Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.[NH2:15][C:16]([CH3:30])([CH2:19][N:20]1[N:24]=[C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]2=[N:21]1)[C:17]#[N:18]>C(Cl)Cl>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2=[N:24][N:20]([CH2:19][C:16]([NH:15][C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)([C:17]#[N:18])[CH3:30])[N:21]=[C:22]2[CH:28]=1
Reactant: CC(N)(C#N)Cn1nc2ccc(Cl)cc2n1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: CC(C#N)(Cn1nc2ccc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
4-trifluoromethoxybenzoyl chloride (0.34 g) was added to a solution of 2-amino-3-(5-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile (0.3 g) in dry DCM mixed with TEA (0.27 mL). The reaction mixture was stirred 48 hours at room temperature. Silica gel was added to the reaction mixture and solvent evaporated under reduced pressure. The resulting crude product loaded on silica gel was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (0.3 g, 54%). Rf=0.7 (1:1 EA/heptane). MS (ES): M/Z [M+H]=424. 1H NMR: (400 MHz, DMSO-d6): 1.74 (s, 3H), 5.39-5.49 (m, 2H), 7.48 (dd, J=9.1, 1.9 Hz, 1H), 7.51 (br d, J=8.0 Hz, 2H), 7.93 (m, 2H), 8.01 (dd, J=9.1, 0.6 Hz, 1H), 8.13 (dd, J=1.9, 0.6 Hz, 1H) and 8.92 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.09 (s, 3F).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 1.54 ml (9.7 mmol) of benzyloxyacetyl chloride and 0.92 ml (8.9 mmol) of diethylamine were dissolved in 35 ml of CH2Cl2. The reaction mixture was stirred at room temperature (RT) for 2 hours and then washed with dilute HCl solution and saturated NaCl solution. The organic phase was dried over Na2SO4 and evaporated to dryness. 2-(Benzyloxy)-N,N-diethylacetamide was obtained as a colorless residue.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[C:15]([C:20]2[C:21]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[C:17]([NH2:19])[CH:18]=1)=[O:12])[CH3:9]>N1C=CC=CC=1.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[CH:14]=[C:15]([C:20]2[C:21]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]=[C:17]([NH:19][C:1](=[O:3])[CH3:2])[CH:18]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc(N)cc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(NC(C)=O)cc(-c2ccccc2-c2cc(Cl)ccc2OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
Acetic anhydride (53 mg, 0.5 mmol) was added to a solution of 5″-amino-2-benzyloxy-5-chloro-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (96 mg, 0.21 mmol) in pyridine (2 ml) and the mixture left at room temperature for 1 hour. The resulting solution was diluted with diethyl ether, washed with 1M hydrochloric acid and saturated sodium bicarbonate solution, dried (MgSO4) and evaporated to dryness to yield the title compound as a colourless gum. (102 mg, 97%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[OH:10])[CH3:2].C1(=O)O[CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[Br:9][C:7]1[CH:6]=[CH:5][C:4]([O:10][CH2:14][CH2:13][OH:12])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: O=C1OCCO1
Reactant: CCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1cc(Br)ccc1OCCO
Temperature: 125 °C
Yield: 82.1 %

Procedure:
To a solution of 2-ethyl-4-bromophenol (3.5 g, 17.4 mmol) and ethylene carbonate (3.22 g, 37 mmol) in NMP (60 mL) was added potassium carbonate (5.17 g, 37.4 mmol). The resulting mixture was heated to 125° C. and maintained for 3 h. The reaction was cooled and poured into water (250 mL) and extracted with EtOAc (2×100 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10–20% EtOAc in hexanes) to give the product (3.5 g, 82% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ: 1.19 (t, J=7.6 Hz, 3 H), 1.89 (brs, 1 H), 2.61 (q, J=7.6 Hz, 2 H), 4.05 (m, 4 H), 6.70 (d, J=8.7 Hz, 1 H), 7.24 (m, 2 H).
Reaction SMILES: [C:1]([CH2:11][CH2:12][C:13]([O:15][CH:16]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([N:26]([CH3:38])[C:27](=[O:37])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH3:17])=[O:14])([O:3]CC1C=CC=CC=1)=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([CH2:11][CH2:12][C:13]([O:15][CH:16]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([N:26]([CH3:38])[C:27](=[O:37])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH3:17])=[O:14])([OH:3])=[O:2]
Reactant: CC(OC(=O)CCC(=O)OCc1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(OC(=O)CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
20-(3-(Carbobenzyloxy)propionyloxy)-4-methyl-5a-4-azapregnan-3-one (0.05 g, 0.095 mM) was reduced with hydrogen in ethyl acetate in the presence of 5% palladium on carbon, to obtain the title compound. MS M+1 calculated for C25H39NO5, mw=433.64; observed m/e 434.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[C:12]([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C>O1CCCC1>[NH2:11][C:3]1[C:2]([Cl:1])=[CH:10][C:6]([C:7](=[O:8])[CH3:12])=[CH:5][N:4]=1
Reactant: O=C([O-])CC(=O)[O-]
Reactant: Nc1ncc(C(=O)Cl)cc1Cl
Agent: CCC(C)(CC)O[Mg+2]
Solvent: C1CCOC1
Product: CC(=O)c1cnc(N)c(Cl)c1
Yield: 84.4 %

Procedure:
7.2 g (37.5 mmol) of 5-chloro-6-aminonicotinoyl chloride in 10 ml of absolute tetrahydrofuran are added to a boiling solution of 8.55 g (37.5 mmol) of diethyl ethoxymagnesium-malonate (prepared in accordance with Org. Synth. Coll. Vol. IV (1963), 285) in 120 ml of absolute tetrahydrofuran and the mixture is heated under reflux for 2 hours. After neutralization with 2N sulphuric acid, the organic phase is separated off and evaporated. The residue is heated under reflux in a mixture of 30 ml of glacial acetic acid, 20 ml of water and 5 ml of concentrated sulphuric acid for 4 hours. The mixture is stirred into ice-water, brought to pH 4 and extracted with ethyl acetate. Drying and evaporation gives 5.4 g (85%) of the title compound, melting point: 188° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15](C3C=CC(Br)=CC=3C)=[N:16][N:17]=2)[CH:6]=[CH:7][C:8]=1[S:9][CH:10]([CH3:12])[CH3:11])#[N:2].[Br-].[CH2:27]([O:29][C:30](=[O:34])[CH2:31][CH2:32][Zn+])[CH3:28]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:14][CH2:15][N:16]([C:8]3[CH:7]=[CH:6][C:5]([CH2:32][CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:34])=[CH:4][C:3]=3[CH3:1])[N:17]=2)[CH:6]=[CH:7][C:8]=1[S:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: Cc1cc(Br)ccc1-c1nnc(-c2ccc(SC(C)C)c(C#N)c2)s1
Reactant: CCOC(=O)CC[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Product: CCOC(=O)CCc1ccc(N2CSC(c3ccc(SC(C)C)c(C#N)c3)=N2)c(C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Bis(tri-tert-butylphosphine)palladium (0) (5 mg) was added to a solution of 2-(3-cyano-4-isopropylthiophenyl)-5-(4-bromo-2-methyphenyl)-1,3,4-thiadiazole (0.15 mmol, 0.066 g, from Step C) in 3-ethoxy-3-oxopropylzinc bromide (0.5M in TI-IF) (0.31 mmol, 0.61 mL) which had been degassed with argon. The reaction mixture was stirred under an atmosphere of argon at rt for 5 h after which it was concentrated in vacuo. Silica gel chromatography eluting with 20% EtOAc/hexane yielded the desired product. ESI-MS (m/z) 452.3; HPLC A: 2.85 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1.C(N(C(C)C)CC)(C)C.C1COCC1>CCOC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)=[C:17]([Br:19])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(Cl)c(Br)c2)c(SC)s1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(NCc3ccc(C(F)(F)F)nc3)c(Br)c2)c(SC)s1

Procedure:
The reaction was conducted following the procedure for Example 156: step a, using 4-(5-bromo-6-chloro-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (0.050 g, 0.113 mmol), (Example 2: step c), 3-aminomethyl-6-trifluoromethyl pyridine (0.026 g, 0.146 mmol), diisopropylethylamine (0.073 g, 0.565 mmol), THF [0.5 mL], DMF [0.5 mL]. Chromatography of the residue (25%–50% EtOAc/Hx) yielded the title compound. ESI-MS (m/z): Calcd. For C19H15BrN3O4S3: 583.44 (M+H); found 582.0, 583.9.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([CH3:13])[C:5]=1[CH3:14])([O-])=O.CO.[Cl-].[NH4+]>[Zn].O>[CH3:10][C:9]1[C:4]([NH2:1])=[C:5]([CH3:14])[C:6]([CH3:13])=[C:7]([CH3:12])[C:8]=1[CH3:11]
Reactant: Cc1c(C)c(C)c([N+](=O)[O-])c(C)c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: Cc1c(C)c(C)c(N)c(C)c1C
Reaction time: 20 h

Procedure:
A one neck 2000 ml round bottom flask was charged with 50 grams of 1-nitro-2,3,4,5,6-pentamethylbenzene and 1000 ml methanol. A solution of 50 g of ammonium chloride and 200 ml of water was then added. Zinc dust (50 g) was then added in portions. The mixture was allowed to stir for 20 hours. The solids were filtered and the solvent was removed from the mother liquor. The product was purified by silica gel column with dichlormethane as the eluent. The good fractions are combined to yield pentamethylaniline as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([OH:17])=O)[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]1([C:66]([NH2:69])([CH3:68])[CH3:67])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:69][C:66]([CH3:68])([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH3:67])=[O:17])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@H](C(=O)NC(C)(C)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. 2-Phenyl-2-propanamine (71 mg, 0.53 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized from CH3CN to afford the title compound (222 mg) as a light yellow solid. LC-MS (ES) m/z=473 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH3:16])=[N:4][C:3]=1[OH:17].CC(CC(O)=O)=O.C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>C(Cl)Cl>[OH:17][C:3]1[N:4]=[C:5]([CH3:16])[C:6]2[C:11]([C:2]=1[NH:1][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2
Reactant: COc1cc2c(C)nc(O)c(N)c2cc1OC
Reactant: CC(C)C(=O)Cl
Agent: CC(=O)CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(C)nc(O)c(NC(=O)C(C)C)c2cc1OC
Reaction time: 1 h
Yield: 39.4 %

Procedure:
4-Amino-3-hydroxy-6,7-dimethoxy-1-methylisoquinoline (BBQ) (1.772 grams, 5 mmol) as the diacetate solvate in 50 ml methylene chloride was treated with 2.5 ml triethylamine (16.5 mmol) for 5 minutes and subsequently with 0.63 ml isobutyryl chloride (6 mmol) with stirring under a nitrogen atmosphere. After 1 hour, the slurry was evaporated to dryness in vacuo and boiled in 50 ml methanol and 5 ml water for 15 minutes. The solid was isolated by filtration, washed successively with methanol and acetone, and then dried in vacuo at 50° C. to provide 0.6 grams of Compound BO (39.4% yield) having a melting point of 292°-294° C. (with decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](C(O)=O)=[C:7]([CH3:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[O:16][CH3:17].N1C2C(=CC=CC=2)C=CC=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH3:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc2c(C(=O)O)c(C)n(C)c2cc1Br
Solvent: c1ccc2ncccc2c1
Product: COc1cc2cc(C)n(C)c2cc1Br
Temperature: 200 °C
Yield: 50.1 %

Procedure:
6-Bromo-5-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid (1.02 g, 3.42 mmol) was separated into two round bottom flasks (each with 500 mg of material), followed by the addition of quinoline (2 mL) in each flask. The reaction mixture was heated at 200° C. for 4 hours and was cooled to RT. The two reaction mixture was combined and loaded directly on a silica gel column, eluting with a gradient of 0-20% ethyl acetate in cyclohexane, to give title compound (435 mg). LCMS (A): m/z (M+H)+ 254/256, C11H12BrNO requires 253/255 (acidic).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=1)=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[CH:9]2)(=[O:4])=[O:3].[CH3:41][S:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[CH:45][C:44]=1B(O)O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:49][C:47]1[CH:46]=[CH:45][C:44]([C:11]2[C:12]([C:16](=[O:32])[C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:21][CH:22]=3)=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:15]=[CH:14]3)=[C:43]([S:42][CH3:41])[CH:48]=1
Reactant: CSc1cc(F)ccc1B(O)O
Reactant: CS(=O)(=O)Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: CSc1cc(F)ccc1-c1ccc2cc(OS(C)(=O)=O)ccc2c1C(=O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methanesulfonyloxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (10.0 g, 16.6 mmol), 2-methylsulfanyl-4-fluoro-benzene boronic acid (7.7 g, 41.6 mmol), palladium acetate (371 mg, 1.66 mmol, tricyclohexylphosphine (700 mg, 2.5 mmol) and cesium fluoride (13 g, 83 mmol) and purge with nitrogen. Dilute with degassed acetonitrile (150 mL) and plunge into an 80° C. oil bath. Cool to room temperature after 1.5 hours and filter through celite and concentrate in vacuo. Partition the residue between methylene chloride and saturate aqueous sodium bicarbonate. Dry the organic layer with sodium sulfate, filter and concentrate. Purify the residue over a silica gel column, eluting with 2% methanol in methylene chloride, to yield 9.0 g (92%) of the title compound. LCMS Rt (0.01% heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient method 25 to 95% B, Purity@254 nm)=2.92 min (95%); mass spectrum (ion spray): m/z=594.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)C(OC)=O)=[O:4].O.[Na+].[Cl-].CN(C=O)C>CCOC(C)=O>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:14]=1
Reactant: COC(=O)C(CCc1ccncc1)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCCc1ccncc1

Procedure:
A solution of diester 10-3 (19.0 g, 80.1 mmol), H2O (1.45 ml, 80.1 mmol), NaCl (10.5 g, 160.2 mmol) and DMF was heated to 170° C. for 18 h. The reaction was diluted with EtOAc and then washed with sat. NaHCO3, brine, dried (MgSO4) and concentrated. Flash chromatography (silica, 60% EtOAc/hexanes) afforded ester 10-4 as a brown oil.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].CS([CH2:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][C:25]=1[CH3:29])(=O)=O.O>CN(C=O)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][CH2:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][C:25]=1[CH3:29])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1ncsc1CCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCCc1scnc1C
Temperature: 75 °C

Procedure:
Vanillin (2.9 mmol) was added to mixture of K2CO3 (14.5 mmol) and 5-(2-Methanesulfonyl-ethyl)-4-methyl-thiazole (5) (2.9 mmol) in DMF (0.2 M), and heated to 75° C. for 16 h. After cooling, water was added and aqueous mixture extracted 5 times with methylene chloride. The methylene chloride layers were combined and concentrated to afford the product (6).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])([CH3:4])([CH3:3])[CH3:2].[I:21]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])([CH3:14])[CH3:12])[CH:8]=[C:7]([I:21])[C:6]=1[O:15][CH2:16][C:17]([F:18])([F:19])[F:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)c1ccc(OCC(F)(F)F)c(C(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1cc(I)c(OCC(F)(F)F)c(C(C)(C)C)c1
Temperature: 38 °C
Yield: 96 %

Procedure:
2,4-Di-tert-butyl-1-(2,2,2-trifluoro-ethoxy)-benzene (5.06 g, 17.5 mmol), N-iodosuccinimide (4.74 g, 21 mmol) and p-toluenesulfonic acid monohydrate (1.33 g, 7 mmol) were combined in dichloromethane (50 mL) and heated at 38° C. for 19 h. The reaction was washed with 10% Na2S2O3 solution (2×40 mL). The aqueous was backwashed with dichloromethane (70 mL) and then the combined organic portions washed with water (75 mL) and the combined organic portions washed with water (100 mL), dried (MgSO4), filtered and evaporated in vacuo to provide a yellow oil (6.96 g). The material was purified by flash chromatography using hexane to give 5.85 g (81%) of a light pink oil. 1HNMR (250 MHz, CDCl3): δ 7.67 (d, 1H, J=2.4), 7.37 (d, 1H, J=2.4), 4.45 (q, 2H, J=8.2), 1.40 (s, 9H), 1.30 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1(OC)[O:9][C@H:8]([CH3:10])[CH2:7][C@@H:6]([CH3:11])[O:5]1)([CH3:3])[CH3:2].CC(C)([O-])C.[Al+3].CC(C)([O-])C.CC(C)([O-])C>>[C:1](=[C:4]1[O:5][C@H:6]([CH3:11])[CH2:7][C@@H:8]([CH3:10])[O:9]1)([CH3:3])[CH3:2]
Reactant: COC1(C(C)C)O[C@H](C)C[C@@H](C)O1
Agent: CC(C)(C)[O-]
Agent: [Al+3]
Product: CC(C)=C1O[C@H](C)C[C@@H](C)O1
Temperature: 180 °C
Yield: 65 %

Procedure:
To 3.8 g (20.2 mmol) of 2-isopropyl-2-methoxy-4(R),6(R)-dimethyl-1,3-dioxane was added 4.97 g (20.2 mmol) of aluminum tert. butoxide and the resulting mixture was heated to 180° C. under nitrogen (over a 30 min. period) and maintained at this temperature for one hour while distilling tert. butanol formed. The residue was cooled and distilled (directly from the reaction flask) to afford 2.05 g (65%) of 2-isopropylidene-4(R),6(R)-dimethyl-1,3-dioxane (Formula V: R3 =R4 =CH3 ; R5 and R6 together are (R,R)--O--CH(CH3)CH2CH(CH3)O--), b.p. 75°-78° C./aspirator vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]([N:16]3[CH2:20][CH2:19][CH:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH2:17]3)=[O:15])[C:9]=2[CH3:26])[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:12]([CH3:13])[N:11]=[C:10]([C:14]([N:16]4[CH2:20][CH2:19][CH:18]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[CH2:17]4)=[O:15])[C:9]=3[CH3:26])[CH:3]=2)[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(-c4ccc(Cl)c(Cl)c4)c3)c2C)C1
Yield: 55 %

Procedure:
In analogy to the procedure described in example 14C], [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and 3,4-dichlorophenylboronic acid gave [5-(3′,4′-dichloro-biphenyl-3-yl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone in 55% yield as light brown foam. MS: 485.2 (MH+, 2 Cl).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH2:22][CH3:23].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)(Cl)Cl.CO>C(Cl)Cl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][O:21][CH2:22][CH3:23])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:31]([NH:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1NCCCNC(=O)Nc1ccccc1
Reaction time: 16 h
Yield: 33.4 %

Procedure:
A solution of N1-(3-aminopropyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.250 g, 0.795 mmol) in 10 mL of CH2Cl2 was cooled to 0° C. under an atmosphere of nitrogen. The reaction mixture was treated dropwise with phenyl isocyanate (0.091 mL, 0.835 mmol). After 16 h, the reaction mixture was quenched by 10% Na2CO3 solution, diluted with CHCl3 and the phases were separated. The organic portion was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield an off-white solid. Chromatography (SiO2, 95:5 CHCl3:MeOH) gave an off-white foam. The foam was triturated with diethyl ether and filtered to give 1-{3-[(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}-3-phenylurea (0.115 g) as an off-white solid. mp 177–179° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.46 (dd, J=8.1, 1.0 Hz, 1H), 8.39 (s, 1H), 7.58 (dd, J=8.4, 0.9 Hz, 1H), 7.44–7.35 (m, 3H), 7.25–7.18 (m, 3H), 6.99 (t, J=5.6 Hz, 1H), 6.90–6.85 (m, 1H), 6.60 (s, 2H), 6.16 (t, J=5.6 Hz, 1H), 4.76 (s, 2H), 3.60 (q, J=7.0 Hz, 2H), 3.26–3.18 (m, 4H), 1.76 (t, J=7.0 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 155.2, 151.8, 149.0, 144.8, 140.4, 132.0, 128.5, 126.9, 125.7, 123.7, 120.9, 120.8, 120.8, 117.6, 114.3, 65.4, 62.7, 49.7, 37.0, 28.1, 14.9; MS (APCI) m/z 434 (M+H)+; Anal. Calcd for C23H27N7O2: C, 63.72; H, 6.28; N, 22.62; Found: C, 63.45; H, 6.04; N, 22.28.