Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[Br:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Br:16][C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:15])[N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example A.11) (1.0 g, 4.18 mmol) and commercially available 3-bromo-benzene-boronic acid (1.09 g, 5.43 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.5 g, 33%). MS (ISP) 361.0 [(M+H)+]; mp 123° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:21]=[CH:20][C:19]=1[NH2:32].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:32][C:19]2[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:23][C:18]=2[O:17][CH3:16])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COc1cc(OCCN2CCCC2)ccc1N
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc(OCCN3CCCC3)cc2OC)c1C(=O)OC
Yield: 69 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 2-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.73 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 20 hours. The reaction mixture was cooled, diluted with CH2Cl2 (15 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (25 mL). The filtrate was evaporated in vacuo, and the residue was purified by ISCO silica gel flash chromatography using a methylene chloride-methanol gradient, eluting 0.9 g of the product at 95:5 methylene chloride-methanol, in 69% yield; 1H NMR (DMSO-d6) δ 1.68-1.71 (m, 4H), 2.49-2.53 (m, 4H), 2.79 (t, J=5.9 Hz, 2H), 3.78 (s, 3H), 3.79 (s, 3H), 3.80 (s, 3H), 4.07 (t, J=5.9 Hz, 2H), 6.53 (dd, J=8.7 Hz, J=2.6 Hz, 1H), 6.69 (d, J=2.6 Hz, 1H), 6.92-6.98 (m, 2H), 7.14 (d, J=8.7 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.73 (s, 1H).
Reaction SMILES: [I:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[I:1][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:4][N:5]([CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[C:6]=1[CH3:7]
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1n[nH]c(C)c1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(C2CCCCO2)c(C)c1I
Yield: 94 %

Procedure:
A solution of ethyl 4-iodo-5-methyl-1H-pyrazole-3-carboxylate (3.6 g, 12.85 mmol, 1.00 equiv), 3,4-dihydro-2H-pyran (3.24 g, 38.52 mmol, 3.00 equiv) and p-toluenesulfonic acid (222 mg, 1.29 mmol, 0.10 equiv) in tetrahydrofuran (150 mL) was stirred at 80° C. for 8 h. The resulting mixture was concentrated under vacuum and the residue was mixed with 100 mL of H2O. The resulting mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-30% of ethyl acetate in petroleum ether to yield 4.4 g (94%) of (R/S) ethyl 4-iodo-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-3-carboxylate as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 5.43 (dd, J=9.9 Hz, 2.7 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.05-4.00 (m, 1H), 3.67-3.60 (m, 1H), 2.43 (s, 3H), 2.12-2.10 (m, 1H), 1.96-1.95 (m, 1H), 1.69-1.58 (m, 4H), 1.40 (t, J=7.2 Hz, 3H) ppm. LCMS (method D, ESI): RT=1.53 min, m/z=365.0 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]2[O:15][CH2:16][O:17][C:12]2=[CH:11][C:10]=1[CH2:18][C:19]([O:21]C)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH2:16]1[O:15][C:13]2=[CH:14][C:9]3[C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:25][NH:24][C:19](=[O:21])[CH2:18][C:10]=3[CH:11]=[C:12]2[O:17]1
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccccc1)OCO2
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1Cc2cc3c(cc2C(c2ccccc2)=NN1)OCO3
Yield: 29.7 %

Procedure:
A solution of methyl 2-benzoyl-4,5-methylenedioxyphenylacetate (110 mg, 0.37 mmol) and hydrazine hydrate (30 μL, 0.53 mmol) in ethanol (15 mL) was refluxed for 5 days. The solvent was removed in vacuo and the resulting residue was separated by chromatography to yield the title compound (30 mg, 0.11 mmol, 29%), mp, 182°-184° C. 1H NMR (CDCl3) 8.59 (s, 1H), 7.60-7.41 (m, 5H), 6.83 (s, 1H), 6.63 (s, 1H), 6.03 (s, 2H), 3.46 (s, 2H). Anal. Calcd. for C16H12N2O3.0.25H2O: C, 67.48; H, 4.42; N, 9.84. Found C, 67.25; H, 4.21; N, 9.88.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=2)[NH:9]1.[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>ClCCl>[CH:24]1([C:27]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[O:28])[CH2:26][CH2:25]1
Reactant: O=C(O)C1CC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1N)N2
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NC(=O)C1CC1)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To an ice-cold mixture of methyl 2-(2-aminophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (80 mg, 0.26 mmol, 1.0 eq.), cyclopropanecarboxylic acid (33 mg, 0.34 mmol, 1.5 eq.), N,N-diisopropylethylamine (63 mg, 0.51 mmol, 2.0 eq.) in dichloromethane (4 mL) was added a solution of phosphorus oxychloride (45 mg, 0.31 mmol, 1.2 eq.). Then the reaction mixture was stirred at room temperature for 30 min. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water and extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=2:1) to afford 57 mg of methyl 2-(2-(cyclopropanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a pale yellow solid; yield: 58%. MS (ESI+APCI) M+1=379.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[C:8](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:32]([NH2:35])[CH2:33][CH3:34]>>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[C:8]([NH:35][CH2:32][CH2:33][CH3:34])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(NC(C)C)c3c2C(=O)c2ccccc2C3=O)cc1
Product: CCCNc1ccc(NC(C)C)c2c1C(=O)c1ccccc1C2=O
Yield: 67 %

Procedure:
1-(isopropylamino)-4-(n-propylamino)anthraquinone was prepared by reaction of 1-(isopropylamino)-4-tosyloxyanthraquinone with n-propyl amine. The isolated and purified reaction product has the structure illustrated below. ##STR13## The yield was 67% and the m.p. 120°-121° C. Mass spec m/e 322 (M+), 307 (M-CH3), 293 (M-C2H5), 279 (307-CO), 251 (M-2CO); 1H-NMR (CD2Cl2)ε10.99 br s, 1H), 10.88 (br s, 1H), 8.39-8.22 (m, 2H); 7.77-7.59 (m, 2H), 7.27 (s, 2H), 3.90 (m, 1H), 3.46-3.28 (m, 2H), 1.81-1.58 (m, 2H), 1.39, 1.32 (d, 6H), 1.26-1.07 (t, 3H); VIS max (Xylenes) 598 nm (ε14 100), 646 (16 200).
Reaction SMILES: [Cl:1][C:2]1[C:11](I)=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.[OH-].[K+].[F:15][C:16]([F:19])([F:18])I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:10][C:5]2[NH:6][C:7]([S:9][C:16]([F:19])([F:18])[F:15])=[N:8][C:4]=2[CH:3]=1
Reactant: S=c1[nH]c2cc(Cl)c(I)cc2[nH]1
Reactant: FC(F)(F)I
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)Sc1nc2cc(Cl)c(-c3ccc(Cl)cc3)cc2[nH]1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Compound number 102 (i.e., 6-chloro-5-(4-chlorophenyl)-2-trifluoromethylthiobenzimidazole) was prepared as follows. A 250-mL 3-necked round-bottom flask was charged with a solution of 5-chloro-6-iodo-2,3-dihydro-1H-1,3-benzodiazole-2-thione (2 g, 6.44 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) and potassium hydroxide (1.1 g, 3.00 equiv). Trifluoro(iodo)methane was introduced to the above. The resulting solution was stirred for 3 h at 120° C. in an oil bath. The resulting solution was diluted with 250 mL of ethyl acetate. The resulting mixture was washed with 3×200 mL of water and 2×200 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 400 mg (16%) of 5-chloro-6-iodo-2-[(trifluoromethyl)sulfanyl]-1H-1,3-benzodiazole as a yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:8]1[C:6]2=[N:7][C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[CH:29]=[N:30][C:25]([C:24]([F:23])([F:38])[F:39])=[CH:26][CH:27]=4)=[CH:32][C:33]3=[O:37])=[CH:3][CH:4]=[C:5]2[C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:9]1=2
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.80 g, 2.2 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (0.58 g, 2.4 mmol), and Cs2CO3 (0.78 g, 2.4 mmol) were suspended in DMSO (13 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (95 mg, 0.65 mmol) and copper iodide (0.54 g, 2.8 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL) and washed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (2×30 mL). Activated charcoal was added to the organic solution, and the resulting suspension was filtered through a Celite® plug and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 12 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 4 column volumes) gave the title compound (0.82 g, 71%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, J=1.5 Hz, 1H), 8.50 (dd, J=8.5, 2.0 Hz, 1H), 8.08-8.05 (m, 3H), 7.39 (d, J=8.5 Hz, 1H), 7.03 (d, J=1.5 Hz, 1H), 6.84 (dd, J=7.0, 2.0 Hz, 1H), 4.59 (s, 2H), 3.77 (t, J=5.5 Hz, 2H), 3.70 (s, 3H), 2.90 (t, J=5.5 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[Br-].[Li+].[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:20][CH2:19]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: OCc1ccc(O)cc1
Agent: [Br-]
Agent: [K+]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCN(Cc2ccc(O)cc2)CC1
Temperature: 25 °C
Yield: 80 %

Procedure:
One mole of 4-hydroxyphenyl methanol (124 g) and 192 g (2 moles) of 1-(2-methoxyphenyl)piperazine were dissolved in 1.5 liters of toluene. One mole (87 g) of lithium bromide and 0.1 mole (5.6 g) of potassium hydroxide were added portionwise, under stirring, and the reaction medium was heated to reflux for 5 hours. The reaction mixture was then allowed to cool to room temperature, and extracted twice with 500 ml of a 1N sodium hydroxide. The basic aqueous liquor was washed with 300 ml of toluene and then acidified to pH 7 with acetic acid to provoke precipitation of the desired product. The precipitate thus obtained was filtered off and then recrystallized from isopropanol, giving 238.4 g (0.80 mole, 80% yield) of the title product, melting at 172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:20][CH2:21][CH:22]=O)[CH:10]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][N:35]([CH2:22][CH2:21][CH2:20][C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:12]=3)[CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2-c2ccccc2)cc1

Procedure:
104 mg (76%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)propanal (75 mg, 0.245 mmol), 1-(3,4-dichlorophenyl)piperazine (57 mg, 0.245 mmol), DIPEA (0.064 mL, 0.368 mmol) and NaBH(OAc)3 (156 mg, 0.735 mmol).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3F)=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([BH-](CC)CC)C.[Li+].C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl.C(O)(C)C>O1CCOCC1.C1COCC1>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[O:18][C:31]4[C:30](=[C:35]([F:36])[CH:34]=[CH:33][CH:32]=4)[C:20]4[C:19]3=[C:28]3[C:23](=[CH:22][CH:21]=4)[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27]3)=[CH:15][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2c(F)cccc2F)ccc2cc(O)ccc12
Agent: CC[BH-](CC)CC
Agent: O=C([O-])O
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Oc1ccc2c3c(ccc2c1)-c1c(F)cccc1OC3c1ccc(OCCN2CCCCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2,6-difluoro-phenyl)-6-hydroxy-naphthalen-1-yl]-methanone (1.3 g, 2.6 mmol) in 125 mL dioxane and add 20 mL (20 mmol) of a 1.0 M solution of lithium triethylborohydride in THF. Stir at room temperature for one hour, then heat at 100° C. for three hours. Pour the reaction into a two phase system consisting of saturated sodium bicarbonate and an organic phase of a 3/1 mixture of chloroform/isopropanol. Extract in a reparatory funnel, separate the organic layer and dry over 3 Å molecular sieves. Evaporate to give 1.5 g of slightly impure product. Purify on a silica column eluting with 0-10% methanol/methylene chloride gradient to give 850 mg (68%) of racemic product: 1H-NMR (CDCl3, 400 MHz) δ8.18 (d, J=8.4 Hz, 1H); 7.73 (d, J=8.8 Hz, 1H); 7.52 (d, J=9.2 Hz, 1H); 7.21 (d, J=2.4 Hz, 1H); 7.08-6.99 (m, 5H); 6.88 (s, 1H); 6.72-6.61 (m, 4H); 4.24-4.23 (m, 2H); 3.26-3.26 (m, 6H); 1.87-1.87 (m, 4H); 1.66-1.66 (m, 4H). The racemic mixture is purified using chiral chromatography (conditions F). The two isomers eluted with retention times of 7.9 and 9.0 minutes.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[N-:33]([C:36]#[N:37])[C:34]#[N:35].[Na+]>C(O)CCC>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[CH:21]=4)[CH2:16][CH2:15][N:14]3[C:36](=[NH:37])[NH:33][C:34]#[N:35])[CH2:10][CH2:11][CH2:12]2)=[CH:5][CH:4]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)N(C(=N)NC#N)CC2

Procedure:
Propane-1-sulfonic acid (2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-1,2,3,4-tetrahydro-isoquinolin-7-yloxy}-ethyl)-amide hydrochloride (example 4, 95.0 mg, 0.19 mmol) was dissolved in 1-butanol (10 ml) and sodium dicyanamide (42.3 mg, 0.48 mmol) was added.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:17][CH:16]([N:18]4[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]4)[CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1.[CH2:32]([C:34]1[NH:35][C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)[CH3:33].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[CH2:32]([C:34]1[N:35]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:15][CH:16]([N:18]5[CH2:23][CH2:22][S:21](=[O:24])(=[O:25])[CH2:20][CH2:19]5)[CH2:17]4)[N:8]3[CH3:11])=[C:4]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:3]=2)[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=1)[CH3:33]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CCN2CC(N3CCS(=O)(=O)CC3)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CC(N4CCS(=O)(=O)CC4)C3)n(C)c2n1
Temperature: 120 °C
Yield: 68.1 %

Procedure:
A mixture of 2-chloro-8-{2-[3-(1,1-dioxo-1-thiomorpholin-4-yl)azetidin-1-yl]-ethyl}-9-methyl-6-morpholin-4-yl-9H-purine (93 mg, 0.20 mmol), 2-ethylbenzimidazole (32 mg, 0.22 mmol), Pd2(dba)3 (4.5 mg, 2.5 mol %), Xphos (9.4 mg, 10 mol %) and Cs2CO3 (97 mg, 0.30 mmol) in dioxane (2.0 mL) was purged with argon gas then heated at 120° C., for 20 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 20-90%) to give 537 (79 mg, 69%) as a beige solid. LCMS: (Method I): RT 2.42 min; [M+H]+ 580.3. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1 H), 7.77-7.72 (m, 1 H), 7.29-7.22 (m, 2 H), 4.57-4.09 (m, 4H), 3.86 (t, J=4.8 Hz, 4 H), 3.77 (s, 3 H), 3.71-3.57 (m, 2 H), 3.34 (q, J=7.5 Hz, 2 H), 3.33-3.22 (m, 1 H), 3.07 (m, 8 H), 3.00-2.89 (m, 2 H), 2.85 (t, J=4.8 Hz, 4 H), 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:28])[N:5]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:6]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[N:7]2.[CH3:29][N:30]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.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>[C:29]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:28])[N:5]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[C:6]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[N:7]2)#[N:30]
Reactant: CN1CCCC1=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Br)c2c(=O)n1-c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(C#N)c2c(=O)n1-c1cccnc1
Temperature: 80 °C
Yield: 87 %

Procedure:
To a solution of (S)-tert-butyl 1-(5-bromo-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate (255 mg, 0.58 mmol) in NMP (2 mL) was added zinc cyanide (74 mg, 0.63 mmol) and (PPh3)4Pd (66 mg, 0.06 mmol). The resulting suspension was degassed under Argon and heated to 80° C. for 5 hours. The reaction was poured into EtOAc, washed twice with aq. NaHCO3 and once with brine. Purification by flash chromatography (0-75% EtOAc/hexanes) provided (S)-tert-butyl 1-(5-cyano-4-oxo-3-(pyridin-3-yl)-3,4-dihydroquinazolin-2-yl)ethylcarbamate 196 mg (87%). ES/MS 392.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[CH3:19]I.[H-].[Na+]>CS(C)=O.CCCCC>[Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]2[N:6]([CH3:19])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: CI
Reactant: O=[N+]([O-])c1cc(Br)cc2c1[nH]c1ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCC
Product: Cn1c2ccc(Br)cc2c2cc(Br)cc([N+](=O)[O-])c21
Reaction time: 0.03 h

Procedure:
3,6-dibromo-1-nitrocarbazole (3.56 g, 0.01 mole) was dissolved in 30 ml of warm DMSO followed by the addition of 30 ml of CH3I. Then 2.0 g of 50% NaH dispersion in mineral oil (0.02 mole) was washed under N2 with 2×50 ml of pentane, dried under N2 and added rapidly to the DMSO solution. The solution turned purple immediately with H2 evolution and became yellow in two minutes. Addition of 0.25 g of NaH did not cause the yellow slurrY to turn purple indicating that the reaction was complete. Methanol (200 ml) was added cautiously to precipitate the product. The product was recovered by filtration, washed with 25 ml of methanol, 10×25 ml of water, 25 ml of methanol and air dried to give 3.40 g of product, m.p. 225°-226° C. (corrected). [H. Lindemann & F. Muhlhaus, Ber., 58, 2371 (1925) report a m.p. of 221° C. for the product].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[OH:27])[C:6](=[O:23])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1.CCN(C(C)C)C(C)C.[CH3:37][O:38][CH2:39]Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH2:37][O:38][CH3:39])[C:6](=[O:23])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:18]([NH2:22])=[N:19][O:20][N:21]=1
Reactant: COc1cc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)ccc1O
Reactant: COCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCOc1ccc(C(=O)Cn2c(-c3nonc3N)nc3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4-[1-(3-methoxy-4-hydroxyphenacyl)-1H-benzimidazol-2-yl]-furazan-3-ylamine (0.10 g, 0.27 mmol), DIPEA and methoxymethyl chloride in dry DMF is stirred at room temperature for 14 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate and concentration of the filtrate under reduced pressure gives the title compound as colorless, pure solid, m.p. 190° C.