Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CCN1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
1-Ethyl-4-piperidone (76 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction-mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (50 mg, yield 41%).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH2:10][CH2:11][C@@H:12]2[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:7][C:6]2=[C:15]4[C:2]1=[CH:3][CH:4]=[C:5]2OCOC.O.[C:32]([OH:35])(=[O:34])[CH3:33]>>[C:32]([O:35][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:18]([CH3:19])[CH2:17][CH2:16][C@:14]45[C:15]=2[C:2]=1[O:1][C@H:13]4[C@@H:12]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:11][CH2:10][C@@H:9]35)(=[O:34])[CH3:33]
Reactant: COCOc1ccc2c3c1C[C@@H]1[C@@H]4CC[C@H](Oc5ccccn5)[C@H](O2)[C@]34CCN1C
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccc2c3c1O[C@H]1[C@@H](Oc4ccccn4)CC[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 100 °C
Reaction time: 6 h

Procedure:
4,5α-Epoxy-methoxymethoxy-17-methyl-6α-((2-pyridyl)-oxy)-morphinane (0.940 g, 2.3 mmol) is mixed with H2O (35 ml) and glacial acetic acid (35 ml) and stirred for 6 hours at 100° C. The mixture is then evaporated down at 40° C. using the Rotavapor and the residue obtained is purified by flash chromatography (90 g silica gel; CH2Cl2 /MeOH=4/1). The product is dissolved in H2O (7 ml) and glacial acetic acid (0.7 ml) and lyophilised.
Reaction SMILES: C[O:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:17](=[O:18])[NH:16][C:15]3[C:10]2=[N:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][Si](C(C)C)(C(C)C)C(C)C)[CH:24]=2)=[N:13][C:14]=3[C:19]([O:21]C)=O)[CH2:5][CH2:4]1.[NH2:40]C1C(C(OC)=O)=NC(C2C=CC=C(O[Si](C(C)C)(C(C)C)C(C)C)C=2)=NC=1N[C@H]1CC[C@@H](OC)CC1>ClCCl>[OH:2][C@@H:3]1[CH2:4][CH2:5][C@H:6]([N:9]2[C:17](=[O:18])[NH:16][C:15]3[C:10]2=[N:11][C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[N:13][C:14]=3[C:19]([NH2:40])=[O:21])[CH2:7][CH2:8]1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@@H](OC)CC1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)nc(N[C@H]2CC[C@@H](OC)CC2)c1N
Solvent: ClCCl
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2[C@H]1CC[C@@H](O)CC1

Procedure:
Methyl 9-(cis-4-methoxycyclohexyl)-8-oxo-2-(3-(triisopropylsilyloxy)phenyl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 5-amino-6-(cis-4-methoxycyclohexylamino)-2-(3-(triisopropylsilyloxy)phenyl)pyrimidine-4-carboxylate (0.223 g, 0.422 mmol) and 1,1′-1,1′-carbonyldiimidazole (0.547 g, 3.38 mmol) in dichloromethane (20 mL) were reacted according to General Procedure F and purified using biotage chromatography (0 to 65% EtOAc in hexanes) to afford the title compound (0.210 g, 90%). MS (ESI) m/z 555.5 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(N)c1N

Procedure:
A mixture of 2-amino-3-nitro-benzoic acid methyl ester (8.0 g, 40.8 mmol) with 10% Pd/C (800 mg) in THF (60 mL) and methanol (60 mL) was rocked under a hydrogen atmosphere (45 psi) for 45 min. Fitration and concentration afforded 2,3-diamino-benzoic acid methyl ester as a tan solid, that was used without further purification. 2-Acetoxymethyl-1H-benzoimidazole-4-carboxylic Acid Methyl Ester
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:17]([O:19][C:20]([CH:22]1[CH2:27][CH2:26][N:25]([C:11]2[N:10]=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:13]([CH3:14])[C:12]=2[CH3:15])[CH2:24][CH2:23]1)=[O:21])[CH3:18]
Reactant: Cc1c(Cl)nnc(Cc2ccccc2)c1C
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Temperature: 210 °C
Yield: 61.7 %

Procedure:
To a solution of 3-benzyl-6-chloro-4,5-dimethyl-pyridazine (1.0 g, 4.31 mmol) in NMP (10 mL) is added piperidine-4-carboxylic acid ethyl ester (2.0 g, 12.9 mmol) and DIPEA (3.7 mL, 21.6 mmol). The mixture is heated in microwave at 210° C. for 1.5 h. The mixture is concentrated at 80° C. by rotovaporation. The crude product is purified by HPLC (CH3CN/H2O: 22%˜45% with 0.1% TFA) to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid ethyl ester (0.94 g, 61%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]3[CH2:18][CH2:19][OH:20])[CH:9]=[CH:8][N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:23](Cl)[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1.[Cl-].C([NH3+])(C)(C)C>CN(C=O)C>[O:29]1[C:30]2[CH:31]=[CH:32][C:24]([CH2:23][O:20][CH2:19][CH2:18][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:12]3[C:10]3[CH:9]=[CH:8][N:7]=[C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[N:11]=3)=[CH:25][C:26]=2[O:27][CH2:28]1
Reactant: OCCC1CCCCN1c1ccnc(-n2ccnc2)n1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: CC(C)(C)[NH3+]
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: c1cn(-c2nccc(N3CCCCC3CCOCc3ccc4c(c3)OCO4)n2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 34.7 %

Procedure:
The above synthesis may be carried out as follows: To DMF (100 ml) was added 4-chloro-2-imidazol-1-ylpyrimidine (0.50 g, 2.77 mmol), 2-piperidineethanol (0.359 g, 2.77 mmol), and Hünig's base (0.536 g, 4.15 mmol). After heating at 80° C. for 5 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH, 19/1) to give 349 mg (46% ) of 1-[(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanol (the compound of formula (XVI)), (1H NMR (CDCl3) δ 8.54 (s, 2), 8.11 (d, 1), 7.82 (t, 1), 7.11 (d, 1), 6.44 (d, 1), 3.60 (m, 2), 3.03 (m, 1), 1.77 (m); MS: 274 (M+H)+). To a solution of 1-[(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanol (25 mg, 0.092 mmol) dissolved in DMF (5 ml) was added NaH (60% dispersion in oil, 5.5 mg, 0.14 mmol) followed by piperonyl chloride (17 mg, 0.10 mmol) and t-butyl ammonium chloride. After stirring for 16 hours at 80° C., the solvent was removed in vacuo and the residue was partitioned with saturated NH4Cl and CH2Cl2. The organic layer was separated, dried (MgSO4), the solvent removed in vacuo, and the residue chromatographed (CH2Cl2/MeOH, 19/1) to give 13 mg (35%) of 4-[2-[[(1,3-benzodioxol-5-yl)methoxy]ethyl]piperidin-1-yl]-2-(1H-imidazol-1-yl)pyrimidine (the compound of formula (Icc)); 1H NMR (CDCl3) δ 8.52 (s, 1), 8.05 (d, 1), 8.05 (d, 1), 7.80 (s, 1), 7.09 (s, 1), 6.73 (m, 3), 6.45 (d, 1), 5.93 (s, 2), 4.30 (s, 2), 3.45 (m, 2), 2.95 (m, 1), 1.55 (m); MS: 408.7 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])C.[Cl:9][C:10]1[CH:11]=[C:12]([N+]([O-])=O)[C:13](C)=[CH:14][C:15]=1[F:16].O.NN>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:3]2[C:13]([CH:12]=[CH:6][NH:4]2)=[CH:14][C:15]=1[F:16]
Reactant: Cc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc2cc[nH]c2cc1Cl
Temperature: 130 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
N,N-Dimethylformamide dimethylacetal (6.3 ml, 45 mmol) was added in one portion to a stirred solution of 3-chloro-4-fluoro-6-methylnitrobenzene (7.0 g, 37 mmol) in N,N-dimethylformamide (30 mL) at 130° C. under Ar. The mixture was stirred at 130° C. for 2 h, cooled to room temperature, concentrated in vacuo and partitioned between ethyl acetate and water and the aqueous was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried (magnesium sulfate), concentrated in vacuo, dissolved in methanol/tetrahydrofuran (1:1; 100 mL) and Raney Nickel®, 50% wt. in water, (5 g) was added. The mixture was cooled to 0° C. and hydrazine hydrate (3 mL, 59 mmol) was added dropwise over 2 min. The mixture was warmed to room temperature, stirred for 1 h then cooled to 0° C. and hydrazine hydrate (1.5 mL) was added over 2 min. The mixture was warmed to room temperature, stirred for 1 h and filtered through celite®. The filter-cake was washed with tetrahydrofuran and the filtrate was concentrated in vacuo and purified by column chromatography [SiO2; heptane-dichloromethane (4:1)] to give the product (3.2 g, 51%) as an off-white solid. An analytical sample was recrystallised (heptane) to give a white solid: mp 105-107° C.; NMR δH (400 MHz, CDCl3) 8.01 (1H, br. s), 7.40 (1H, d, J 6 Hz), 7.35 (1H, d, J 9.4 Hz), 7.25 (1H, t, J 2.8 Hz), 6.50-6.51 (1H, m).
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18].CC[OH:24]>O.C(OC)(C)(C)C.[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])=[O:24]
Reactant: CCO
Reactant: C[Si](C)(C)CNC(=O)c1ccc(C(Br)Br)c(C(F)(F)F)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: COC(C)(C)C
Product: C[Si](C)(C)CNC(=O)c1ccc(C=O)c(C(F)(F)F)c1
Yield: 100 %

Procedure:
4-(dibromomethyl)-3-(trifluoromethyl)-N-[(trimethylsilyl)methyl]benzamide (22.0 g, 49.1 mmol) and AgNO3 (16.7 g, 98.3 mmol) in EtOH and H2O were refluxed for 2 hours, then diluted with t-BuOMe and washed with brine. Dried over MgSO4 and evaporation yielded the product (15.0 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][NH:5][C:4]([C:16]([NH:18][N:19]2[CH2:23][CH2:22][N:21]([C:24]([NH:26][NH2:27])=[O:25])[C:20]2=[O:28])=[O:17])=[CH:3]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[H][H]>C(#N)C.[Pd]>[OH:8][C:7]1[C:2](=[O:1])[CH:3]=[C:4]([C:16]([NH:18][N:19]2[CH2:23][CH2:22][N:21]([C:24]([NH:26][NH2:27])=[O:25])[C:20]2=[O:28])=[O:17])[NH:5][CH:6]=1
Reactant: NNC(=O)N1CCN(NC(=O)c2cc(=O)c(OCc3ccccc3)c[nH]2)C1=O
Reactant: [H][H]
Agent: [Pd]
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC#N
Product: NNC(=O)N1CCN(NC(=O)c2cc(=O)c(O)c[nH]2)C1=O
Reaction time: 1 h
Yield: 52.4 %

Procedure:
3-[[[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2pyridinyl]carbonyl]amino]-2-oxo-1-imidazolidinecarboxylic acid, hydrazide (21.9 g) was suspended in 250 ml of acetonitrile. To the suspension was added 75 ml of bis-trimethylsilylacetamide and the mixture was stirred to form a solution. To the solution was added 10 g of palladium on charcoal (10%) and hydrogen was passed through the vigorously stirred mixture. The debenzylation was complete after 1 hour. After filtration, 15 ml of methanol and 10 drops of acetic acid were added to precipitate the title compound. Yield: 10.8 g. This crude material was stirred with 150 ml of ethanol to yield 8.8 g of the title compound, melting point <205° C., dec.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].ClC1[N:51]=[CH:50][C:49]([F:52])=[CH:48][N:47]=1>C(Cl)Cl.CS(C)=O>[F:52][C:49]1[CH:48]=[N:47][C:25]([N:22]2[CH2:23][CH2:24][CH:19]([CH2:18][O:17][C:14]3[CH:15]=[N:16][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:12][CH:13]=3)[CH2:20][CH2:21]2)=[N:51][CH:50]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(c4ncc(F)cn4)CC3)cn2)cc1

Procedure:
The title compound (91 mg, 84%) was prepared as a white solid from 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (prepared as in Example 150, Step 2, 0.11 g, 0.25 mmol) and TFA (0.20 mL) in CH2Cl2 (6 mL) then K2CO3 (0.75 g) and 2-chloro-5-fluoropyrimidine (47 μL, 0.27 mmol) in DMSO (5 mL) in a manner similar to Example 80. The crude material was purified by chromatography on a silica gel column eluted with 1:15 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.42 (d, 1H, J=2.7 Hz), 8.18 (s, 2H), 8.14 (d, 2H, J=8.3 Hz), 8.02 (d, 2H), J=8.3 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.45-7.35 (m, 1H), 4.80-4.70 (m, 2H), 3.94 (d, 2H, J=6.1 Hz), 3.07 (s, 3H), 3.00-2.85 (m, 2H), 2.10-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.45-1.30 (m, 2H); LRMS (ESI), m/z 443 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.[Cl-].[Na+].O.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.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2ccccc2)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 100 °C
Yield: 66 %

Procedure:
A mixture of 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (150 mg, 0.40 mmol), phenylboronic acid (60 mg, 0.48 mmol), Pd(PPh3)4 (46 mg, 0.040 mmol) and Cs2CO3 (261 mg, 0.80 mmol) in DMF (4 mL) was heated at 100° C. for 16 h under N2 atmosphere. After cooling the mixture to r.t., brine (20 mL) and EtOAc (50 mL) were added. 1 M HCl was added with stirring until pH was ˜2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by column chromatography (0-25% EtOAc/hexanes+2% AcOH) to give 98 mg of the title compound as a white solid. MS: (+) m/z 372.09 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:29]=[C:14]3[N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH:16]=[N:17][C:18](Cl)=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].[F:31][C:32]1[C:40]([OH:41])=[CH:39][CH:38]=[C:37]2[C:33]=1[CH:34]=[C:35]([CH3:42])[NH:36]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:29]=[C:14]3[N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH:16]=[N:17][C:18]([O:41][C:40]4[C:32]([F:31])=[C:33]5[C:37](=[CH:38][CH:39]=4)[NH:36][C:35]([CH3:42])=[CH:34]5)=[C:13]3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncn(Cc4ccc(OC)cc4)c-3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc3c(Oc4ccc5[nH]c(C)cc5c4F)ncn(Cc4ccc(OC)cc4)c-3n2)cc1
Temperature: 95 °C

Procedure:
A mixture of 3.96 g (9.4 mMol) of 4-[4-chloro-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid ethyl ester, 2.14 g (13 mMol) of 4-fluoro-5-hydroxy-2-methyl-1H-indole (preparation see WO 00/47212; Ex. 237) and 2.44 (17.7 mMol) of K2CO3 in 90 ml of DMF is heated for 9 h at 95° C. The reaction mixture is concentrated in vacuuo, the residue dissolved in EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2, EtOAc/hexane 1:1) gives the title compound; TLC (EtOAc/hexane 1:1) Rf=0.24; MS-ES+: (M+H)+=551.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25](B(O)O)[CH:26]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([C:23]3[CH:22]=[C:21]([Cl:20])[CH:26]=[CH:25][C:24]=3[O:30][CH3:31])[N:15]=[C:14]([NH2:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(NCCNc2cc(Cl)nc(N)n2)n1
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1-c1cc(NCCNc2ccnc(N)n2)nc(N)n1

Procedure:
The product of Example 6A (50 mg, 0.178 mmol) and 5-chloro-2-methoxyphenyl boronic acid (37 mg, 0.196 mmol) were treated under the conditions described in Example 6B to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.85 (d, J=2.78 Hz, 1H) 7.61 (d, J=5.55 Hz, 1H) 7.39 (dd, J=8.92, 2.97 Hz, 1H) 7.12 (d, J=8.73 Hz, 1H) 7.02 (s, 1H) 6.88 (s, 1H) 6.42 (s, 1H) 5.97 (s, 2H) 5.86 (s, 2H) 5.74 (d, 1H) 3.82 (s, 3H) 3.34-3.43 (m, 4H); MS (ESI+) m/z 387.2 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:12][CH2:11]2.[CH3:25][C@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:25][C@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C@H:31]1[CH2:35][CH2:34][N:33]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:12][CH2:11]3)[CH2:32]1
Reactant: C[C@H]1CCCN1[C@H]1CCNC1
Reactant: O=C1c2ccc(Cl)cc2CCN1C1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(C2CCOCC2)C3=O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.1 %

Procedure:
An 8-mL vial containing a stir bar was charged with Pd2(dba)3 (0.01 equiv., 4 pmol, 4 mg.), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 1 (0.05 equiv., 0.02 mmol, 10 mg) and sodium t-butoxide (2.5 equiv., 1.03 mmol, 99 mg.). To this solution was transferred a solution of 6-chloro-2-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-isoquinolin-1-one (110 mg, 0.41 mmol) in anhydrous toluene (2 mL) under N2 with stirring at rt. Then, a solution of the (2S,3′S)-2-methyl-[1,3]-bipyrrolidinyl (1.3 equiv., 0.53 mmol, 83 mg) in anhydrous toluene (2 mL) was transferred. The vial was capped with a rubber septum, evacuated and backfilled with N2. To this vial was introduced 2 mL of anhydrous toluene. The reaction was heated in an oil bath set at 90° C. for 5 h, allowed to cool down to room temperature and quenched with water (2 mL). Extraction with ethyl acetate (3×10 mL) followed by chromatography on silica gel column with 0-5% 7N NH3/MeOH in DCM to give 85 mg (54% yield) of the title compound as a yellow solid.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:37])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:18])(C(C)(C)C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O>[OH:8][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:18])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:37]
Reactant: CCCCCC/C=C\COC(=O)CCCCCCCC(CCCCCCCC(=O)OC/C=C\CCCCCC)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC/C=C\COC(=O)CCCCCCCC(O)CCCCCCCC(=O)OC/C=C\CCCCCC
Reaction time: 48 h
Yield: 39 %

Procedure:
The silyl protected diester 8 (0.3 g, 0.44 mmol) was dissolved in 1 M solution of TBAF in THF (6 mL) and the solution was kept at 40° C. for two days after which the TLC showed the completion of the reaction. The reaction mixture was diluted with water (60 mL) and extracted with ether (2×50 mL). The combined organic layers were concentrated and the thus obtained crude product was purified by column to isolate the pure product (0.097 g, 39%). 1H NMR (400 MHz, CDCl3) δ 5.64 (dt, J=10.9, 7.4 Hz, 2H), 5.52 (dt, J=11.0, 6.8 Hz, 2H), 4.61 (d, J=6.8 Hz, 4H), 3.57 (s, 1H), 2.30 (t, J=7.5 Hz, 4H), 2.09 (q, J=7.1 Hz, 4H), 1.75-1.53 (m, 4H), 1.53-1.06 (m, 36H), 0.88 (t, J=6.8 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.98, 135.64, 123.57, 77.54, 77.22, 76.91, 72.14, 60.41, 37.69, 34.54, 31.89, 29.70, 29.60, 29.44, 29.29, 29.07, 27.76, 25.80, 25.15, 22.82, 14.29.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9](=[O:21])[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:23]([O-])([O-:25])=[O:24].[Na+]>S(=O)(=O)(O)O>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:18])([F:19])[F:20])=[C:14]([N+:23]([O-:25])=[O:24])[CH:15]=3)[NH:10][C:9](=[O:21])[C:8]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n(C2CCCCC2)c1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]c2cc(C(F)(F)F)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 20 g (64 mmol) of 1-cyclohexyl-6-trifluoromethyl-2,3(1H,4H)-quinoxalinedione in 400 ml of concentrated sulfuric acid was cooled to 0° C., 5.4 g (64 mmol) of sodium nitrate were added a little at a time over the course of one hour, and the mixture was stirred at room temperature for 3 hours. It was then poured into ice-water, and the crude product was filtered off with suction and recrystallized from methanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(Cl)(Cl)Cl>C(Cl)Cl.O>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNS(C)(=O)=O
Reaction time: 18 h
Yield: 23.2 %

Procedure:
A solution of the compound of Example 53, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.98 mmol) in 20 mL of CH2Cl2 was treated with triethylamine (1.04 mL, 7.45 mmol) and chilled in an ice water bath. With vigorous stirring, the solution was treated dropwise with methanesulfonyl chloride (0.242 mL, 3.13 mmol). After 18 h, the reaction was treated with 40 mL CH2Cl2, 20 mL CHCl3, 25 mL water and the layers were separated. The organic portion was washed with 1% Na2CO3 solution, water and brine. The organic portion was then dried over Na2SO4, filtered and concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 90:10:0.5 CHCl3:MeOH:NH4OH) followed by recrystallization from CH2Cl2 gave 282 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide as light yellow crystals.