Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:7][N:6]([CH3:21])[CH:5]=1)(=[O:3])C.ClN1C(=O)CCC1=O.[Cl:30][CH2:31][Cl:32]>>[Cl:30][CH:31]([Cl:32])[C:1]([C:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)=[CH:7][N:6]([CH3:21])[CH:5]=1)=[O:3]
Reactant: ClCCl
Reactant: CC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C1CCC(=O)N1Cl
Product: Cn1cc(C(=O)C(Cl)Cl)c(=O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
A 4.5 g. portion of 3-acetyl-1-methyl-5-(3-trifluoromethylphenyl)-4(1H)-pyridinone was dissolved in 125 ml. of dichloromethane, and 2 g. of N-chlorosuccinimide was added. The mixture was stirred under reflux for 60 hours. The mixture was then cooled, and washed successively with 150 ml. each of 1 N sodium hydroxide, 1 N hydrochloric acid, and saturated sodium chloride solution. It was then dried over magnesium sulfate, and evaporated under vacuum to obtain a tan solid. The residue was chromatographed on a 350 g. silica gel column, with 1:10 ethyl acetate:dichloromethane as the eluting solvent. The first product off the column was the dichloroacetyl compound of Example 22, m.p. 184°-186° C., of which 0.6 g. was obtained. Nmr analysis in DMSOd6 showed the following peaks: δ8.4 (s, 1H, CHCl2); 7.6-8.3 (m, 6H, aromatic); 3.9 (s, 3H, N--CH3).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]([NH2:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17].[CH3:25][C:26]([CH3:28])=O>ClCCl>[CH:26]([NH:24][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[CH3:15])([CH3:28])[CH3:25]
Reactant: CC(C)=O
Reactant: CC(C)(N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)NC(C)(C)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (4.5 g, 21.2 mmol) was added portionwise to a solution of 1-methyl-1-phenylethylamine (0.96 g, 7.1 mmol) in a mixture of acetone (5 ml) and dichloromethane (120 ml). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between aqueous sodium hydroxide solution (2M, 100 ml) and ethyl acetate (200 ml). The ethyl acetate layer was washed with water (100 ml) and brine (100 ml) and then dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to give the title compound (1 g) as a colourless oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[C:32]([CH2:33][O:34]C3CCCCO3)=[CH:31][N:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[C:32]([CH2:33][OH:34])=[CH:31][N:30]=[N:29]4)[CH:23]=3)[CH2:20][C:19](=[O:42])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionyl-amino)-phenyl]-carbamic acid tert.-butyl ester (Example M3) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a beige solid (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]([N:11]2[C:15](=[O:16])[NH:14][C:13](=[O:17])[O:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:21][CH:22]([CH3:25])[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:18]([CH3:20])[CH3:19])[C:9]([N:11]2[C:15](=[O:16])[N:14]([CH2:21][CH:22]([CH3:25])[CH3:23])[C:13](=[O:17])[O:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)CO
Reactant: CC(C)N(C(=O)n1oc(=O)[nH]c1=O)c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)on(C(=O)N(c2ccc(F)cc2)C(C)C)c1=O
Temperature: 15 °C
Reaction time: 18 h
Yield: 84.9 %

Procedure:
A 50 mL round bottom flask equipped with a thermometer, a stirrer, an addition funnel, and a nitrogen inlet was charged with N-(4-fluorophenyl)-N-(1-methylethyl)-3,5-dioxo-1,2,4-oxadiazolidine-2-carboxamide (5.5 g, 0.019 m), 2-methyl-1-propanol (3 g, 0.04 mol), triphenylphosphine (6.3 g, 0.021 mol) and tetrahydrofuran (60 mL). The reaction solution was cooled to 15° C. and diethyl azodicarboxylate (4.2 g, 0.024 mol) in tetrahydrofuran (10 mL) was added dropwise over a period of 10 min. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was flash chromatographed (silica gel, 9:1 hexane-ethyl acetate) to provide the title compound as a white solid (5.6 g, 88%). The solid has a melting range of 80-81° C., and was identical to the material prepared in Example 8, Step B.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[CH3:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13]([C:14]1[CH:19]=[CH:18][C:17]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:16][CH:15]=1)=[O:21])[CH3:11]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-n2ccc3ccccc32)cc1

Procedure:
Using the general procedure, indole (0.117 g, 1.00 mmol) was coupled at 80° C. with ethyl-4-iodobenzoate (0.331 g, 1.20 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), K3PO4 (2.1 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (32 μL, 0.20 mmol, 20 mol %) and toluene (1.0 mL) to give the crude product. The above product was identified by comparison (GC) to a previously prepared sample and the GC yield was determined to be 96%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[Cl:13])=[O:3].C(O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O.[Fe]>[CH3:1][C:2]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:13])=[O:3]
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(N)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5 g of solid 2-chloro-5-nitroacetophenone (see J. Am. Chem. Soc. 76, 5482 (1952)) are introduced in portions and with stirring at 65° C. to a mixture of 5.6 g of iron powder, 40 ml of ethanol, 9 ml of water and 1 ml of concentrated hydrochloric acid. Stirring of the reaction mixture is continued for 1 hour at 70° C. The mixture is allowed to cool to room temperature and then diluted with 300 ml of water, and a pH of 9 is established by adding 2N potassium carbonate solution. The mixture is filtered with suction through Celite, and the residue is washed with 200 ml of ethyl acetate. The filtrate is transferred to a separating funnel, and the aqueous phase is discarded. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][O:18][N:19]=[C:20]([CH3:22])[CH3:21])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:5][C:4]=2[N:3]=1.C([BH3-])#N.[Na+].O1CCCC1.C(O)(=O)C>CO>[CH2:25]([O:24][CH2:23][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][O:18][NH:19][CH:20]([CH3:21])[CH3:22])[C:10]2[C:9]3[N:8]=[CH:7][C:6]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:26]
Reactant: CCOCc1nc2c(N)nc3cc(-c4ccccc4)cnc3c2n1CCCON=C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCOCc1nc2c(N)nc3cc(-c4ccccc4)cnc3c2n1CCCONC(C)C
Yield: 99.6 %

Procedure:
A slurry of acetone O-{3-[4-amino-2-(ethoxymethyl)-7-phenyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propyl}oxime (1.00 g, 2.31 mmol), 1 M sodium cyanoborohydride in tetrahydrofuran (4.62 mL, 4.62 mmol), methanol (12 mL), and acetic acid (4.5 mL) was stirred overnight at ambient temperature. The resulting solution was concentrated under reduced pressure and the residue was dissolved in chloroform (200 mL). The solution was washed with saturated aqueous sodium bicarbonate (2×40 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 1.0 g of 2-(ethoxymethyl)-1-{3-[(isopropylamino)oxy]propyl}-7-phenyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a yellow powder, mp 142.0-144.0° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrBr.[NH2:22][C:23]1[N:24]=[C:25]([NH2:35])[C:26]2[CH:32]=[C:31]([CH2:33]O)[CH:30]=[N:29][C:27]=2[N:28]=1.[NH2:36][C:37]1[CH:58]=[CH:57][C:40]([C:41]([NH:43][C@H:44]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[O:42])=[CH:39][CH:38]=1>CC(N(C)C)=O>[NH2:22][C:23]1[N:24]=[C:25]([NH2:35])[C:26]2[CH:32]=[C:31]([CH2:33][NH:36][C:37]3[CH:38]=[CH:39][C:40]([C:41]([NH:43][C@H:44]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[O:42])=[CH:57][CH:58]=3)[CH:30]=[N:29][C:27]=2[N:28]=1
Reactant: Nc1nc(N)c2cc(CO)cnc2n1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OCC
Agent: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of triphenylphosphine (430 mg, 1.64 mmol) in anhydrous DMAC (4 ml) at 0° C. was treated dropwise under N2 with bromine (84 μL, 1.64 mmol). The solution was stirred at 0° C. for 15 minutes, treated with the compound obtained in Example 2 (100 mg, 0.76 mmol), and stirred at 25° C. for 1.7 hours to give the compound of Formula IIIA. This solution was treated with diethyl p-aminobenzoyl-L-glutamate (194 mg, 0.603 mmol), stirred at 25° C. for 17 hours and poured into ice water (40 ml). The resulting solution (pH 2) was filtered to remove triphenylphosphine oxide, adjusted to pH 6.8 with 50% NaOH, and cooled in an ice bath. The precipitate of crude product (VII; R=H, R1 =C2H5) was collected by centrifugation, washed with H2O and dried in vacuo (P2O5); yield 136 mg (73%). The retention time (HPLC) and rf value (TLC) of this product were identical to those obtained from the analytical sample obtained in Part A of this example. Mass spectrum: m/e 496 (M+1)+.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:17]1[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1)([O-])=O>O1CCCC1>[F:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:17]3[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: Fc1ccc2nc(S)[nH]c2c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3cc(F)ccc3[nH]2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
A solution of 2-mercapto-5-fluoro-benzimidazole (2.24 g, 13.3 mmol) in tetrahydrofuran (10 ml) is added dropwise to a mixture of sodium hydride (60% dispersion in mineral oil, 0.852 g, 21.3 mmol) and tetrahydrofuran (5 ml). The mixture is stirred at room temperature for 2 hours. A solution of 5-nitro-2-furaldehyde (1.88 g, 13.3 mmol) in tetrahydrofuran (15 ml) is then added dropwise over a 15 minute period and the mixture is stirred for 2 hours at room temperature. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in 200 ml of ethyl acetate and washed with water (2×60 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is purified on a silica gel column (40 g) eluted with dichloromethane to yield 700 mg of 5-(5-fluoro-1H-benzoimidazol-2-ylsulfanyl)-furan-2-carbaldehyde as an orange powder. Yield=20%. Analytical LC/MS (method B): retention time=3.08 min., m/z=263.05 (positive ion mode).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C(C)=CC=CC=1C>>[CH2:16]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc(O)c(Cc2ccccc2)c1
Solvent: Cc1cccc(C)n1
Product: COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Trifluoromethanesulfonic anhydride (10.0 mL, 60 mmol) was added over 3 min to a solution of 2-benzyl-4-methoxyphenol (10.71 g, 50 mmol; prepared according to J. Am. Chem. Soc. 1949, 71, 64) and anhydrous 2,6-lutidine (12.0 mL, 100 mmol) in anhydrous CH2C2 (250 mL) at -78° C. under argon. The reaction was stirred at -78° C. for 0.5 h, then was warmed to RT. After 1 h, the reaction was diluted with hexanes (250 mL) and washed sequentially with 1.0 N HCl (2×100 mL), 1.0 N NaOH (2×50 mL), H2O (100 mL) and brine (50 mL). Drying (Na2SO4), concentration, and silica gel chromatography (10% EtOAc/hexanes) gave the title compound as a light yellow solid (16.65 g, 96%): TLC Rf 0.51 (10% EtOAc/hexanes); 1H NMR (250 MHz, CDCl3) δ 7.10-7.40 (m, 6H), 6.77 (dd, J=9.0, 3.1 Hz, 1H), 6.66 (d, J=3.1 Hz, 1H), 4.03 (s, 2H), 3.73 (s, 3H); FTIR (CCl4) 1492, 1423, 1405, 1249, 1216, 1161, 1144, 1039, 869 cm 1 ; MS (ES) m/e 369 (M+Na)+, 364.0 (M+NH4)+, 347.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:30]=[CH:29][C:16]([CH2:17][N:18]([CH2:26][CH2:27][OH:28])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=2)[N:3]=1.CCN(CC)CC.[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([O:49][CH3:50])=[O:48])#[CH:39].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:21]([O:20][C:19]([N:18]([CH2:17][C:16]1[CH:29]=[CH:30][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:39]#[C:38][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH2:46][C:47]([O:49][CH3:50])=[O:48])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)[CH2:26][CH2:27][OH:28])=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CN(CCO)C(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl(2-hydroxyethyl)carbamate (A71) (0.518 g, 1.15 mmol), Et3N (0.75 mL), methyl 2-(2-ethynylphenyl)acetate (K1) (0.242 g, 1.39 mmol), PdCl2(PPh3)2 (0.041 g, 0.058 mmol), CuI (0.022 g, 0.116 mmol) and PPh3 (0.030 g, 0.12 mmol) in DMF (4.5 mL) was heated under microwave irradiation at 120° C. for 15 minutes. The volatiles were evaporated in vacuo and the residue purified using silica gel column chromatography (CombiFlash Rf, 40 g SiO2 cartridge, 20-50% EtOAc in cyclohexane) to give the title compound A72 as an orange foam (0.589 g, 86%); 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 7.70 (d, J=7.0 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.48-7.28 (m, 6H), 4.49 (brs, 2H), 3.97 (s, 2H), 3.72 (m, 5H), 3.47 (brs, 2H), 3.01 (brs, 1H), 1.51 (s, 9H). LCMS-B: rt 8.350 min; m/z 585 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]([OH:12])[C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CCO.O>[F:9][C:8]([F:11])([F:10])[C:7]([C:5]1[S:6][C:2]([C:18]2[CH:19]=[CH:20][C:15]([S:14][CH3:13])=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)=[O:12]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: OC(c1ccc(Br)s1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CSc1ccc(-c2ccc(C(=O)C(F)(F)F)s2)cc1

Procedure:
1-(5-Bromo-4-thienyl)-1,2,2-trifluoroethanol (C1) in DUE added to Polymer-Bound Triphenylphosphine Pd(0) (0.5% eq) followed by 4-(methylthio)phenylboronic acid (1.3 eq)) in EtOH and K2CO3 (1.5 eq) in water and the mixture was stirred at 75° C. for 24 h. The suspension was filtered and the filtrate was purified by reverse phase HPLC as described for Example 3. MS (ES) C13H9F3OS2 requires: 302, found: 303 (M+H+).
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15](N3C=NC=N3)[C:16]=2[N:17]=1.CC(O)C>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15]([O:4][CH:2]([CH3:3])[CH3:1])[C:16]=2[N:17]=1
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Oc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Potassium tert-butoxide (4.0 mL; 1M in THF) was added to a suspension of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (1.0 g) and 2-propanol (0.313 mL) in DCM (50 mL). After stirring at room temperature for 30 minutes, the mixture was diluted with DCM (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford 6-chloro-4-(2-propoxy)-pyrido[3,2-d]pyrimidin-2-ylamine as a yellow solid (0.65 g, yield: 67%) which was characterized by its mass spectrum as follows: MS (m/z) 239.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][C:19]4([CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22]4)[CH2:18]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:30]([O-])=O.Cl>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:30][C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:2]=1[NH2:1])[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][C:19]3([CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22]3)[CH2:18]2)=[CH:13][CH:14]=1)=[O:7]
Reactant: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc(N)c([N+](=O)[O-])c4)cc3)C2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCN1CCC2(CCN(CCc3ccc(NC(=O)c4ccc(N)c(N)c4)cc3)C2)C1

Procedure:
4-Amino-N-{4-[2-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenyl}-3-nitro-benzamide from above was dissolved in ethanol (25 ml) and 1N HCl (6 ml) to which was added 20% Pd(OH)2 and the mixture hydrogenated overnight under an atmosphere of hydrogen gas. The reaction was then filtered thru Celite and the filtrate evaporated to afford crude 3,4-Diamino-N-{4-[2-(7-ethyl-2,7-diaza-spiro[4.4]non-2-yl)-ethyl]-phenyl}-benzamide (1.18 g, 4×HCl salt) as a tan foam which was used as is in the next step.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[C:28]([O:31][CH2:32][CH2:33]Br)(=[O:30])[CH3:29]>C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:33][CH2:32][O:31][C:28](=[O:30])[CH3:29])[C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(=O)OCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Anhydrous DMF solution (10 ml) of 2-t-butoxycarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2.72 g, 10 mol) was mixed with 60% sodium hydride (0.4 g, 10 mmol) and stirred at room temperature for 1 hour. The reaction solution was cooled to −60° C., mixed with 2-acetoxy-1-bromoethane (1.67 g, 10 mmol) and then returned to room temperature while stirring for 1 hour. The reaction solution was mixed with ethyl acetate, washed with water and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure, the thus obtained residue was mixed with diisopropyl ether (20 ml) and the thus precipitated crystals were collected by filtration to obtain 1.90 g of the title compound (5.3 mmol, 53% in yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:6](Cl)=[O:7].CCN(C(C)C)C(C)C.[NH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]1>C(Cl)Cl>[NH2:12][C:11]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCC(N(C)C)CC2)ccc1N
Reaction time: 2 h
Yield: 113.9 %

Procedure:
3-methoxy-4-nitro-benzoyl chloride (Intermediate 189; 1.0 g, 4.64 mmol) was dissolved in DCM (20 mL) and cooled on an ice bath. DIPEA (970 uL) was added dropwise. 1-amino-4-dimethylaminocyclohexane (ABChem. Inc.; 660 mg, 4.64 mmol) was dissolved in DCM (10 mL) and added to the reaction solution. The reaction mixture was brought back to room temperature and stirred for 2 hours. The reaction mixture was washed with brine and NaOH (aq). The organic layer was extracted by filtering through a PTFE cup and evaporated to yield the title compound as an orange solid (1.54 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:2]=1>C(O)C.[Ni]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:13])[CH:2]=1
Reactant: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc(-c2cccnc2)c1

Procedure:
3-(3-pyridyl)-nitrobenzene (9.1 g, 45.5 mmol) in ethanol (125 ml) is hydrogenated at ambient pressure for 1.75 hours using Raney Nickel as the catalyst. Filtration of the resulting solution through celite followed by evaporation of solvent quantitatively yields 3-(3-pyridyl)aniline.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[O:14]([C:21]([N:23]1[CH2:28][CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[CH2:25][CH:24]1[CH3:37])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Li+]>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.C(OCC)(=O)C.C1(P(C2[C-](Cl)C=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Pd+2]>[O:14]([C:21]([N:23]1[CH2:28][CH:27]=[C:26]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:25][CH:24]1[CH3:37])=[O:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC1CC(OS(=O)(=O)C(F)(F)F)=CCN1C(=O)Oc1ccccc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Cl[c-]1cccc1P(c1ccccc1)c1ccccc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC1CC(c2ccc3ccccc3c2)=CCN1C(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
A mixture of 5.46 gm (31.8 mMol) naphthalene-2-boronic acid, 8.28 gm (22.7 mMol) 1-phenoxycarbonyl-2-methyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine, 0.741 gm (0.91 mMol) palladium(II) diphenylphosphino-ferrocenyl chloride, and 2.88 gm (68 mMol) lithium chloride in 25 mL 2M aqueous sodium carbonate and 96 mL dimethoxyethane was heated at reflux for about 18 hours. The reaction mixture was cooled to room temperature and was diluted with ethyl acetate and saturated aqueous sodium carbonate. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane containing 10% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 3.87 gm (50%) of the title compound as a viscous oil.