Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:20]/[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[O:35][N:34]=[C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:32]=3)=[CH:25][CH:24]=2)/[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.C(O)C>[C:4]1(/[C:10](=[N:20]/[O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[O:35][N:34]=[C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:32]=3)=[CH:25][CH:24]=2)/[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)no2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)no2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
Lithium hydroxide monohydrate (194 mg) was added to a solution of ethyl E-6-phenyl-6-[4-(3-phenyl-1,2,4-oxadiazol-5-ylmethoxy)benzyloxyimino]hexanoate (790 mg) in tetrahydrofuran (6 ml)-water (4 ml)-ethanol (4 ml) and stirred at room temperature for 4 hours. 1N hydrochloric acid (4.7 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-6-phenyl-6-[4-(3-phenyl-1,2,4-oxadiazol-5-ylmethoxy)benzyloxyimino]hexanoic acid (637 mg, yield 85%) as colorless crystals. m.p. 91-92° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[N:14]([S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)(=[O:17])=[O:16])[CH2:13][C:12]2[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=2[CH2:10][O:9][CH2:8]1)(=O)=O.CS(C)=O.C([O-])([O-])=O.[Cs+].[Cs+].[NH:42]1[CH:46]=[CH:45][CH:44]=[N:43]1>CC(=O)OCC>[N:42]1([CH2:6][C@H:7]2[N:14]([S:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:27]=3[N:26]=[CH:25][CH:24]=[CH:23]4)(=[O:16])=[O:17])[CH2:13][C:12]3[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=3[CH2:10][O:9][CH2:8]2)[CH:46]=[CH:45][CH:44]=[N:43]1
Reactant: c1cn[nH]c1
Reactant: CS(=O)(=O)OC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2COC[C@H]1Cn1cccn1
Temperature: 110 °C
Yield: 32.9 %

Procedure:
Compound 17a (100 mg, 0.21 mmol) was added to DMSO (1 mL) and Cs2CO3 (500 mg, 1.5 mmol). 1H-Pyrazole (70 mg, 1.0 mmol) was added in the mixture and sealed in a microwave tube. The mixture was heated to 110° C. for 30 min under microwave irradiation. The reaction mixture was poured into ice/water (50 mL) and extracted with EA (3×50 mL) and washed with brine (2×50 mL) and dried over anhydrous Na2SO4. The residue was purified by CC eluting with PE:EA=3:1 to give compound 17 as white solid (30 mg, 32% yield). 1H-NMR (400 MHz, CD3OD) δ: 8.73 (d, J=1.6 Hz, 1H), 8.33 (d, J=7.2 Hz, 1H), 8.20 (d, 1H), 7.97 (d, 1H), 7.52-7.50 (m, 2H), 7.40-7.38 (m, 2H), 6.80 (d, 1H), 6.70 (t, 1H), 6.14 (s, 1H), 5.10 (m, 1H), 4.92 (d, J=14.4 Hz, 1H), 4.80 (m, 2H), 4.43 (d, J=14.4 Hz, 1H), 4.35 (q, 1H), 4.22 (q, 1H), 3.76 (d, 1H), 3.66 (d, 1H). MS (ESI+) m/z: 435.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[CH:8]=[N:7]2.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].C(Cl)Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=[N:7]2
Reactant: CC(C)(C)N
Reactant: Clc1cnc2cccc(Br)c2n1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)Nc1cnc2cccc(Br)c2n1
Yield: 99.5 %

Procedure:
A solution of 8-bromo-2-chloroquinoxaline (Example 210e; 1.53 g, 6.28 mmol) and tert-butylamine (Aldrich; 3.30 mL, 31.4 mmol) in DMSO (15 mL) was stirred at 100° C. for 2 h. The mixture was treated with DCM (100 mL), and washed with saturated aq. NaHCO3 (2×50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The crude material was purified on a silica gel column (23-32% EtOAc in hexanes) affording 8-bromo-N-(tert-butyl)quinoxalin-2-amine (1.75 g, 97% yield) as a yellow viscous oil which crystallized upon standing. 1H NMR (400 MHz, CDCl3) δ ppm 8.05 (1H, s), 7.85 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=7.8 Hz), 7.19 (1H, t, J=7.9 Hz), 4.89 (1H, br. s.), 1.61 (9H, s). m/z (ESI, +ve) 280/282 (M+H)+.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].S(=O)(=O)(O)[OH:11].[N+]([O-])([O-])=O.[Na+].[Cl-].[Na+]>O>[OH:11][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: O=S(=O)(O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](O)C(=O)O

Procedure:
L-Leu-OH (10.0 g) was dissolved in water (150 ml) containing concentrated sulfuric acid (3.2 ml) at 0° C. To the solution was added dropwise a solution of sodium nitrate (7.9 g) in water (50 ml) over 1 hour. The mixture was saturated with sodium chloride and extracted with ethyl acetate (500 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residual solid was triturated with hexane to give (2S)-2-hydroxy-4methylvaleric acid (6.51 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([C:27](=O)[CH3:28])[CH:24]=[CH:25][CH:26]=1.C(O)C.[Si](Cl)(Cl)(Cl)Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:28]=[C:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=3)[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CC(=CC(=O)c1cccc(Br)c1)c1cccc(Br)c1
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Clc1cccc(-c2cc(-c3cccc(Br)c3)cc(-c3cccc(Br)c3)c2)c1

Procedure:
1,3-bis(3-bromophenyl)but-2-en-1-one (6.15 g, 16.2 mmol) and m-chloroacetophenone (2.50 g, 16.2 mmol) were added to a 100 mL of three neck round bottom flask. To this flask, dry ethanol (40 mL) was added. The mixture was stirred vigorously, and then silicon tetrachloride (7 ml, 56 mmol) was added slowly. The mixture turned red and stirred 12 hours at room temperature. Then water (10 ml×2) was added and stirred for 20 minutes. Then filter the solution to get grey solid. Washed the solid with NaOH solution (10%), water and acetone separately. Dried the crude product and dissolved in THF (3 ml), then added the THF solution to methanol (100 ml) under stirring vigorously. Get the precipitation by filtration, and then recrystallize the crude product from ethanol and dichloromethane, the fine 1,3-Bis(3-bromophenyl)-5-(3-chlorophenyl) benzene will be obtained. Yield is 3.23 g (C24H15Br2Cl), 40%. 1H NMR (δ, CDCl3) 7.84 (m, 2H), 7.74 (m, 3H), 7.69 (s, 1H), 7.63-7.55 (m, 5H), 7.46-7.36 (m, 4H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]([CH3:32])[CH:28]([CH3:31])CC)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:36]([O:38]CCN)[CH3:37].CC(N)CC>>[CH2:36]([O:38][CH2:31][CH2:28][N:27]([CH2:26][C:24]1[S:23][CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)[CH:25]=1)[CH3:32])[CH3:37]
Reactant: CCOCCN
Reactant: CCC(C)N(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Agent: CCC(C)N
Product: CCOCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 11.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide, substituting 2-(ethyloxy)ethanamine (1 mmol) for added 2-butanamine to afford 6.1 mg of the title compound (11.5%).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:6](F)=[N:7][C:8]([F:15])=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.O>C(O)CC>[Cl:4][C:5]1[C:6]([NH:2][NH2:3])=[N:7][C:8]([F:15])=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: NN
Reactant: Fc1nc(F)c(C(F)(F)F)cc1Cl
Solvent: CCCO
Solvent: O
Product: NNc1nc(F)c(C(F)(F)F)cc1Cl
Reaction time: 2 h

Procedure:
10.5 g (0.21 mol) of hydrazine hydrate were added to a stirred mixture of 21.8 g (0.1 mol) of 3-chloro-2,6-difluoro-5-trifluoromethylpyridine in 100 ml of propanol at 50° C. in the course of 15 minutes, and stirring was continued for 2 hours at the same temperature. After cooling, the batch was poured into 1.5 l of water and the precipitate which had separated out was filtered off with suction. It was taken up in ethyl acetate for purification and extracted using water. After drying and concentration, 20.9 g (91% of theory) of the title compound of m.p. 104°-106° C. were obtained; a sublimated sample melted at 111°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH3:34]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH2:34])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethoxy-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) ammonia in THF, gave the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][NH:9][C:10]2=[O:13])=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)OC(C)(C)C)=[CH:16][CH:15]=2)[CH:5]=1)([O-:3])=[O:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]3[C:7]=2[CH2:8][NH:9][C:10]3=[O:13])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc([N+](=O)[O-])cc3c2CNC3=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2cc([N+](=O)[O-])cc3c2CNC3=O)cc1
Yield: 42.2 %

Procedure:
A solution of tert-butyl 4-(6-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)phenylcarbamate (0.276 g, prepared by substituting Example 128B for Example 1A in Examples 1B and 1C) in TFA (3 mL) and CH2Cl2 (3 mL) was stirred at room temperature for 1 hour, then concentrated to give 0.085 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 4.66 (s, 2H), 5.50 (s, 2H), 6.70 (d, J=8.5 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 8.20 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.0 Hz, 1H), 9.03 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:19]1[CH2:22][CH2:21][C:20]1=[O:23]>CC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH:19]1[CH2:22][CH2:21][C:20]1=[O:23]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C1CCC1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=C1CCC1Oc1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-(trifluoromethyl)phenol (2.72 g, 16.8 mmol) in acetone (147 mL) at 0° C. was treated with cesium carbonate (5.47 g, 16.8 mmol), followed by drop-wise addition of C3 (2.5 g, 16.8 mmol). The mixture was stirred at 0° C. for 1.5 hours, filtered through Celite, and concentrated in vacuo to afford the title compound as a colorless oil. Yield: 3.5 g, 15 mmol, 89%. 1H NMR (400 MHz, CDCl3) δ 7.56 (br d, J=7.7 Hz, 1H), 7.45-7.50 (m, 1H), 7.14 (d, J=8.3 Hz, 1H), 7.07 (br dd, J=7.6, 7.6 Hz, 1H), 5.31-5.37 (m, 1H), 2.92-3.00 (m, 2H), 2.55-2.66 (m, 1H), 2.19-2.30 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](Cl)(=[O:30])[CH3:29].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]1([CH:7]2[CH2:8][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:10][CH2:11][N:12]2[C:28](=[O:30])[CH3:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(c4ccccc4)C3)cc2)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCN(Cc2ccc(-c3cc(C)ccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made the following manner: 55 mg of 3-phenyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine were dissolved in THF, 2 equiv. of acetylchloride and 2 equiv. of N,N-diisoproylethylamine were added. The reaction was shaken at room temperature overnight. The reaction was concentrated in vacuo. The residue was diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentratation in vacuo afforded 43 mg of the title compound as hydrochloride salt. Yield 67%, ES MS m/z 419
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].B>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: B
Product: O=[N+]([O-])c1cc(CO)ccc1Cl

Procedure:
4-chloro-3-nitrobenzoic acid was subjected to borane reduction to yield 4-chloro-3-nitrobenzyl alcohol. The benzyl alcohol compound was treated with sodium sulfide, and 4,4'-dithiobis(3-aminobenzyl alcohol) thus obtained was caused to react with triphenylphosphine in dioxane, and further with 1-cyanoguanidine to yield 5-hydroxymethyl-2-guanidinobenzothiazole. Then, the hydroxymethyl compound (0.5 g) was refluxed with heating for 15 minutes in an aqueous 47% hydrobromic acid solution (5 ml) to yield 5-bromomethyl-2-guanidinobenzothiazole.hydrobromide (0.63 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].C(N(CC)CC)C.[C:21](O)(=[O:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:21](=[O:23])[CH3:22])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(C)=O)cc1OC
Yield: 84 %

Procedure:
To a mixture of 29.0 g (0.16 mole) of methyl-4-amino-2-methoxybenzoate, 0.5 g of 4-dimethylaminopyridine, and 16.0 gm (0.16 mole) of triethylamine in 500 ml of dichloromethane was added in batches 22 ml (ca. 0.23 mole) of acetic acid. After two hours the reaction mixture was neutralized with sodium bicarbonate (in solution and as a solid). The organic phase was washed successively with aqueous sodium bicarbonate. The organic phase was washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from toluene gave 30 g of methyl-4-acetamido-2-methoxybenzoate. To 100 ml of fuming nitric acid, stirred at −40° C., was slowly added 22.3 g (0.10 mole)of the acetylated intermediate. After about twenty minutes the mixture was warmed to 0° C. and stirred for another twenty minutes. The mixture was poured onto one liter of ice and the resultant precipitate was collected. Recrystallization from toluene/ethanol gave 14.2 g of the nitrated and deacetylated compound, methyl-4-amino-2-methoxy-5-nitrobenzoate. (Under similar conditions in which the acetyl group is not removed, saponification with methanolic sodium hydroxide gives the same product.) Hydrogenation of the nitro intermediate in tetrahydrofuran using Raney nickel as catalyst gave methyl-4,5-diamino-2-methoxybenzoate. A mixture of 4.83 g (24.6 mmole) of the diamine and 7.08 g (49.2 mmole) of potassium ethylxanthate was heated at reflux under argon in 40 ml of water. The resultant product mixture was chromatographed on silica gel to give 1.5 g of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate. (Analysis. Calc'd. for C10H10N2O3S: C, 50.41; H, 4.23; N, 11.76; S, 13.46. Found: C, 50.30; H, 4.19; N, 11.71; S, 13.12.) The title compound was then prepared by the method of Example 1 using 1.19 g (5.0 mmole) of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate instead of 2-mercaptobenzimidazole and 0.97 g (5.5 mmole)of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Analysis. Calc'd. for C17H17N3O3S*2HCl: C, 49.05; H,4.60; N, 10.09; S, 7.70; C1, 17.03. Found: C, 49.37; H, 4.77; N, 9.72; S, 7.43; C1, 16.77.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[NH:37][CH:36]=[C:35]2[CH3:43]>>[CH3:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[N:37]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]3)=[CH:5][CH:4]=1)[CH:36]=[C:35]2[CH3:43]
Reactant: O=C(N1CCC(c2ccc(CCl)cc2)CC1)C(F)(F)F
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]cc(C)c3c2)c1
Product: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccc(C5CCN(C(=O)C(F)(F)F)CC5)cc4)cc(C)c3c2)c1

Procedure:
The sub-title compound was prepared by the method of Intermediate 4 using the product of step ii) and the product of Example 93 step ii).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[C:14]([CH2:21][O:22][CH2:23][CH3:24])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.BrC1C=CC2C3N(CCCOC(C)C)C(COCC)=NC=3C=NC=2C=1.[CH2:50]([S:52]([NH2:55])(=[O:54])=[O:53])[CH3:51].C(N)(=O)C(C)C>>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:21][O:22][CH2:23][CH3:24])[N:15]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[C:6]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:55][S:52]([CH2:50][CH3:51])(=[O:54])=[O:53])=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: CCS(N)(=O)=O
Agent: CC(C)C(N)=O
Agent: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Product: CCOCc1nc2c(N)nc3cc(NS(=O)(=O)CC)ccc3c2n1CC(C)(C)O

Procedure:
The general method described in Part A of Example 3 was followed using 7-bromo-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application Publication No. US 2004/0147543, Examples 125-135) in lieu of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline and ethanesulfonamide in lieu of isobutyramide. Purification using a HORIZON HPFC system (silica cartridge, eluting with a linear gradient of 2-25% CMA in chloroform), followed by recrystallization from acetonitrile afforded 0.108 g of N-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]ethanesulfonamide as white crystals, mp 124.0-127.0° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[Li]CCCC.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[CH3:10][O:9][C:4]1[CH:3]=[C:2]([B:16]([OH:19])[OH:17])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: COB(OC)OC
Reactant: COc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1F
Reaction time: 18 h
Yield: 33.7 %

Procedure:
To a solution of 7B (2.7 g, 13.1 mmol) in THF (25 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 11.0 mL, 17.7 mmol). The mixture was stirred at −78° C. for 40 min before trimethyl borate (2.7 mL, 24.3 mmol) was added. The reaction was left stirring from −78° C. to rt over 18 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 7C (0.75 g, 35% yield) was collected as a white solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.86 (s, 3H) 7.03-7.45 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[NH2:18].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23])[NH:18][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:3]=1
Reactant: O=C(Nc1cc(Br)ccn1)C1CC1
Reactant: Nc1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(Nc2ccc([N+](=O)[O-])c(F)c2)ccn1)C1CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 26.6 %

Procedure:
Under N2, mix N-(4-bromo-2-pyridyl)cyclopropanecarboxamide (460 mg, 1.9 mmol), 3-fluoro-4-nitroaniline (359 mg, 2.3 mmol), palladium(II) acetate [Pd(OAc)2, 43.2 mg, 0.19 mmol], 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos, 158 mg, 0.38 mmol), Cs2CO3 (1.2 g, 3.8 mmol) and anhydrous toluene (10 mL). Stir the mixture at 120° C. under N2 for 16 hrs. Cool to room temperature, pour the reaction mixture to water (50 mL), extract with EtOAc (15 mL×3), combine the organic layers and dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, PE:EtOAc=54:46) affords the target compound (160 mg, 22%). MS: (M+1): 317.2.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10]>[Pd].C(O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][CH:6]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10]
Reactant: CN(C)CCC(=CCCCl)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(CCCCl)c1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 10 g. (0.037 mole) of 6-chloro-N,N-dimethyl-3-phenyl-3-hexenylamine hydrochloride in 150 ml. of 95% ethanol was hydrogenated using palladium on carbon catalyst. Hydrogenation was complete after 15 minutes at room temperature. The catalyst was removed by filtration and the filtrate was evaporated to a solid. Recrystallization of the solid from isobutyl methyl ketone gave 7 g. (70%) of a hygroscopic solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:48](=[O:55])[C:49]2[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=2)[CH2:42][CH2:41]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccncc2)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using of N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and isonicotinoyl chloride as starting materials in 43% yield. LCMS for C30H30ClN8O2 (M+H)+: m/z=569.2.