Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([C:14]2[N:15]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:16]([CH3:23])=[C:17]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:18]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:31]([NH:35][C:11](=[O:13])[C:9]1[CH:8]=[C:7]([C:14]2[N:15]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:16]([CH3:23])=[C:17]([S:19](=[O:21])(=[O:22])[NH2:20])[CH:18]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:10]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)O)nc(C(C)(C)C)c2)n1CC1CCCCC1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)NC(C)(C)C)nc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.7 %

Procedure:
A mixture of compound 19 (150 mg, 0.34 mmol), tert-butylamine (36 mg, 0.48 mmol), HATU (207 mg, 0.54 mmol) and DIPEA (146 mg, 1.14 mmol) in DMF (5 mL) was stirred at rt for 20 min, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (PE/EA=2/1) to give compound 20 (46 mg, 30%) as a white powder. 1H-NMR (300 MHz, CDCl3) δ: 8.17 (s, 1H), 7.93 (d, 1H, J=1.5 Hz), 7.40 (d, 1H, J=1.5 Hz), 6.61 (s, 1H), 4.70 (d, 2H, J=5.4 Hz), 3.84 (d, 2H, J=6.9 Hz), 2.55 (s, 3H), 1.61 (m, 3H), 1.50 (s, 9H), 1.42 (s, 9H), 1.30-1.38 (m, 3H), 0.97-1.03 (m, 3H), 0.63 (m, 2H). MS Calcd.: 488; MS Found: 489 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[C:20](=[O:27])[NH:19][C:18]3[CH:28]=[CH:29][CH:30]=[N:31][C:17]2=3)=[O:15])[CH2:9][CH2:8]1)[CH3:2].[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([Cl:40])=[O:39])=[CH:36][CH:35]=1>C(OCC)(=O)C>[ClH:40].[ClH:40].[CH3:32][O:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([CH2:2][CH2:1][NH:3][CH2:4][CH2:5][CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:16]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[C:20](=[O:27])[NH:19][C:18]4[CH:28]=[CH:29][CH:30]=[N:31][C:17]3=4)=[O:15])[CH2:9][CH2:8]2)=[O:39])=[CH:36][CH:35]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCNCCCC1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CCNCCCC2CCN(CC(=O)N3c4ccccc4C(=O)Nc4cccnc43)CC2)cc1
Product: Cl
Yield: 81 %

Procedure:
Prepared analogously to Example 1 from 5,11-dihydro-11-[[4-[3-(ethylamino)propyl]-1-piperidinyl]acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 4-methoxybenzoic acid chloride. The free base is dissolved in ethyl acetate and the dihydrochloride is precipitated by the addition of ethereal hydrochloric acid. The desired compound is obtained in a yield of 81% by recrystallisation from ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:45])[N:24]([CH2:34][C:35]([O:37]CC1C=CC=CC=1)=[O:36])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd].CCOC(C)=O>[C:1]([O:5][C:6](=[O:46])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:45])[N:24]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:34][C:35]([OH:37])=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)CC(=O)O
Yield: 80 %

Procedure:
17-[Benzyloxycarbonylmethyl-(2-tert-butoxycarbonyl-ethyl)-carbamoyl]-heptadecanoic acid tert-butyl ester (0.054 g, 0.08 mmol) was dissolved in THF (2 ml). 10% Palladium on Charcoal was added and the mixture was hydrogenated at 1 atm and RT over the week-end. The dry reaction mixture was dissolved in EtOAc and filtered 3 times to remove the carbon. The filtrate was concentrated to give 17-[(2-tert-Butoxycarbonyl-ethyl)-carboxymethyl-carbamoyl]-heptadecanoic acid tert-butyl ester in 80% yield (37 mg).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][NH2:8])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][NH:8][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: C=CCOCC(O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOCC(O)CNC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Allyloxy-2-hydroxy-propylamine made in Example 8 (110 g, 0.84 mol), triethylamine (85.6 g, 0.84 mol), and methylene chloride (300 mL) were mixed in a two-liter, two-neck flask, which was placed in an ice bath. To the above mixture, methacryloyl chloride (90.36 g, 84 mol) was added dropwise through an additional funnel at 0° C. After completion of the addition of methacryloyl chloride, the whole mixture was allowed to warm up to room temperature and stirred at ambient temperature overnight (˜15 hours). The reaction suspension was diluted with 250 mL of methylene chloride and washed with 5% aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, 5% aqueous sodium chloride solution and then followed by washing with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate (100 g). After the removal of sodium sulfate by filtration, 4-methoxyphenol (0.5 g) was added to the filtrate. The solution was concentrated under vacuum using a rotovap to give about 122 g of crude N-(3-allyloxy-2-hydroxy-propyl)-2-methyl acrylamide. N-(3-Allyloxy-2-hydroxy-propyl)-2-methyl acrylamide was purified by distilling the raw material inhibited with 1% of 4-methoxyphenol under vacuum at 168° C.-170° C. (7-8 mbar) using Kugelrohr distillation equipment.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:20])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:10]([CH3:11])[C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][O:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:14][CH2:13]2)=[O:20])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CO)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.6 g (2.03 mmol) of trans-(4-Hydroxymethyl-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester in 15 ml CH2Cl2 was treated with 0.17 ml (2.24 mmol) methanesulfonylchloride, 0.5 ml (6.1 mmol) pyridine and 0.25 g (2.03 mmol) DMAP at 0° C. The reaction mixture was warmed up over night to room temperature, water (2 ml) was added and the reaction mixture was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×), the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 0.74 g (96%) of trans-Methanesulfonic acid 4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexylmethyl ester, mp: 134-135° C.; MS: 376 (MH+, 1 Cl).
Reaction SMILES: Cl[C:2]1C=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])=[CH:12][CH:11]=1.CC[N:23](C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:18][CH2:17][C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)([CH3:20])[CH3:19])=[N:23][CH:6]=1
Reactant: CC(C)(CN)c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ccc(Br)cn1
Solvent: Cc1ccccc1
Product: CC(C)(CNc1ncc(Br)cn1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
To a 20 dram vial was added 2-chloro-5-bromopyridine (440 mg, 2.3 mmol, 1.1 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (350 mg, 2.1 mmol, 1.0 equiv), DIPEA (1.0 mL, 5.7 mmol, 2.7 equiv), and toluene (5 mL). The vial was heated in an oil bath to 80° C. and stirred for 12 h, concentrated, and purified by silica gel column chromatography (0-30% EtOAc/hexanes) to give 270 mg (40%) of 5-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:20].[Na+].OO>C1COCC1.O.CCOC(C)=O>[OH:20][C@@H:8]1[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][C@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC=C(c2ccccc2)C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Temperature: 22 °C
Reaction time: 0.08 h
Yield: 77.8 %

Procedure:
Add slowly over 35 minutes a 1M solution of borane tetrahydrofuran complex (137.35 mmol; 137.35 mL) to a solution of tert-butyl 5-phenyl-3,6-dihydro-2H-pyridine-1-carboxylate (137.35 mmol; 36.20 g) in anhydrous THF (362.00) at 0° C. under nitrogen and warm the mixture to 22° C. for 18 h. Then, add slowly a 2M aqueous solution of NaOH (54.94 mmol; 27.47 mL) at 0° C. and stir the mixture for 5 min. Add a 35% aqueous solution of hydrogen peroxide (274.70 mmol; 23.88 mL) at 0° C. and stir the mixture at 22° C. for 2 h, dilute with water (300 mL). Dilute the mixture with EtOAc (250 mL) and separate the organic layer. Extract the aqueous layer with EtOAc (250 mL). Wash the combined organic layers with sodium bisulfate (214.39 mL) and concentrate. Purify the residue by flash chromatography (750 g column; eluent:hexane/EtOAc 80:20 to 60:40; 400 mL fractions, charge in DCM (100 mL)) and then by chiral chromatography Chiralpak AD, 20 um, 8×25 cm; mobile phase: Isocratic 100% MeOH-0.2% DMEA Flow rate: 300 ml/min UV detection: 225 nm Loading: 3 g/6 min. Collect the first eluting isomer to give the title compound (11.85 g, 31%). MS (m/z): 222 (M-tBu+1) [Alpha]Na=−22.89 (in methanol, 25° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:62]=[CH:61][C:55]([O:56][CH2:57][CH2:58]CO)=[CH:54][CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:58][CH2:57][O:56][C:55]2[CH:61]=[CH:62][C:52]([F:51])=[CH:53][CH:54]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCCCOc1ccc(F)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCOc4ccc(F)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 44 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2,3-dimethylaniline (68 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (94 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-fluorophenoxy)-1-propanol (53 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1Br.C([Li])CCC.[C:15]([O:18][CH2:19][C:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])=[O:21])(=[O:17])[CH3:16].Cl>C(OCC)C.CCCCCC>[C:24]([O:23][CH2:22][C:20]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:21])[CH2:19][O:18][C:15](=[O:17])[CH3:16])(=[O:26])[CH3:25]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: Fc1ccc(Br)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Temperature: -30 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
Under an atmosphere of argon, 22.5 g of 2,4-difluorobromobenzene was dissolved in 200 ml of diethyl ether and to the resulting solution was added dropwise 73 ml of 1.63M n-hexane solution of n-butyllithium at -30° C. The resulting liquid was stirred for 1 hour and stored at -60° C. This liquid was carefully added dropwise using an injection cylinge to 150 ml of diethyl ether solution of 17.4 g of 1,3-diacetoxyacetone which was previously cooled to -30° C. After the resulting liquid was stirred at -60° C. for 2 hours, a temperature thereof was gradually raised to room temperature. Then, the reaction mixture was transferred to 100 ml of 1.2N aqueous solution of hydrochloric acid at 5° C. or below, and the organic layer was separated therefrom and the aqueous layer was extracted twice with 100 ml of ethyl acetate. The organic layers were combined and washed with saturated aqueous solution with sodium chloride, dried over anhydrous magnesium sulfate. The resulting organic layer was filtered and the solvent was removed under reduced pressure. Thus obtained concentrate was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 8 g of the desired compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:11])[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5]1.[CH:12](OCC)=[O:13].C(O)C>C(OCC)C.C(O)C>[OH:13]/[CH:12]=[C:7]1\[C:6](=[O:10])[CH2:5][C:4]([CH3:11])([CH3:3])[CH2:9][CH2:8]\1
Reactant: CCOC=O
Reactant: CC1(C)CCCC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC1(C)CC/C(=C/O)C(=O)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.4 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 475 mg, 11.9 mmol) in diethyl ether (25 mL) at 0° C. was added ethanol (0.06 ml, 1.03 mmol) dropwise. The grey suspension was stirred at 0° C. for 20 min. A solution of 3,3-dimethylcyclohexanone (1.50 g, 11.9 mmol) and ethyl formate (1.45 ml, 17.8 mmol) in diethyl ether (3 mL) was added dropwise over 10 min. The yellow heterogeneous reaction mixture was stirred at 0° C. for 1 h then warmed to room temperature and stirred for 2 h. Ethanol (1 mL) was added and the mixture was stirred at room temperature for 1 h then quenched with water (25 mL). The layers were separated and the aqueous phase was washed with diethyl ether. The aqueous layer was acidified with 1M HCl until pH=2 and then extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4 and concentrated to afford 1.64 g (90%) of 2-[1-hydroxy-meth-(Z)-ylidene]-5,5-dimethyl-cyclohexanone as a light yellow oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 14.38 (br. s., 1H), 8.79 (s, 1H), 2.34-2.47 (m, 2H), 2.16 (s, 2H), 1.42-1.53 (m, 2H), 1.00 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([OH:12])=O)[NH:7][C:6]=2[CH:13]=1.C[CH:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:28](OC(C)C)(C)C>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]([N:25]3[CH2:24][CH2:23][CH:22]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:28])=[CH:20][CH:21]=4)[CH2:27][CH2:26]3)=[O:12])[NH:7][C:6]=2[CH:13]=1
Reactant: CC(c1ccccc1)C1CCNCC1
Reactant: O=C(O)c1nc2ccc(O)cc2[nH]1
Reactant: CC(C)OC(C)C
Product: Cc1ccc(CC2CCN(C(=O)c3nc4ccc(O)cc4[nH]3)CC2)cc1

Procedure:
The title compound is prepared from 6-hydroxy-1H-benzoimidazole-2-carboxylic acid [Example elözö d] and 4-(-methylbenzyl)piperidine [J. Org. Chem., 64, 3763 (1999)] according to the method described in Example 25. Mp.: 93° C. (diisopropyl ether).
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2Cl)(=O)C.[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].Cl.N1C=CC=CC=1>C(OC(O)C)C>[NH2:4][C:5]1[N:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]#[N:16])=[C:8]2[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([Br:18])[CH:20]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)Nc1ccc2ncc(C#N)c(Cl)c2n1
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1cnc2ccc(N)nc2c1Nc1cccc(Br)c1
Yield: 56 %

Procedure:
A solution of 6-acetamido-4-chloro-[1,5]naphthyridine-3-carbonitrile (200 mg, 0.81 mmol), 3-bromoaniline (0.5 ml) and pyridine HCl (188 mg) in ethoxyethanol (20 ml) was heated at reflux for 3 hrs. After cooling, the solvent was removed by rotary evaporation, and the residue was cooled and made basic with NH4OH. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed (brine), dried (Na2SO4), and concentrated. The residue was chromatographed (flash column, silica gel, CH2Cl2: ether: MeOH=5:2:0.5) giving the title compound as a yellow solid (229 mg, 56%). mass spectrum (electrospray, m/e): 341.8 (M+H); IR cm-1: 2215, 1628; H-NMR δ (DMSO-d6): 6.816 (2H, bs, NH2), 7.093 (1H, d, C7-H), 7.35-7.43 (3H, m), 7.567 (1H, s), 7.931 (1H, d, C8-H), 8.333 (1H, s, C2-H), 9.236 (1H, s, NH).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][N:8]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][C:3]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N)CCC.[ClH:33]>C(O)C>[ClH:33].[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][NH2:8])=[CH:4][C:3]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Solvent: CCCCN
Solvent: CCO
Product: NOCc1ccc(F)c(Oc2ccccc2)c1
Reaction time: 1.5 h
Yield: 87 %

Procedure:
N-(4-fluoro-3-phenoxybenzyloxy)phthalimide 5 g, 14 mmol), n-butylamine (1.13 g, 15 mmol) and absolute ethanol (3 ml) were placed in a dry flask under a nitrogen atmosphere. This reaction mixture was stirred at 60°-75° for 1.5 hours, cooled and adjusted to pH 3 using dry hydrogen chloride gas. The solution was concentrated to 10 ml and poured into dry ether. The resulting white precipitate was filtered off and recrystallized from petroleum spirit (40°-60°)/dichloromethane to give 3.2 g (87%) of a white solid, m.p. 149.3°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[Li]CCCC.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([NH:33][C:34]([C:11]2[N:12]([CH3:13])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:10]=2)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C=NC1CCCCC1
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A solution of 5.5 g (16.2 mmol) of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-1-methyl-imidazole in 70 mL of THF was cooled in a −78° C. bath and 15 mL of 1.6 M n-BuLi was slowly added. After stirring for 1 h, 5.2 mL (40.7 mmol) of cyclohexylisocyanate was added. The cooling bath was removed and the solution was stirred for 3 h. The reaction mixture was poured into a mixture of water/EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried and concentrated. The residue was purified on a flash column using a gradient of 2-10% EtOAc-hexane. The isolated product was crystallized from EtOAc-hexane (˜1:10) to obtain the title compound as a white solid with a melting point of 165° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[N:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.Cl.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39](=O)[NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[CH:43][CH:42]=2)=[CH:34][CH:33]=1)([O-:31])=[O:30].[CH3:54][N:55]([CH3:58])[CH2:56][CH3:57].N1C2C(=CC=CC=2)C=NC=1.C(=O)([O-:71])N>C(Cl)Cl.CO>[N:47]1([C:44]2[CH:43]=[CH:42][C:41]([NH:40][C:39]([N:25]3[CH2:24][CH2:23][CH:22]([C:16]4[C:15]5[C:20](=[CH:21][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)=[CH:13][CH:14]=5)[N:19]=[CH:18][N:17]=4)[CH2:27][CH2:26]3)=[O:38])=[CH:46][CH:45]=2)[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1.[N+:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[OH:71])([O-:31])=[O:30].[CH3:54][N:55]([CH3:58])[CH2:56][CH3:57]
Reactant: CN1CCN(CCCOc2ccc3c(C4CCNCC4)ncnc3c2)CC1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)[O-]
Agent: CCN(C)C
Agent: Cl
Agent: c1ccc2ncncc2c1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(CCCOc2ccc3c(C4CCN(C(=O)Nc5ccc(N6CCOCC6)cc5)CC4)ncnc3c2)CC1
Product: O=[N+]([O-])c1ccccc1O
Temperature: 0 °C

Procedure:
A solution of 7-[3-(4-Methyl-piperazin-1-yl)-propoxy]-4-piperidin-4-yl-quinazoline (3.654 g, 9.9 mmol), as prepared in the previous step, in 98:2 DCM/MeOH (15 mL) was added rapidly dropwise under air in 2 mL portions to an ice bath-chilled stirred mixture of (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride (4.13 g, 10.9 mmol), as prepared in Example 66a, and dimethylethylamine (DMEA) (1.4 mL, 13 mmol) in 98:2 DCM/MeOH (20 mL). Residual quinazoline derivative was then transferred to the carbamate reaction mixture with 2×7 mL additional 98:2 DCM/MeOH. The resulting homogeneous dark amber solution was stirred for another 5 min, and the ice bath was then removed and the reaction stirred at “rt” for 1.5 hr. The homogeneous reaction solution was then directly applied to a silica flash column (79 mm diameter×6″ length) pre-equilibrated with acetone. The title compound was eluted with 1.5 L acetone→2 L 9:1 acetone/MeOH→2 L 9:1 acetone/MeOH/3% DMEA. The combined fractions were concentrated to afford the title compound contaminated with nitrophenol and DMEA, and this material was partitioned with DCM (100 mL) and 2 M aqueous K2CO3 (2×20 mL). The organic layer was dried (Na2SO4) and concentrated under high vacuum at 90° C. to afford the title compound as a lavender foam that was crushed to a powder [3.89 g, 70% over three steps from 4-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester].
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][N:28]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:29](=[O:42])[C:30]([CH3:41])=[CH:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)(Cl)(Cl)Cl>[CH3:27][N:28]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[C:29](=[O:42])[C:30]([CH2:41][Br:1])=[CH:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCCCCCCCN(C)C(=O)C(C)=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)C(=Cc1ccc([N+](=O)[O-])cc1)CBr
Temperature: 25 °C

Procedure:
18 g of N-bromosuccinic acid imide and 0.5 g of benzoyl peroxide were added to a solution of 47 g of N-methyl-N-octadecyl-α-methyl-4-nitrocinnamic acid amide in 400 ml of carbon tetrachloride. The mixture was gradually heated from room temperature under reflux for about 1 hour. The mixture was heated under reflux for 10 hours while being irradiated with light from an incandescent lamp, and then allowed to cool. After the solvent was distilled off under reduced pressure, the residue was then subjected to silica gel column chromatography. The desired substance was obtained from a fraction extracted with a 1:2 mixture of hexane and ethyl acetate. (Yield: 23 g (42%))