(O[Cl:19])(C)(C)C>CO>[Cl-:19].[Cl:1][N:6]1[C:5]([CH2:4][N+:3]([CH3:13])([CH3:12])[CH3:2])([CH3:11])[CH2:9][O:8][C:7]1=[O:10]
Reactant: CC(C)(C)OCl
Reactant: CC1(C[N+](C)(C)C)COC(=O)N1
Agent: [Cl-]
Solvent: CO
Product: CC1(C[N+](C)(C)C)COC(=O)N1Cl
Reaction time: 3 h
Yield: 31.3 %

Procedure:
To a solution of N,N,N-trimethyl-1-(4-methyl-2-oxooxazolidin-4-yl)methanaminium chloride (1.52 mmol) in MeOH (1 ml) was added, dropwise, tert-butylhypochlorite (250 uL, 2.10 mmol). The solution was stirred for 3 h, evaporated, and purified by preparatory HPLC (H2O/CH3CN) to afford the title compound as a yellow foam (115.6 mg, 0.475 mmol, 31% over two steps). 1H NMR (D2O, 400 MHz) δ 1.64 (s, 3H), 3.31 (s, 9H), 3.80 (d, J=15.2 Hz, 1H), 3.88 (d, J=14.8 Hz, 1H), 4.61 (d, J=9.6 Hz, 1H), 4.93 (d, J=10.0 Hz, 1H). ESI/APCI expected for C8H16ClN2O2+: 207.09. Found: 207 (M+).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCN(Cc2ccccc2)CC1Cc1ccccc1
Reaction time: 1 h

Procedure:
Sodium borohydride (0.3 g, 9.0 mmole) was added to the stirred solution of 1,3-dibenzylpiperidin-4-one (1.8 g, 6.45 mmole) in methanol (25 ml) at 0-5° C. over a period of 5 min, and stirring was continued for 1 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 1,3-dibenzyl-4-hydroxypiperidine as oil. Yield 1.7 g (91%), C19H23NO, m/z 282 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[F:26][C:27]([F:33])([F:32])[S:28]([NH2:31])(=[O:30])=[O:29]>>[F:26][C:27]([F:33])([F:32])[S:28]([NH:31][C:17]([C:14]1[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH2:9][CH3:10])=[CH:12][CH:13]=1)=[O:18])(=[O:30])=[O:29]
Reactant: CCN(Cc1cc(Cl)ccc1OCC1CC1)c1ccc(C(=O)O)nn1
Reactant: NS(=O)(=O)C(F)(F)F
Product: CCN(Cc1cc(Cl)ccc1OCC1CC1)c1ccc(C(=O)NS(=O)(=O)C(F)(F)F)nn1
Yield: 18 %

Procedure:
The title compound was prepared from 6-[N-(5-chloro-2-cyclopropylmethoxybenzyl)-N-ethylamino]pyridazine-3-carboxylic acid (example 22) and trifluoromethanesulphonamide using a similar method to that of example 7. (Yield 18%). m.p. 150°-dec.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([Br:25])[CH:9]=1.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)(Cl)Cl>[C:26]([NH:7][C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:21])[F:22])=[CH:15][C:14]=2[Cl:24])[N:11]=[C:10]([Br:25])[CH:9]=1)(=[O:28])[CH3:27]
Reactant: Nc1cc(Br)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Br)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 95.3 %

Procedure:
Pyridine (4.0 ml) was added dropwise to a stirred solution of 5-amino-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (5.0 g), acetyl chloride (3.0 g) and dry chloroform (30 ml), causing an exothermic reaction (maximum temperature 60° C.). The reaction mixture was stirred at laboratory temperature for 2h and evaporated to dryness. The residue was dissolved in ethanol (25 ml), ammonia solution (d. 0.880; 25 ml) was added, and the solution was boiled under reflux for 1 h. The cooled reaction mixture was evaporated to dryness, dissolved in dichloromethane (100 ml), washed with dilute hydrochloric acid (3×50 ml) and water (50 ml), dried over anhydrous magnesium sulphate, filtered, and evaporated to give 5-acetamido-3-bromo-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole (5.3 g), m.p. 180-187° C., in the form of a pale brown solid.
Reaction SMILES: [Sn](Cl)Cl.[Br:4][C:5]1[CH:14]=[CH:13][C:8]([NH:9][CH:10]([CH3:12])[CH3:11])=[C:7]([N+:15]([O-])=O)[CH:6]=1.[OH-].[Na+]>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([NH2:15])[C:8]([NH:9][CH:10]([CH3:11])[CH3:12])=[CH:13][CH:14]=1
Reactant: CC(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Nc1ccc(Br)cc1N
Yield: 75.4 %

Procedure:
Tin(II) chloride (1.69 g, 8.90 mmol) is added to a solution of 4-bromo-N-isopropyl-2-nitroaniline (770 mg, 2.97 mmol) in ethanol. The mixture may be heated to reflux for an appropriate time (such as 4 hr) and cooled. 4 N sodium hydroxide is added to the solution which then may be filtered. The filtrate is extracted with ethyl acetate. The combined organic layer may be washed with brine and concentrated. The residue may be purified by any appropriate method including Biotage column chromatography to give 4-bromo-N-1-isopropylbenzene-1,2-diamine (513 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22]([OH:24])=O)=[CH:16][CH:15]=1)=[O:12].C(Cl)Cl.Cl.[NH2:29][OH:30]>CN(C)C=O.O1CCCC1>[OH:30][NH:29][C:22]([CH:21]=[CH:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])=[CH:15][CH:16]=1)=[O:24]
Reactant: NO
Reactant: O=C(O)C=Cc1ccc(NC(=O)c2ccc3ccccc3c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(C=Cc1ccc(NC(=O)c2ccc3ccccc3c2)cc1)NO
Temperature: 40 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
(Method H8) To a suspension of 3-{4-[(naphthalene-2-carbonyl)-amino]-phenyl}-acrylic acid (5c) (0.740 g, 1.75 mmol) in methylene chloride (8 ml) oxalyl chloride (0.54 ml, 6.14 mmol) and one drop of dimethylformamide were added. The mixture was stirred for 30 min. at room temperature and for 1 hour at 40° C. Then the mixture was concentrated under reduced pressure and the residue was diluted with tetrahydrofuran (8.0 ml). In an another vessel, to a suspension of hydroxylamine hydrochloride (0.695 g, 10.0 mmol) in tetrahydrofuran (12 ml) saturated NaHCO3 solution (8.0 ml) was added and the mixture was stirred at room temperature for 5 min. The both mixtures were combined and vigorously stirred at room temperature for 30 min. The solvents were evaporated and the residue was acidified with 3% HCl to pH 5. The resulting precipitate was filtered off and washed with water (3×10 ml). The crystallization from methanol/water provided the title compound as a white solid (0.262 g, 45%). M.p. 231-233° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.41 (d, 1H, J=15.8 Hz); 7.45 (d, 1H, J=15.8 Hz); 7.52-7.70 (m, 4H); 7.82-8.16 (m, 6H); 8.59 (s, 1H); 9.02 (s, 1H); 10.58 (s, 1H); 10.73 (s, 1H). HPLC analysis on Zorbax SB-C18 column: impurities <1% (column size 4.6×150 mm; mobile phase methanol×-0.1% H3PO4, gradient from 50:50 to 90:10; sample concentration 0.05 mg/ml; flow rate 1.5 ml/min.; detector UV 220 nm). Anal. Calcd for C20H16N2O3 containing 1% of inorganic impurities, %: C, 71.55; H, 4.80; N, 8.34. Found, %: C, 71.60; H, 4.78; N, 8.39.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:29][C:30]1[CH:42]=[CH:41][C:40]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][C:32]=2[CH:31]=1>CN(C=O)C>[CH:31]1[C:32]2[NH:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]=2[CH:41]=[CH:42][C:30]=1[O:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(c3)[nH]c3ccccc34)ncnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Yield: 21.3 %

Procedure:
To a solution of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), in DMF (10 ml) was added potassium carbonate (124 mg, 0.9 mmol, 3 eq.) followed by 2-hydroxycarbazole (66 mg, 0.36 mmol, 1.2 eq.) and the reaction heated at 100° C. for 4 hours. The DMF was removed in vacuo, the residue dissolved in dichloromethane and placed onto a 2g SCX ion-exchange column. Elution with dichloromethane, followed by 20% methanol/dichloromethane then 20% methanol/dichloromethane+3% ammonium hydroxide, gave the crude product as a brown solid. Further purification by silica bond elut chromatography eluting with dichloromethane to 15% methanol/dichloromethane+1% ammonium hydroxide, followed by trituration with ether gave 4-(9H-carbazol-2-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (31 mg, 22%) as a white solid.