Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH:17]([N:20]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:24]2[N:20]([CH:17]([CH3:19])[CH3:18])[N:21]=[CH:22][CH:23]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C(C)C)c(C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a solution of 2-amino-4-trifluoromethyl-5-iodo-benzoic acid methyl ester (1.56 g, 4.52 mmol) in dioxane (40 mL) were added 1-isopropyl-5-tributylstannanyl-1H-pyrazole (2.34 g, 1.3 eq) and Pd(dppf)2Cl2 (369 mg, 0.1 eq) and the resulting mixture was stirred at 100° C. for 18 h. A second portion of catalyst (0.1 eq) was added and the mixture was stirred at 100° C. for 24 h. A last portion of catalyst (0.1 equiv) was added and the mixture was kept at 100° C. for 72 h. The solvent was removed in vacuo to provide a dark oil which was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 50:50)) to give the title compound (666 mg, 45%) as an off-white solid (ES-MS: m/z 328.3 [M+H]+, rt 5.60 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([OH:19])=O)[C:10](=[O:26])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][O:22]3)[C:17]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=3)=[O:19])[C:10](=[O:26])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C[C@H]2CCCO2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(C[C@H]2CCCO2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
585 mg (purity 73%, 1.1 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[(2R)-tetrahydrofuran-2-yl]propanoic acid (mixture of enantiomerically pure diastereomers 1 and 2) and 225 mg (1.2 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 327 mg (53% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[CH:15]2[CH2:19][CH2:20][CH:21]=[CH:22][CH:14]12>>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:13]([C@H:14]1[CH2:22][CH:21]=[CH:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:23])[CH3:12]
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: CCOc1cc(Br)ccc1OC
Product: CCOc1cc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)ccc1OC

Procedure:
Prepared from 1-Bromo-3-ethoxy-4-methoxybenzene and tetrahydrophthalic anhydride as described for compound D. M.p. 132-135° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](Br)=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6](=[O:15])[N:5]=1)[CH3:2].[NH3:16]>C(#N)C>[CH2:1]([O:3][C:4]1[C:8]([NH2:16])=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6](=[O:15])[N:5]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)C1=C(Br)C(OCC)=NS1=O
Solvent: CC#N
Product: CCOC(=O)C1=C(N)C(OCC)=NS1=O
Temperature: 0 °C
Yield: 78 %

Procedure:
3-Ethoxy-4-bromo-5-ethoxycarbonylisothiazole-1-oxide (1.48 g, 5.0 mmol) was dissolved in fifteen ml of dry acetonitrile. The solution was cooled in ice and a solution of anhydrous ammonia in cold acetonitrile (0.105 mol in 5 ml) was added dropwise in excess. After stirring in the ice bath for 41/4 hours the reaction was complete. The title compound (1.16 g 78%, mp 153.5°-155° C.) was obtained as a yellow solid by chromatography on silica gel (chloroform).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([CH2:13][C:14](OCC)=[O:15])#[N:12]>CN(C)C=O.C(OCC)(=O)C>[C:11]([CH2:13][C:14]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:15])#[N:12]
Reactant: CCOC(=O)CC#N
Reactant: NCCc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCC(=O)NCCc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
1.28 g (9.33 mmol) of tyramine is added to a solution containing 1.00 g (8.84 mmol) of ethyl cyanoacetate in 13 mL of dimethylformamide under an inert atmosphere. The mixture is stirred at 110° C. for 4 hours, then at room temperature for 12 h. The reaction medium is then diluted in 100 mL of ethyl acetate and washed with 50 mL of an aqueous acid solution at pH=3. The aqueous phase is again extracted with 50 mL of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and the solvent is evaporated under reduced pressure. The resulting viscous brown solid is then dissolved several times in toluene and the toluene azeotrope/DMF is evaporated. Finally, the solid is washed with dichloromethane and ether. The product is isolated in the form of a pale brown solid with a yield of 65%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:37])[CH:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:36])[NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])=[O:16])[CH2:12][NH2:13].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[S:79]1[CH:83]=[CH:82][CH:81]=[C:80]1[C:84](O)=[O:85]>CN(C=O)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:37])[C@@H:11]([NH:14][C:15]([C:17]1[S:18][C:19]([C:26](=[O:36])[NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:20][C:21]=1[C:22]([F:25])([F:23])[F:24])=[O:16])[CH2:12][NH:13][C:84]([C:80]1[S:79][CH:83]=[CH:82][CH:81]=1)=[O:85]
Reactant: COC(=O)C(CN)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(F)(F)F
Reactant: O=C(O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21.2 %

Procedure:
To a solution of S)-3-Amino-2-{[5-(3-hydroxy-benzylcarbamoyl)-3-trifluoromethylthiophene-2-carbonyl]-amino}-propionic acid methyl ester trifluoro-acetic acid salt (0.34 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.14 mL, 1.02 mmol), HBTU (0.19 g, 0.51 mmol), HOBT (0.055 g, 0.41 mmol), and 2-Thiophenecarboxylic acid (0.048 g, 0.37 mmol). The mixture was stirred at room temperature 1.5 h, treated with EtOAc (50 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column (50-80% EtOAc in hexane) to give 0.040 g (61%) colorless oil product. MS m/e 556.0 (M+H+).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=2)[NH:14][N:13]=1>C1COCC1>[CH2:1]([NH:8][C:9]([NH:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1ccc2[nH]nc(I)c2c1
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)Nc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
Benzyl isocyanate (0.25 mL, 2.0 mmol) was added to 3-iodo-1H-indazol-5-ylamine (Preparation #28, 0.50 g, 1.9 mmol) in THF (10 mL). After stirring at ambient temperature for about 2.5 hours, the mixture was filtered and washed with Et2O to give 1-benzyl-3-(3-iodo-1H-indazol-5-yl)-urea (0.41 g, 55%) as an ivory solid; RP-HPLC (Table 1, Method e) Rt 0.98 min, m/z (ESI+) 393.0 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Cl[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][CH3:24])=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19])(=[O:12])=[O:11]>O>[CH2:23]([O:22][C:16]1[CH:15]=[CH:14][C:13]([S:10]([N:6]2[CH2:5][C@@H:4]([CH3:8])[NH:3][C@@H:2]([CH3:1])[CH2:7]2)(=[O:12])=[O:11])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19])[CH3:24]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Solvent: O
Product: CCOc1ccc(S(=O)(=O)N2C[C@@H](C)N[C@@H](C)C2)cc1C(=O)O
Yield: 70.1 %

Procedure:
In a 250 ml three-neck flask, 52.6 g (0.23 mol) of cis-2,6-dimethylpiperazine was added to the suspension of compound (II) (53 g, 0.20 mol) in water (170 ml) at about 10° C. with stirring, at the same time the temperature of reacting mixture was kept below 20° C. The reaction was then stirred at 10° C. for another 2 hours. The precipitate was filtered, ice-water washed, dried, and refluxed in acetone for 1 hour, and purified, gave 48 g compound (III) (yield 70%) as white crystalline, m.p. 260.5-273.0° C. (Dec.). HNMR(DMSO) δ: 7.72-7.75(2H, H-4 and H-6 on benzene ring), 7.26-7.28(1H, H-3 on benzene ring), 4.12-4.17(2H, —CH2— on —OCH2CH3), 3.5-3.53(2H, —CH2— on piperazine ring), 2.89-2.92(2H, —CH— on piperazine ring), 1.80-1.86(2H, —CH2— on piperazine ring), 1.31-1.34(3H, —CH3 on —OCH2CH3), 1.0-1.04(6H, two —CH3 groups on piperazine ring).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)=[O:12])[CH:3]=[CH:2]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Solvent: CN(C)C=O
Product: O=C(c1cccc2cc[nH]c12)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Indole-7-carboxylic acid (3.20 g, 0.02 mole) was dissolved in 30 ml of dimethylformamide (DMF) and chilled with ice-water. N,N'-Carbonyldiimidazole (3.30 g, 0.02 mole) was then added and the reaction mixture was allowed to stir for 1 hour. At the end of this time N-phenylpiperazine (4.0 g, 0.025 mole) was added, the cold bath was removed., and the reaction mixture was allowed to come to room temperatureover 3 hours. The product was filtered off and recrystallized form toluene to give 3.30 g (54%) of 1-(1H-indol-7-ylcarbonyl)-4-phenylpiperazine, m.p.217°-219° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CN=C1>CN(C=O)C>[Si:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:4]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(O)ccc1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc(O)c(N2C(=O)c3ccccc3C2=O)c1)(c1ccccc1)c1ccccc1
Yield: 68.1 %

Procedure:
A mixture of Example 73B (5.31 g, 20.81 mmol), tert-butyldiphenylsilyl chloride (5.68 mL, 21.85 mmol), imidazole (2.83 g, 41.62 mmol) in anhydrous DMF (100 mL) was heated at 50° C. for 2 days. The solvent was removed via vacuum pump. THF (200 mL) was added. The mixture was ultrosonicated. The suspension was filtered. The solution was dried with silica gel powder (20 g). 20% ethyl acetate in hexanes (1 L) and 30% ethyl acetate in hexanes (1 L) were used to perform flash chromatography to give the title compound (7 g, 68%). MS (APCI) m/z 492.19 (M−H)−; 1H NMR (500 MHz, CDCl3) δ ppm 1.10 (s, 9H) 6.64 (dd, J=8.73, 2.81 Hz, 1 H) 6.78 (d, J=8.73 Hz, 1 H) 6.86 (d, J=2.81 Hz, 1 H) 7.34–7.45 (m, 6 H) 7.70–7.75 (m, 4 H) 7.78 (dd, J=5.46, 2.96 Hz, 2 H) 7.92 (dd, J=5.30, 3.12 Hz, 2 H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:32][CH2:33][CH2:34][CH3:35])[N:21]([CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1>ClCCl>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:32][CH2:33][CH2:34][CH3:35])[N:21]([CH2:22][CH2:23][NH2:24])[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of 1,1-dimethylethyl N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate (5.7 g, 15 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with dichloromethane and then extracted with 10% hydrochloric acid. The hydrochloric acid extract was washed twice with dichloromethane and then it was made basic with ammonium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 3.7 g of 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine as a white powder, m.p. 175-176° C. Analysis: Calculated for C15H20N6: % C, 63.36; % H, 7.09; % N, 29.55; Found: % C, 62.98; % H, 6.92; % N, 29.89. HRMS (EI) calcd for C15H20N6 (M+) 284.1749, found 284.1748.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:4].[O:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:16])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)[CH3:4]
Reactant: BrCCCCCCCCCCCCOc1ccccc1
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1ccc(OCCCCCCCCCCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a suspension of 0.162 g (4.06 mmol) of 60% sodium hydride on oil in 10 ml of anhydrous DMF was added 0.75 g (3.87 mmol) of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester. The reaction mixture was stirred at room temperature under argon for 15 minutes and then 1.4 g (4.06 mmol) of 12-phenoxydodecyl bromide in 20 ml of anhydrous DMF was added. The mixture was stirred and heated at 60° for 24 hours. The usual workup followed by chromatography on 45 g of silica gel gave alpha-oxo-4-[(12-phenoxydodecyl)oxy]benzeneacetic acid ethyl ester (83% yield, mp 58°-59°).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[N:6][CH:7]=1.O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[C:23](=[O:29])[CH2:22]2>COCCOC.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.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23](=[O:29])[CH2:22]3)[CH:5]=[N:6][CH:7]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: CN1C(=O)Cc2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CN1C(=O)Cc2cc(-c3cncc(F)c3)ccc21
Temperature: 150 °C

Procedure:
To a solution of 5-fluoropyridine-3-boronic acid (CAS#872041-86-6, 80 mg, 0.57 mmol) in 1,2-dimethoxyethane (0.7 mL) was added water (0.3 mL) and ethanol (0.2 mL. The solution was then charged with sodium carbonate (60 mg, 0.57 mmol), 5-bromo-1-methyl-1,3-dihydro-indol-2-one (CAS#20870-90-0, 132 mg, 0.57 mmol), and dichlorobis(triphenylphosphine)palladium (II) (CAS#13965-03-2, 20.3 mg, 0.029 mmol). The reaction vessel was sealed and is heated by microwave irradiation at 150° C. for 10 minutes. The reaction mixture was cooled to room temperature, filtered and concentrated. The resulting residue was partially purified by semi-preparative reverse phase HPLC (20 to 90% acetonitrile/water vii 0.1% TEA). Final purification was accomplished via silica gel flash chromatography (methanol-dichloromethane, 0 to 7%) to afford 5-(5-fluoro-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one, MS: (ES+) m/z 243 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.18 (s, 3H), 3.64 (s, 2H), 7.13 (d, J=7.8 Hz, 1H), 7.73-7.77 (m, 2H), 8.03 (d, J=9.7 Hz, 1H), 8.53 (d, J=2.7 Hz, 1H), 8.79 (s, 1H).
Reaction SMILES: I[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[I:14]C1C=CC([N+]([O-])=O)=CC=1C(O)=O>>[I:14][C:4]1[CH:3]=[CH:2][C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1I
Reactant: NC(=O)c1ccc(I)c([N+](=O)[O-])c1
Product: NC(=O)c1cc([N+](=O)[O-])ccc1I

Procedure:
2-iodo-5-nitro-benzamide was synthesized by the method previously described for 4-iodo-5-nitro-benzamide using 2-iodo-5-nitro benzoic acid (Chemica Alta Ltd., Edmonton, Alberta, Canada) as the starting material.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH3:22].CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[C:36](Cl)=[O:37]>C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([Cl:42])[CH:41]=1)[C:36]([N:9]([CH3:8])[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH3:22])=[O:37]
Reactant: CNc1cnccc1N1CCCCC1C
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(Cl)cc(Cl)c1
Yield: 16 %

Procedure:
Methyl-(2-methyl-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-3′-yl)-carbamic acid tert-butyl ester (60 mg, 0.20 mmol, example 20, intermediate b) was stirred in a solution of TFA (300 μL) and CH2Cl2 (2 mL) for 1 h after which all volatiles were removed under reduced pressure to give crude methyl-(2-methyl-3,4,5,6-tetrahydro-2H-[1,4]bipyridinyl-3′-yl)-amine TFA salt. The crude TFA salt was dissolved in CH2Cl2 (2 mL) and treated with DIPEA (100 μL, 590 mmol) and 3,5-dichlorobenzoyl chloride (54 mg, 0.26 mmol, CAS RN 2905-62-6). The reaction mixture was loaded directly on a silica gel column and elution with 66% EtOAc in n-hexane gave the title product (12 mg, 16%). MS (ESI): m/z=378.0 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:19])=[C:6]2[C:10](=[C:11]([N+:14]([O-])=O)[C:12]=1[CH3:13])[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]2)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:5]([CH3:19])=[C:6]2[C:10](=[C:11]([NH2:14])[C:12]=1[CH3:13])[C:9]([CH3:17])([CH3:18])[CH2:8][CH2:7]2
Reactant: Cc1c2c(c([N+](=O)[O-])c(C)c1[N+](=O)[O-])C(C)(C)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1c(N)c(C)c2c(c1N)C(C)(C)CC2

Procedure:
One hundred seventy-five grams (0.662 mol) of the 5,7-dinitro-1,1,4,6-tetramethylindane thus obtained were dissolved in 500 g of methanol, and after addition of 17.5 g of 5% Pd/C (water content: 50%) to the resultant solution, the mixture was stirred at 50-60° C. for 84 hours in a hydrogen gas atmosphere. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The thus-obtained residue was distilled under reduced pressure to obtain 5,7-diamino-1,1,4,6-tetramethylindane as pale yellow crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]([CH3:20])[C:9]([C:11]2[CH:19]=[CH:18][C:14]3=[N:15][O:16][N:17]=[C:13]3[CH:12]=2)=[O:10])[CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[CH3:20][N:8]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]1)[C:9]([C:11]1[CH:19]=[CH:18][C:14]2=[N:15][O:16][N:17]=[C:13]2[CH:12]=1)=[O:10]
Reactant: CN(C(=O)c1ccc2nonc2c1)C1CCCC(O)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CN(C(=O)c1ccc2nonc2c1)C1CCCC(=O)C1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
N-(3-Hydroxycyclohexyl)-N-methyl-[2,1,3]-benzoxadiazole-5-carboxamide (0.38 g, 1.38 mmol) was dissolved in dichloromethane (10 ml) and PCC (3 g) was added and the mixture stirred for 3 h at 20° C. The solvent was evaporated onto silica gel and the product chromatographed on silica gel eluting with ethyl acetate/chloroform (3:1) to give the title product as a white solid after trituration with diethyl ether (0.19 g). Mp=164-165° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 7.93 (d, J=9.3 Hz, 1H); 7.84 (s, 1H); 7.40 (d, J=9.3 Hz, 1H); 4.90-4.67 and 4.00-3.75 (m, 1H); 3.00 (sb, 3H); 2.71-1.30 ppm (s, 8H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[NH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15]([NH:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])=[C:5]2[OH:20]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(F)ccc2C(C)(C)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)ccc2C(C)(C)C1=O
Temperature: 95 °C
Reaction time: 15 h
Yield: 77.7 %

Procedure:
A mixture of ethyl 6-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (1.1 g, 4.0 mmol), tert-butyl 2-aminoacetate hydrochloride (0.99 g, 5.9 mmol) in 10 mL dioxane, was treated with N-ethyl-N-isopropylpropan-2-amine (1.5 g, 12 mmol). The mixture was warmed to 95° C. and stirred for 15 hours. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 1.13 g of the title compound as a white solid. MS m/e=364 (M+Na)+.
Reaction SMILES: [NH:1]1[C:5](=O)[CH:4]=[CH:3][C:2]1=O.[F:8][C:9]([F:26])([F:25])[C:10]1[CH:19]=[C:18]([S:20][CH2:21][C:22]([NH2:24])=[O:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[C:3]1([C:21]2[C:22](=[O:23])[NH:24][C:22](=[O:23])[C:21]=2[S:20][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:9]([F:8])([F:25])[F:26])[CH:19]=2)[C:4]2=[C:5]3[C:17](=[CH:12][CH:13]=[CH:14]2)[CH2:18][CH2:19][CH2:10][N:1]3[CH:2]=1
Reactant: O=C1C=CC(=O)N1
Reactant: NC(=O)CSc1cc(C(F)(F)F)nc2ccccc12
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1Sc1cc(C(F)(F)F)nc2ccccc12

Procedure:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4¶-trifluoromethyl-quinolin-4-yl-sulfanyl)-pyrrole-2,5-dione was prepared according to Example 1, steps 1-6, employing 2-[[2-(trifluoromethyl)-4-quinolinyl]thio]acetamide in place of indole-3-acetamide in step 6. 1H NMR (CDCl3) 400 MHz δ: 8.3(d, 1H, J=7.6 Hz), 8.11(d, 1H, J=8.4 Hz), 8.05(s, 1H), 7.68-7.82(m, 4H), 7.23(s, 1H), 6.83(m, 2H), 4.21(t, 2H, J=6 Hz), 2.92(t, 2H, J=6 Hz), 2.21(m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[SH:12])=[CH:3][CH:2]=1.[C:13]1(=[O:31])[N:17]([C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[CH2:20]Cl)[C:16](=[O:26])[C:15]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:14]12>>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[S:12][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[N:17]2[C:16](=[O:26])[C:15]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:14]3[C:13]2=[O:31])=[CH:5][CH:6]=1
Reactant: Sc1nccn1-c1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1c1ccccc1CCl
Product: O=C1c2ccccc2C(=O)N1c1ccccc1CSc1nccn1-c1ccncc1

Procedure:
1-(4-pyridyl)-2-mercaptoimidazole and 2-phthalimidobenzyl chloride are treated in the same manner as described in Example 1-(1) to give 1-(4-pyridyl)-2-(2-phthalimidobenzylthio)imidazole.