Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:17]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18]C)[C:8]=2[C:7]2[O:20][CH2:21][O:22][C:6]=2[CH:5]=1)([OH:3])=[O:2].Cl.N1C=CC=CC=1>Cl>[C:1]([C:4]1[C:17]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[OH:18])[C:8]=2[C:7]2[O:20][CH2:21][O:22][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: COc1cccc2c1ccc1c(C(=O)O)cc3c(c12)OCO3
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1cc2c(c3c1ccc1c(O)cccc13)OCO2

Procedure:
1.0 g. 1-carboxy-3,4-methylenedioxy-8-methoxyphenanthrene is melted with 2.0 g. pyridine hydrochloride in an oil bath at 170° C. and maintained at this temperature for 1 hour while gassing with nitrogen. After cooling, the solidified mass is taken up with 10 liters 5% hydrochloric acid and extracted three times with 10 liter amounts of chloroform. The extracts are combined, washed neutral with water and dried by filtering through silanised filter paper (Whatman 1 PS). After evaporation of the solvent at 30° C. on a rotary evaporator, the mixture of starting material and hydrolysate is esterified for separation by boiling under reflux for 3 hours with a mixture of 2.5 liters methanol and 0.1 liter concentrated sulphuric acid. The reaction mixture is then poured into 10 liters of water and the aqueous methanolic phase shaken out three times with 10 liter amounts of diisopropyl ether. The organic solvent, after having been washed several times with water, is extracted with 10 liters of sodium hydroxide solution, the methyl ester of the 8-methoxy compound remaining in the organic phase, whereas the 8-hydroxy compound is transferred into the aqueous phase, with simultaneous hydrolysis of the ester. After washing with fresh diisopropyl ether, the alkaline phase is acidified and shaken out several times with chloroform. The chloroform solution is dried over phase separation paper (Whatman 1 PS) and the solvent stripped off on a rotary evaporator, 1-carboxy-3,4-methylenedioxy-8-hydroxyphenanthrene remaining behind in solid form as a thin layer chromatographically-uniform compound. Yield 0.714 g. (75% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[N:9]2[CH2:12][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH2:41][CH3:42]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH:8]([N:9]2[CH2:10][C:11](=[CH:13][S:14]([CH2:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:34][CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][N:37]3[CH2:41][CH3:42])=[O:23])(=[O:16])=[O:15])[CH2:12]2)[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:28][CH:29]=1
Reactant: O=C(O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cccc(CS(=O)(=O)C=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1

Procedure:
The operation is carried out under the conditions described in Example 124 starting with 150 mg of activated 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP resin (165 μM) and 0.0396 cm3 of 2-(aminomethyl)-N-ethylpyrrolidine. 58 mg of 3-({-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide are thus obtained in the form of an ochre-colored foam.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]1([F:17])[CH2:14][CH:13]1[CH2:15][OH:16]>>[F:11][C:12]1([F:17])[CH2:14][CH:13]1[CH2:15][O:16][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCC1CC1(F)F
Reactant: O=C(O)c1ccc(Cl)nc1
Product: O=C(O)c1ccc(OCC2CC2(F)F)nc1

Procedure:
Using 6-chloronicotinic acid and 2,2-difluorocyclopropanemethanol, and in the same manner as in Step A of Example 40, the title compound was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[CH3:9][CH:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)[CH2:11]1.O.[ClH:27]>C(O)(=O)C.CCOCC>[ClH:27].[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][N:6]1[C:13]2[CH2:14][CH2:15][CH:10]([CH3:9])[CH2:11][C:12]=2[CH:17]=[C:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: CCN(CC)CCN
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)CCn1c(-c2ccccc2)cc2c1CCC(C)C2

Procedure:
A solution of 5.94 g (0.05 mole) of 2-diethylaminoethylamine and 11.52 g (0.05 mole) of 4-methyl-2-phenacyl-cyclohexanone in glacial acetic acid is refluxed under nitrogen for 8 hours. Water is added to the mixture, and the mixture is acidified with dilute hydrochloric acid and washed with ether. The aqueous solution is basified with 10% sodium carbonate and extracted with ether to give a light brown oil. The oil is dissolved in ether and ethereal hydrogen chloride is added to give a granular off-white salt. The salt is recrystallized from an isopropanol-ether mixture and then from a methanol-ether pair to give 1-(2-diethylaminoethyl)-2-phenyl-5-methyl-4,5,6,7-tetrahydroindole hydrochloride as light tan crystals, m.p. 171°-177° C.
Reaction SMILES: [CH2:1]([C:8]([NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][OH:19])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[CH2:1]([C:8]([NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18]=[O:19])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccccc1)Nc1cc(Cl)ccc1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Cl)cc1NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.2 %

Procedure:
To a solution of N-(benzylcarbonyl)-5-chloro-2-hydroxymethyl aniline (15.50 g) in dichloromethane (400 ml) under nitrogen at room temperature, was added pyridinium chlorochromate (24.30 g) and crushed 4 Å molecular sieves (0.50 g). The reaction mixture was stirred at room temperature for 90 mins, then ethyl acetate added, and the solution was filtered through a 2 inch plug of silica gel. The solvent was removed in vacuo and the material was redissolved in ethyl acetate and filtered through silica gel. Removal of the solvent under vacuum and trituration of the solid residue with diethyl ether gave the desired compound (10.50 g). δ (360 MHz, DMSO-d6) 3.82 (2H, s, NHCOCH2Ph), 7.27-7.39 (6H, m, Ph+5-H), 7.87 (1H, d, J=8.30 Hz, 6-H), 8.36 (1H, d, J=1.87 Hz, 3-H), 9.89 (1H, s, CHO), 10.97 (1H, bs, NHCOCH2Ph).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]O)[N:11]=2)[N:9]=1)[NH2:3].S(Cl)([Cl:20])=O.C(OCC)C>ClCCl.O1CCCC1>[Cl:20][CH2:16][C:12]1[N:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: NC(N)=Nc1nc(-c2cccc(CO)n2)cs1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(N)=Nc1nc(-c2cccc(CCl)n2)cs1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-(6-hydroxymethylpyridin-2-yl)thiazole (1.0 g) and thionyl chloride (10 ml) in a mixture of dichloromethane (10 ml) and tetrahydrofuran (10 ml) was stirred for 70 hours at ambient temperature. To the reaction mixture was added a diethyl ether (30 ml) and isolated precipitate was collected by filtration. The precipitate was added to a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 4-(6-chloromethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.97 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:19][CH:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=4)=[CH:23][N:22]=3)[CH2:17]2)=[O:15])[CH:8]=1.[CH3:34][O:35][CH2:36][CH2:37]Br>CN(C=O)C>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:19][CH:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:37][CH2:36][O:35][CH3:34])[CH:28]=4)=[CH:23][N:22]=3)[CH2:17]2)=[O:15])[CH:8]=1
Reactant: COCCBr
Reactant: O=C(Nc1cccnc1)N1CC(Oc2ccc(-c3cccc(O)c3)cn2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(-c2ccc(OC3CN(C(=O)Nc4cccnc4)C3)nc2)c1
Temperature: 100 °C
Yield: 29 %

Procedure:
Potassium carbonate (23 mg, 165 μmol) was added to a solution of 3-[5-(3-hydroxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyridin-3-ylamide (20 mg 55 μmol), in DMF (0.5 mL). 2-Bromoethyl methyl ether (6 μL, 66 μmol) was added and the reaction mixture was heated to 100° C. in microwave synthesiser for 1 hr. The reaction mixture was allowed to cool and solvent removed in vacuo. The crude product was purified by preparative HPLC to afford the title product as a colourless solid (6.7 mg, 29%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:30])(=[O:29])[NH2:28])=[CH:17][CH:16]=2)[C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[C:31]([NH:28][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][N:8]([CH:10]([CH3:11])[CH3:12])[C:7]2=[O:13])=[CH:16][CH:17]=1)(=[O:29])=[O:30])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Reaction time: 12 h
Yield: 64.6 %

Procedure:
To a solution of 52.7 mg (0.123 mmole) of 5-n-butyl-2,4-dihydro-2-isopropyl-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step I) in 1 ml of dry pyridine stirred at room temperature under argon was added 143 μL (173 mg; 1.23 mmole) of benzoyl chloride. After 12 hours at room temperature, the mixture was treated with saturated NaH2PO4 solution and extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography of the residue on silica gel (elution with 4% MeOH and 0.2% ammonium hydroxide in CH2Cl2) gave 42.3 mg (69%) of the title compound as a white solid; satisfactory purity by TLC in 94:6:0.2 CH2Cl2 --MeOH-concd. NH4OH; mass spectrum (FAB) m/e 533 (M+1)+.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C(N(CC)CC)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:25][CH:22]1[CH2:24][CH2:23]1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NC1CC1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NC3CC3)c2)N1C

Procedure:
6.6 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 1.5 g of cyclopropyl amine and 4 g of triethyl amine in 50 ml of ethanol and worked up. Fair yellow crystals, melting point: 180° C (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[K+].C(Cl)(=O)C(Cl)=O.[NH3:31].C(=O)(O)[O-].[Na+].Cl>ClCCl.CN(C=O)C.CO.O>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:21])([CH3:22])[C:17]([NH2:31])=[O:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: COC(=O)C(C)(C)Cn1cnc2c(N)nc3ccccc3c21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)(Cn1cnc2c(N)nc3ccccc3c21)C(N)=O
Reaction time: 8 h

Procedure:
A modification of the methods described in Part C of Example 61 was used to treat methyl 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate (1.61 g, 5.4 mmol) with potassium hydroxide (22 mL of 0.5 M); the reaction was heated at reflux overnight. The reaction with oxalyl chloride (0.96 mL) in dichloromethane (55 mL total) was stirred for one hour before more oxalyl chloride (1.0 mL) and DMF (three drops) were added, and then the reaction was stirred overnight. The precipitate isolated after the reaction with ammonia and treatment with sodium bicarbonate was combined with material from another run and recrystallized from methanol/water. The resulting solid was isolated by filtration and heated gently in a mixture of methanol (35 mL), water (10 mL), and concentrated hydrochloric acid (0.83 mL). The mixture was filtered to remove a small amount of insoluble material, and a precipitate formed in the filtrate. The precipitate was isolated by filtration, recrystallized twice from methanol/water, dried overnight in a vacuum oven at 70° C., and recrystallized four times from ethyl acetate/methanol/water with a filtration through a 20 micron filter prior to the last two crystallizations. The resulting crystals were dried overnight in a vacuum oven at 70° C. to provide 3-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanamide as white crystals, mp 287-289° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[NH:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccc(NN)cc1C
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Yield: 156.7 %

Procedure:
A solution of 3,4-dimethylphenylhydrazine (7.3 g; 0.053 mol.) and ethyl acetoacetate (6.9 g; 0.053 mol.) in glacial acetic acid (50.0 mL) was stirred and heated at 100° for 24 h. The solvent was evaporated and the product purified by chromatography (silica gel, 50% ethyl acetate/hexanes) to afford the title compound (16.8 g; 64%). MS(ES) m/z 203 [M+H].
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[C:36]2=[O:52])[S:28][C:29]=1[C:30]([O:32]CC)=[O:31]>>[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=3)[C:36]2=[O:52])[S:28][C:29]=1[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Yield: 64 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 64% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.42 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 4.43 (s, 2H), 3.98 (t, J=8.1 Hz, 2H), 3.44 (t, J=8.1 Hz, 2H), 2.46 (s, 3H); MS (ES+) m/z 402.1 (M+1).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CC(C)([O-])C.[Na+].O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O>[N:20]1([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2N2CCOCC2)C1
Yield: 73.7 %

Procedure:
A solution of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), morpholine (0.159 ml, 1.83 mmol), X-phos (17.4 mg, 0.0365 mmol), tris(dibenzylideneacetone)dipalladium(0) (11.0 mg, 0.0120 mmol), sodium tert-butoxide (87.5 mg, 0.912 mmol) and dioxane (4 ml) was stirred under an argon atmosphere for 2 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (150 mg, 73.7%) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCCN1CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CCCN1CCCCN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-bromobutyl)-2-pyrrolidinone (2.0 g/9.1 mmol) and benzylpiperazine (1.58 ml/9.1 mmol) in ethanol (4.5 ml) was stirred overnight at ambient temperature. The mixture was basified with 2 N NaOH and extracted with dichloromethane (50 ml×2). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (100 g/dichloromethane=100:5-100:10) to give a pale yellow oil (1.6 g/56%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1.S(=O)(=O)(O)O>>[OH:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cnc(O)c([N+](=O)[O-])c1
Temperature: 45 °C

Procedure:
Fuming nitric acid(10.4 ml) was added dropwise to a mixture of 6-hydroxynicotinic acid (15 g) and concentrated sulfuric acid(45 ml) at 0° C. The reaction mixture was slowly heated to 45° C. and maintained at the same temperature for 3 hours. The mixture was poured into ice-water, and the resultant precipitate was collected by suction filtration, washed with water, and air-dried to give 6-hydroxy-5-nitronicotinic acid (8.63 g) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH:26][C:27]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34](O)=[O:35])[O:29][N:28]=1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:34](=[O:35])[CH2:33][CH2:32][C:30]4[O:29][N:28]=[C:27]([OH:26])[CH:31]=4)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CCc1cc(O)no1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(C(=O)CCc4cc(O)no4)CC3)cc2)c1

Procedure:
N-(3-tert-Butyl-phenyl)-4-{1-[3-(3-hydroxy-isoxazol-5-yl)-propionyl]-piperidin-4-yl}-benzamide was prepared by the ECDI coupling of N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 3-(3-hydroxy-isoxazol-5-yl)-propionic acid in a manner similar to the one described in the synthesis of 4-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclonexanecarboxylic acid methyl ester, above. LCMS calcd for C28H33N3O4 (m/e) 475, obsd 476 (M+H).
Reaction SMILES: FC1C=CC=C(F)C=1CN1C2C=CC=CC=2N=C1C1C(F)=CC=CC=1F.FC1C=CC=C(F)C=1C(Cl)=O.Cl[Sn]Cl.Cl.CC(OC(C)=O)=O.[BH4-].[Na+].OS(O)(=O)=O.N([O-])=O.[Na+].Br.[F:61][C:62]1[CH:88]=[CH:87][CH:86]=[C:85]([F:89])[C:63]=1[CH2:64][N:65]1[C:69]2[CH:70]=[CH:71][CH:72]=[C:73]([N+:74]([O-])=O)[C:68]=2[N:67]=[C:66]1[C:77]1[C:82]([F:83])=[CH:81][CH:80]=[CH:79][C:78]=1[F:84]>C1COCC1.CC(O)=O>[NH2:74][C:73]1[C:68]2[N:67]=[C:66]([C:77]3[C:82]([F:83])=[CH:81][CH:80]=[CH:79][C:78]=3[F:84])[N:65]([CH2:64][C:63]3[C:62]([F:61])=[CH:88][CH:87]=[CH:86][C:85]=3[F:89])[C:69]=2[CH:70]=[CH:71][CH:72]=1
Reactant: O=[N+]([O-])c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: Nc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F

Procedure:
FIG. 9 provides a schematic approach for the preparation of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole substituted with chloro, bromo, nitro, amino, acetylamino, dimethylamino groups at the C-4 position of the benzimidazole ring. In this Figure, “a” comprises 2,6-difluorobenzoyl chloride, pyridine: TBF (1:1); “b” comprises AcOH reflux; “c” comprises 2,6-F2-BnBr, NaH,THF; “d” comprises SnCl2, AcOH, HCl; “e” comprises Ac2O, THF; “f” comprises H2CO, NaBH4, H2SO4; and “g” comprises NaNO2, HBr or HCl. As shown in this Figure, reduction of the 4-nitro group of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (Example 83) was accomplished with tin (II) chloride, which gives 4-amino-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole 3300 (Example 85). Compound 3300 was used to prepare 4-bromo-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (Example 86) and 4-chloro-1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (Example 87) via the Sandmeyer reactions (i.e., methods known in the art). Monoacylation of compound 3300 with acetic anhydride gave 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetamidobenzimidazole (Example 88), while treatment of 3300 with formaldehyde and sodium borohydride yielded the dimethylamino compound 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-N,N-dimethylaminobenzimidazole (Example 89).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N+:21]([O-])=O)=[C:10]([CH:12]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][C:15]=2I)[OH:13])[CH:11]=1.ClC1C=CC(CC2C=CC([N+]([O-])=O)=C(C(C3N(C)N=CC=3I)O)C=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:21][C:15]3[CH:16]=[N:17][N:18]([CH3:19])[C:14]=3[C:12](=[O:13])[C:10]=2[CH:11]=1
Reactant: COc1ccccc1Cc1ccc([N+](=O)[O-])c(C(O)c2c(I)cnn2C)c1
Agent: Cn1ncc(I)c1C(O)c1cc(Cc2ccc(Cl)cc2)ccc1[N+](=O)[O-]
Product: COc1ccccc1Cc1ccc2[nH]c3cnn(C)c3c(=O)c2c1

Procedure:
The title compound was prepared according to the procedure of step 4 in EXAMPLE 13 using [5-(2-methoxybenzyl)-2-nitrophenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanol (EXAMPLE 21, step 2), instead of [5-(4-chlorobenzyl)-2-nitrophenyl](4-iodo-1-methyl-1H-pyrazol-5-yl)methanol.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6](=[O:42])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31](C(OC(C)(C)C)=O)[N:30]=[CH:29]4)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[C:32]2[C:28](=[CH:27][C:26]([NH:25][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]([C:11]4[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=4)[O:8][CH2:7][C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:43])=[O:42])[N:24]=3)=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(2-(2-(dimethylamino)ethylamino)-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.18 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-(dimethylamino)ethyl)acetamide. (19 mg, 0.039 mmol, 22%).