Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[CH:21](O)[CH2:22][CH2:23][C:24]1([C:41]([O:43][CH3:44])=[O:42])[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[CH2:26][CH2:25]1)=[CH:18][C:17]([O:46][CH3:47])=[CH:16][CH:15]=2.C(=O)([O-])O.[Na+]>ClCCl>[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[CH:21]([F:7])[CH2:22][CH2:23][C:24]1([C:41]([O:43][CH3:44])=[O:42])[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][O:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[CH2:28][CH2:29]1)=[CH:18][C:17]([O:46][CH3:47])=[CH:16][CH:15]=2
Reactant: COC(=O)C1(CCC(O)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)ccc2F)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CCC(F)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCOc2cc(F)ccc2F)CC1
Temperature: 3 °C

Procedure:
0.2 cm3 of diethylaminosulfur trifluoride was added to a solution of 0.5 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylate in 20 cm3 of dichloromethane, with stirring and under an inert atmosphere, at a temperature in the region of 3° C. After stirring for 7 hours at a temperature in the region of 20° C., saturated sodium hydrogencarbonate solution was added to the reaction mixture. The aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200μ; diameter 1.5 cm; mass: 15 g), eluting with a mixture of ethyl acetate/petroleum ether (40-60° C.) (8/2 by volume). Fractions 9 to 11 were combined and then concentrated to dryness under the above conditions. 0.21 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenoxy)ethyl]piperidine-4-carboxylate was obtained in the form of a thick yellow oil.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:10]=1>C(O)C.[Pd]>[CH3:5][C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:10]=1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cn(-c2ccc(N)cc2)cn1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
Ammonium formate (2.202 g, 34.9 mmol) and palladium (10% w/w on carbon, 50% wet, 0.473 g, 4.44 mmol) were added to a solution 4-methyl-1-(4-nitrophenyl)-1H-imidazole (4.73 g, 23.28 mmol) in ethanol (150 mL) and the resulting mixture was refluxed under nitrogen for 1 h then cooled to room temperature. An extra portion of ammonium formate (2.202 g, 34.9 mmol) was then added and the resulting mixture was refluxed for a further hour then cooled to room temperature and filtered through celite. Most of the solvent was removed in vacuo and the residue was loaded on a 50 g SCX column which was eluted with MeOH (5 CV) then with 2N NH3 in MeOH (5 CV). The ammonia fractions were combined and concentrated in vacuo to give 4-(4-methyl-1H-imidazol-1-yl)aniline (3.92 g, 21.06 mmol, 90%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][CH:9]=[O:10])[S:6][CH:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][S:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[N:4]=1)=[O:10]
Reactant: O=CNc1nc(CCl)cs1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CNc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 100 °C
Yield: 78.2 %

Procedure:
A mixture of 4-chloromethyl-2-formylaminothiazole (1.76 g), 4-nitrothiophenol (1.7 g) and potassium carbonate (1.8 g) in N,N-dimethylformamide (20 ml) was heated at 100° C. with stirring. The reaction mixture was poured into ice-water and stirred at 5° C. for an hour. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-formylamino-4-(4-nitrophenylthiomethyl)thiazole (2.3 g, yield: 78%). mp: 158°-160° C. IR (Nujol): 3500, 1680, 1595, 1550, 1330 cm-1
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[N:16]=[C:17]=[O:18]>C1C=CC=CC=1>[F:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[NH:16][C:17]([NH2:1])=[O:18]
Reactant: N
Reactant: CCOC(=O)Oc1cc(N=C=O)c(F)cc1Cl
Solvent: c1ccccc1
Product: CCOC(=O)Oc1cc(NC(N)=O)c(F)cc1Cl
Yield: 80 %

Procedure:
An ammonia gas was introduced into a solution of 2-fluoro-4-chloro-5-ethoxycarbonyloxyphenyl isocyanate (16.7 g, 64 mmol) in benzene (300 ml) while vigorously stirring on cooling in an ice bath. Precipitation of white solid was immediately observed. After thirty minutes the solid deposited was obtained by filtration and sufficiently washed with benzene and dried. This product was identified as 2-fluoro-4-chloro-5-ethoxycarbonyloxyphenyl urea (14.2 g, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][OH:10])[CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:9][OH:10])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: OCc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCc1cc(Cl)ccc1OCc1ccccc1
Yield: 106.4 %

Procedure:
4-Chloro-2-(hydroxymethyl)phenol (5 g, 31 mmol), benzyl bromide (3.74 ml, 31 mmol), and potassium carbonate (4.78 g, 34 mmol) were refluxed in acetone (30 ml) for two hours. TLC showed no more SM (starting material). Cooled down, filtered off the solid and vacuumed down (the filtrate) to give a clear oil (8.2 g).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[O:18]=[C:19]1[NH:27][C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C@@:20]21[CH2:39][C:30]1=[N:31][CH:32]=[C:33]([C:35](OC)=[O:36])[CH:34]=[C:29]1[CH2:28]2>C1COCC1>[OH:36][CH2:35][C:33]1[CH:34]=[C:29]2[CH2:28][C@@:20]3([C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:27][C:19]3=[O:18])[CH2:39][C:30]2=[N:31][CH:32]=1
Reactant: COC(=O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1Nc2ncccc2[C@@]12Cc1cc(CO)cnc1C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of diisobutylaluminum hydride (DIBAL) in toluene (1 M, 2.2 mL, 2.2 mmol) was added dropwise to a solution of methyl (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylate (described in Intermediate 5) (0.184 g, 0.62 mmols) in anhydrous THF at 0° C. The resulting mixture was stirred for 1 h at 0° C., then gradually warmed to ambient temperature and stirred for an additional 1 h. Excess DIBAL was quenched with ice and the mixture was partitioned between water and EtOAc (4×20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 5% MeOH in chloroform, to afford the title compound. MS: m/z=268.0 (M+1).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2].ClCCl.[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][CH:22]=1>C(N(CC)CC)C>[C:1]([NH:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[C:20]([C:21]3[CH:29]=[CH:28][C:24]([CH3:25])=[CH:23][CH:22]=3)[NH:16][C:11]=2[CH:10]=1)([CH3:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)NCC(C)(C)c1ccc(N)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC(C)(C)c1ccc2nc(-c3ccc(C)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4.4 g. of the 4-(2-acetamidomethylpropan-2-yl)-1,2-diaminobenzene (prepared in Example 1f) in 120 ml. dry dichloromethane are added 3.3 ml. triethylamine and then, with ice cooling, 3.06 g. 4-methylbenzoic acid chloride. After stirring the reaction mixture for 3 hours at ambient temperature, the solvent is removed in a vacuum. The residue is dissolved in water and extracted three times with dichloromethane, the organic phase is dried over anhydrous sodium sulphate, filtered and the solvent is removed in a vacuum. The residue (6.7 g.) is dissolved in glacial acetic acid and stirred for 3 hours at 70° C. The solvent is removed in a vacuum and the residue is purified by column chromatography (silica gel; dichloromethane containing 5% methanol). There is obtained 1.55 g. of the title compound; m.p. 230°-232° C.
Reaction SMILES: [CH2:1]([C:3]([CH2:11][C:12]([O:14]C(C)C)=[O:13])([OH:10])[C:4]([O:6][CH:7](C)C)=[O:5])[CH3:2].[OH-].[K+]>O1CCOCC1>[CH3:7][O:6][C:4](=[O:5])[C:3]([CH2:1][CH3:2])([CH2:11][C:12]([OH:14])=[O:13])[OH:10]
Reactant: CCC(O)(CC(=O)OC(C)C)C(=O)OC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(O)(CC(=O)O)C(=O)OC

Procedure:
The diisopropyl ethylmalate (diastereoisomeric mixture) prepared as described above is saponified in aqueous dioxane with potassium hydroxide at the reflux temperature. The diacid is recovered by passing the cooled reaction mixture over Dowex resin (sulfonic acid form) and evaporating the eluate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1.Cl>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:14][CH:15]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[5-(4-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.05 (s, br, 1H), 7.74–6.68 (m, 12H) 5.08–4.99 (m, 1H), 3.67–3.56 (m, br, 2H), 3.02–2.82 (br, 2H), 2.80–2.57 (m, br, 4H), 2.57–2.38 (m, br, 2H), 2.05–1.80 (m, br, 6H), 1.64–1.40 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz). Anal. Calc. for C32H39Cl2FN2O2.1.3EtOAc: C, 64.93; H, 7.24; N, 4.07. Found: C, 65.01; H, 6.97; N, 3.85. ESMS m/e: 537.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:25](OC(=O)C)(=[O:27])C>C(O)=O>[CH:25]([NH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1)=[O:27]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Solvent: O=CO
Product: O=CNc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Temperature: 50 °C
Yield: 15 %

Procedure:
To a solution of (E)-5-amino-1-(2-pyridyl)-2-styryl-1H-benzimidazole (300 mg, 0.96 mmol) in formic acid (5 ml) was added acetic anhydride (1 ml) via syringe and the reaction mixture was warmed to 50° C. for 1 h. Volatiles were removed under reduced pressure and the residual viscous oil was poured into saturated aqueous sodium bicarbonate solution (50 ml) and the aqueous mixture was extracted with ethyl acetate (100 ml). The organic extract was washed consecutively with water (50 ml) and brine (50 ml), dried (sodium sulfate) and concentrated in vacuo. Recrystallization of the residue from ethyl acetate afforded 50 mg (15%) of the titled compound as light brown solids. MW: 340.39; mp: 189.9-192.1° C.; 1H-NMR (DMSO-d6) δ: 10.26 (1H, br.s), 8.81-8.73 (1H, m), 8.30 (1H, d, J=1.8 Hz), 8.18 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 8.10-8.05 (1H, m), 7.87 (1H, d, J=16.1 Hz), 7.73 (1H, d, J=7.7 Hz), 7.66-7.55 (3H, m), 7.44-7.30 (5H, m), 7.16 (1H, d, J=16.1 Hz).
Reaction SMILES: C1([C:7](=[S:23](=[O:25])=[O:24])[CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[NH:20][C:19](=[O:22])[CH2:18][CH2:17]3)C=CC=CC=1.Cl[C:27]1[C:28](=O)[C:29](C#N)=[C:30](C#N)[C:31](=O)[C:32]=1Cl>>[C:27]1([S:23]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[NH:20][C:19](=[O:22])[CH:18]=[CH:17]3)(=[O:24])=[O:25])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=C1CCc2cccc(OCCCC(c3ccccc3)=S(=O)=O)c2N1
Product: O=c1ccc2cccc(OCCCCS(=O)(=O)c3ccccc3)c2[nH]1

Procedure:
Prepared analogous to Example 86 from 8-(4-phenyl-sulfonyl-butoxy)-3,4-dihydro-carbostyril and 2,3-dichloro-5,6-dicyano-benzoquinone.
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:16]2[N:15]=[CH:14][NH:13][C:12]=2[CH:11]=[C:10]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=1.[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C>[O:21]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[C:16]2[N:15]=[CH:14][N:13]([CH2:24][CH3:25])[C:12]=2[CH:11]=[C:10]([C:17]([O:19][CH3:20])=[O:18])[CH:9]=1
Reactant: CCI
Reactant: COC(=O)c1cc(N2CCCCS2(=O)=O)c2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cnc2c(N3CCCCS3(=O)=O)cc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 160.2 %

Procedure:
To a solution of methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1H-benzimidazole-6-carboxylate (D253) (230 mg, 0.74 mmol, 1 equiv) in DMF (10 ml) at room temperature was added NaH (60% dispersion in mineral oil, 33 mg, 0.82 mmol, 1.1 equiv) and the resulting mixture was stirred 5 min at this temperature. Ethyl iodide (66 μl, 0.82 mmol, 1.1 equiv) was added and the resulting solution was stirred for 30 min at 60° C. then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt and a 5% aqueous citric acid solution. The two layers were separated and the aqueous phase saturated with NaCl and extracted twice with AcOEt. The combined organic phases were dried over MgSO4 and concentrated in vacuo to give methyl 4-(1,1-dioxidotetrahydro-2H-1,2-thiazin-2-yl)-1-ethyl-1H-benzimidazole-6-carboxylate (B151) (400 mg, 160%) as a pale yellow viscous oil which was used in the next step without further purification. [M+H]+=338.1, RT=2.43 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]([C:17]([O-:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)[CH3:2]>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:19][C:17]1[C:5]2[C:6](=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=CNc1ccc(CC)cc1)C(=O)[O-]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(CC)cc2c1O
Temperature: 250 °C

Procedure:
A mixture of the oil of Step A and 70 ml of phenyl oxide was stirred under an inert atmosphere and was then heated at 250° C. for one hour while distilling the formed ethanol. The mixture was cooled and 30 ml of acetone were added thereto. The mixture was vacuum filtered and the product was empasted with 30 ml of acetone and was dried and crystallized from ethanol to obtain 36 g of ethyl 4-hydroxy-6-ethyl-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].CO.C[O-].[Na+].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>Cl>[CH:16]1([CH2:15][O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Oc1ccccc1O
Reactant: BrCC1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Oc1ccccc1OCC1CCCCC1
Temperature: 25 °C
Yield: 31 %

Procedure:
An oven-dried 10 mL round-bottom flask equipped with condenser was charged with catechol (198 mg, 1.80 mmol), MeOH (2 mL), and NaOMe (102 mg, 1.89 mmol) and purged with nitrogen. (Bromomethyl)cyclohexane (319 mg, 1.80 mmol) was added and the reaction was heated to reflux for 48 hours. After cooling to room temperature the reaction was diluted with 50 mL 1M HCl and extracted with DCM (3×25 mL). The combined organic layers were washed with saturated NaCl (1×25 mL), dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (3:1 hexane:Ethyl acetate) afforded an off-white solid weighing 114 mg (31% yield). Off-white solid; 1H NMR (CDCl3): δ 1.03-1.11 (m, 2H), 1.18-1.35 (m, 3H), 1.71-1.88 (m, 6H), 3.84 (d, J=6.35 Hz, 2H), 5.64 (s, 1H), 6.80-6.88 (m, 3H), 6.92-6.94 (m, 1H); 13C NMR (CDCl3): δ 25.88, 26.59, 30.05, 37.80, 74.39, 111.77, 114.55, 120.20, 121.14, 121.38, 145.99; HRMS (FAB): 206.13068 calcd for C13H18O2 [M]+. found 206.12952 (−5.7 ppm, −1.2 mmu).
Reaction SMILES: NCCCN[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11]N.C1C2[C:19]3[C:30](=O)[C:29]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:20]=3OC(=O)C=2C=CC=1>C(Cl)(Cl)Cl>[CH:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[CH:20]=[C:19]1[C:24]3=[C:20]4[C:27](=[CH:26][C:25]3=[C:6]3[C:11]([CH:10]=[CH:9][N:8]=[CH:7]3)=[C:30]12)[CH:28]=[CH:29][CH:30]=[CH:19]4
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Reactant: NCCCNCCNCCCN
Solvent: ClC(Cl)Cl
Product: C1=c2ccccc2=c2c1c1cnccc1c1c2=Cc2ccccc2-1

Procedure:
Bis-1,2-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-(6-propyl-tert-BOCamino)}ethane (13b), N,N′-Bis(3-aminopropyl)-1,2-ethanediamine (11h) (0.16 g, 0.85 mmol) was added to a stirred solution of indenobenzopyran 4d (0.46 g, 1.87 mmol) in CHCl3 (150 mL) and the reaction mixture was stirred under reflux for 72 h, providing bisindenoisoquinoline 12 h as a crude intermediate. Upon allowing the reaction mixture to cool to room temperature, Et3N (0.6 mL, 4.24 mmol) and Boc2O (0.56 g, 2.60 mmol) were added to the reaction mixture and the mixture was allowed to stir at room temperature for 8 h. The crude reaction mixture was purified by flash column chromatography (SiO2/20% EtOAc in hexane, then 1-5% MeOH in CHCl3) to provide Boc-protected bisindenoisoquinoline 13b (550 mg, 76%) as an orange solid: mp 106-108° C. 1HNMR (CDCl3) δ 8.60 (bs, 2H), 8.23 (bs, 2H), 7.65 (bs, 2H), 7.55 (d, J=6.7 Hz, 2H), 7.40-7.32 (m, 8H), 4.48 (bs, 4H), 3.45 (bs, 8H), 2.12 (bs, 4H), 1.44 (s, 9H), 1.39 (s, 9H); ESIMS m/z (rel intensity) 835 (MH+, 22), 735 (MH+-Boc, 100). Anal. Calcd for C50H50N4O8.0.3H2O: C, 71.46; H, 6.07; N, 6.67. Found: C, 71.15; H, 6.19; N, 6.61.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1Cl.[CH3:29][O:30][NH2:31].[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1[NH:31][O:30][CH3:29]
Reactant: CON
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(Cl)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CONc1nc(Nc2ccc(C#N)cc2)nc(Oc2c(C)cc(C#N)cc2C)c1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.4 %

Procedure:
To a pressure vessel was added 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile (0.00064 mol), tetrahydrofuran (3 ml), O-methylhydroxylamine (0.06 g), tetrahydrofuran and NaOH 1N (0.00067 mol). The reaction mixture was stirred for 3 days at room temperature, then for 1 day at 75° C., for 1 day at 90° C. and for 2 days at 110° C. To O-methylhydroxylamine (0.60 g) was added tetrahydrofuran (4 ml) and NaOH 50% (0.00719 mol). The liquid was decanted into the reaction flask and the reaction mixture was heated at 110° C. for 3 days. The solvent was evaporated. The residue was dissolved in CH2Cl2, washed with a saturated NaHCO3 solution and water, dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN, filtered off and dried, yielding 0.15 g of 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-(methoxyamino)-2-pyrimidinyl]amino]benzonitrile (51%); mp. 185-186° C. The sample was dried (0.2 mm Hg, 80° C., 16 hours) (comp. 48).
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH:10]([CH3:21])[CH:9]([OH:8])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)=[CH:33][CH:32]=1
Reactant: Clc1ccc(I)cc1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)C(O)CCc1cccnc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 4-chloro-iodobenzene (0.24 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in toluene (4 ml) and ethanol (1 ml). The reaction mixture was heated at 100° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml) and the suspension was stirred at room temperature for 3 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give a gum, from which the oxalate salt was made (0.11 g).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1I.[Br-].[CH3:17][CH:18]([Zn+])[CH3:19].[OH-].[Na+]>>[CH:18]([C:5]1[CH:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:15])([CH3:19])[CH3:17]
Reactant: CC(C)[Zn+]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1I
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
In analogy to the procedure described for the synthesis of example B.10, the title compound was prepared from 2-iodo-4-trifluoromethyl-benzoic acid methyl ester and 2-propyl zinc bromide followed by saponification with sodium hydroxide. MS (m/e): 231.0 (M−H)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[F:10][C:11]([F:22])([F:21])[C:12]([C:17]([F:20])([F:19])[F:18])([CH3:16])[C:13](F)=[O:14].C(N(CC)CC)C>C(#N)C>[F:10][C:11]([F:21])([F:22])[C:12]([C:17]([F:18])([F:20])[F:19])([CH3:16])[C:13]([O:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:14]
Reactant: OCCN1CCOCC1
Reactant: CC(C(=O)F)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C(=O)OCCN1CCOCC1)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 20 h
Yield: 69.9 %

Procedure:
A mixture of 26.2 g of 2-morpholinoethanol, 21.2 g of 2,2-bis(trifluoromethyl)propionic acid fluoride, 20.2 g of triethylamine, and 100 g of acetonitrile was stirred at 60° C. for 20 hours. This was followed by conventional aqueous work-up and purification by silica gel column chromatography. There was obtained 22.6 g of 2-morpholinoethyl 2,2-bis(trifluoromethyl)propionate (yield 70%).