Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-])=O.[OH-:14].[Na+].Cl>[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([S:10]([OH:12])(=[O:11])=[O:14])[CH:6]=2)=[CH:6][C:5]=1[S:10]([OH:12])(=[O:14])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Agent: [Zn]
Product: Nc1ccc(-c2ccc(N)c(S(=O)(=O)O)c2)cc1S(=O)(=O)O
Temperature: 80 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
A 500 mL flask equipped with mechanical stirrer, condenser, addition funnel, and thermometer was charged with 50.0 g (0.255 mol) of 2-nitrobenzene sulfonyl chloride (Aldrich). Upon dropwise addition of 5M aqueous sodium hydroxide (125 mL, 0.625 mol) the reaction mixture warmed to 80° C. and a dark red/brown solution resulted. The mixture was stirred for 1 hour and the flask allowed to cool to room temperature. Next, 52.5 g of zinc dust (0.803 mol, Mallinckrodt) was added in one portion. The reaction mixture turned green and warmed to 40° C. Sodium hydroxide (50 percent w/w, 113.75 g, 1.42 mol) was then cautiously added dropwise. The temperature of the reaction mixture rose quickly and vigorous reflux ensued. The reaction mixture turned black, then light green, and finally gray. After addition was complete, the reaction mixture was heated to 90° C. and stirred for 30 minutes. The reaction mixture was cooled and filtered through diatomaceous earth. The zinc salts were washed several times with water yielding 850 mL of an orange/brown filtrate. The filtrate was immediately transferred to a 2 L flask equipped with mechanical stirrer, condenser, addition funnel, nitrogen inlet, and thermometer. Concentrated hydrochloric acid (250 mL) was added dropwise. A light yellow precipitate formed, leaving a clear yellow supernatant (pH=7). Further addition of acid caused the solid to dissolve and the solution to turn orange and then brown (pH=4). More acid caused a tan precipitate to form and persist. After HCl addition was complete, the temperature had risen to 45° C. and the pH was 1. The reaction mixture was stirred for an additional hour and then cooled in an ice bath. The precipitate was collected by filtration and dried in a vacuum oven at ambient temperature yielding a cake which weighed 11.69 g. The product was purified by dissolving it in 150 mL of hot water containing 13.5 mL of 5M sodium hydroxide. Concentrated HCl (15 mL) was then slowly added to reprecipitate the product. Vacuum filtration and drying in a vacuum oven at ambient temperature yielded 11.07 g (28.6 percent) of 4,4'-diaminobiphenyl-3,3'-disulfonic acid.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.[C-:20]#[N:21].[K+].S([O-])(O)=O.[Na+].O>O1CCCC1>[C:20]([CH:15]([OH:16])[C:12]1[CH:11]=[CH:10][C:9]([C:7]2[NH:8][C:4]3[CH:3]=[C:2]([Cl:1])[C:18]([Cl:19])=[CH:17][C:5]=3[N:6]=2)=[CH:14][CH:13]=1)#[N:21]
Reactant: [C-]#N
Reactant: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
To a solution of 5,6-dichloro-2-(4-formylphenyl)benzimidazole (291 mg, 1.00 mmol) in tetrahydrofuran (40 mL) were added potassium cyanide (260 mg, 4.00 mmol), sodium hydrogen sulfite (500 mg), and water (10 mL). The mixture was stirred at room temperature for 12 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 2-[4-[cyano(hydroxy)methyl]phenyl]-5,6-dichlorobenzimidazole (278 mg, 87%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[I-:13].[Na+].C(Cl)(=O)C>C(#N)C>[I:13][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [I-]
Reactant: Clc1cc(-c2cccs2)ccn1
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: Ic1cc(-c2cccs2)ccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A 20 mL microwave vial was charged with 2-chloro-4-thiophen-2-yl-pyridine (428 mg, 2.19 mmol), sodium iodide (3.28 g, 21.9 mmol) and acetonitrile (3.5 mL). Acetyl chloride (0.24 mL, 3.4 mmol) was added and the vial was flushed with Argon and closed. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and quenched with 10 mL saturated Na2CO3 solution then extracted with 50 mL dichloromethane. The organic layer was washed with 10 mL 10% Na2S2O3 solution. The aqueous layers were extracted twice with 50 mL dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 24 g SiO2 with EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to afford 563 mg (90%) of 2-iodo-4-thiophen-2-yl-pyridine as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:26]1[N:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([O:19][C:26]3[C:27]([C:28]#[N:29])=[CH:30][CH:31]=[CH:32][N:33]=3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(Cc1c[nH]c2c(O)cccc12)NC(=O)OC(C)(C)C
Reactant: N#Cc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(Cc1c[nH]c2c(Oc3ncccc3C#N)cccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 95.7 %

Procedure:
To a solution of [2-(7-Hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (274 mg, 0.900 mmol) in dimethylformamide (15 mL) is added sodium hydride (26 mg, 1.07 mmol). The mixture is stirred at ambient temperature for 25 minutes under nitrogen. 2-Chloro-nicotinonitrile (187 mg, 1.35 mmol) is added and the mixture is heated in an oil bath to eighty degrees Celsius for 15 hours, under nitrogen. Water (50 ml) is added to quench the reaction and the mixture is extracted three times with 50 mL of ethyl acetate. The organic layers are combined and washed twice with 50 mL of 1.00 N sodium hydroxide. The organic layer is dried with sodium sulfate, filtered and the solvent evaporated. The residue is dissolved in dichloromethane and purified using silica gel chromatography (6% 2M ammonia in methanol, 94% dichloromethane used as mobile phase) to give 350 mg (96%) of {2-[7-(3-cyano-pyridin-2-yloxy)-1H-indol-3-yl]-1,1-dimethyl-ethyl}-carbamic acid tert-butyl ester. FDMS m/e=407 (M++1).
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23](O)[C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([CH3:33])[CH:31]=3)[N:26]([Si](C(C)C)(C(C)C)C(C)C)[CH:25]=2)=[C:19]([F:45])[N:18]=1)CC1C=CC(OC)=CC=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:45][C:19]1[N:18]=[C:17]([NH2:7])[CH:22]=[CH:21][C:20]=1[CH2:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[C:30]([CH3:33])[CH:31]=2)[NH:26][CH:25]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Temperature: 50 °C
Yield: 62.6 %

Procedure:
To {6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrol [2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (136, 21 g, 32.4 mmol) in 500 mL of acetonitrile, triethylsilane (51.7 mL, 324 mmol) and trifluoroacetic acid (24.93 mL, 324 mmol) were added. The reaction was stirred at 50° C. for several hours, solvents removed under vacuum, and the residue taken up in 250 mL of dichloromethane and 250 mL of trifluoroacetic acid was added. The mixture was stirred at reflux for several hours, then concentrated under vacuum. The residue was taken up in ethyl acetate and poured into aqueous potassium carbonate. The organic layer was separated, concentrated under vacuum and purified by silica gel column chromatography, eluting with 0-5% methanol in dichloromethane. Appropriate fractions were combined and the solvents removed under vacuum to provide the desired compound (137, 5.2 g, 20.29 mmol, 62.7% yield).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:38])[CH2:33][C:34]([OH:37])([CH3:36])[CH3:35]>>[OH:37][C:34]([CH3:36])([CH3:35])[CH2:33][C:32]1[N:38]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:31]=1
Reactant: CC(C)(O)CC(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: CC(C)(O)Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
80 mg (0.188 mmol) of the compound from Example 100A and 52 mg (0.281 mmol) of N′,3-dihydroxy-3-methylbutanimidamide were reacted according to the General Method 2. Yield: 65 mg (67% of theory)
Reaction SMILES: C([O-])(=O)C.[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][C:16]1[NH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH+:20]=1.[S:25](=[O:29])(=[O:28])([OH:27])[OH:26]>>[S:25](=[O:27])(=[O:26])([OH:29])[OH:28].[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: c1ccc2c(c1)OCC(Cc1[nH]c3ccccc3[nH+]1)O2
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Product: c1ccc2c(c1)OCC(Cc1nc3ccccc3[nH]1)O2

Procedure:
2-(1,4-benzodioxan-2-ylmethyl)benzimidazolium acetate (1.0 g) is dissolved in 50 ml 50% aqueous sulfuric acid, and the solution evaporated to dryness. The product is suspended in ethanol and filtered, air dried and recrystallized from methanol/acetone to yield 2-(1,4-benzodioxan-2-ylmethyl)benzimidazole bisulfate.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH:13]([NH2:17])[CH:14]([CH3:16])[CH3:15])[CH3:12].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:17][CH:13]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)C(N)C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C(N=Cc1ccc(Br)cc1)C(C)C
Yield: 94.9 %

Procedure:
A mixture of 4-bromobenzaldehyde (7.3 g, 40.0 mmol), 2,4-dimethylpent-3-ylamine (4.8 g, 41.4 mmol), and para-toluenesulfonic acid (0.05 g, 0.29 mmol) in 125 mL of toluene was heated under reflux while water was removed with a Dean-Stark trap. The toluene then was removed under vacuum and distillation of the remaining residue gave (4-bromobenzylidene)(1-isopropyl-2-methylpropyl)amine (10.71 g) as a clear colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:14][N:12]1[CH:13]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:3]=[CH:4][C:5]=2[O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]2[CH:18]=[CH:17][NH:16][C:10]=2[C:11]1=[O:15]
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.6 %

Procedure:
To a solution of Example 3 (0.125 g, 0.377 mmol) and triethylamine (0.131 mL, 0.943 mmol) in dichloromethane (3.0 mL) was added dropwise methanesulfonyl chloride (0.064 mL, 0.830 mmol). The reaction mixture was stirred for 2 hours at ambient temperature and then concentrated. The residue was dissolved in a mixture of dioxane (5 mL) and 1M sodium hydroxide (2 mL) and heated for 1 hour at 90° C. The reaction mixture was cooled and diluted with ethyl acetate, brought to pH 7 with 1 M HCl and partitioned. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 0-4% methanol in dichloromethane) to afford 0.20 g (77%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.02 (s, 3H) 3.48 (s, 3H) 6.23-6.30 (m, 1H) 6.85 (d, J=7.46 Hz, 2H) 6.99 (t, J=7.29 Hz, 1H) 7.04 (d, J=8.82 Hz, 1H) 7.20-7.29 (m, 5H) 7.39 (d, J=2.71 Hz, 1H) 9.72 (s, 1H) 12.01 (s, 1H). MS (ESI+) m/z 410 [M+H]+.
Reaction SMILES: CC1C=CC([C@@H](N[C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])C)=NC=1.Cl.[CH2:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C@@H:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=1)[CH3:24]>>[CH2:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C@@H:32]([NH:34][C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[CH3:33])=[CH:28][CH:27]=1)[CH3:24]
Reactant: Cc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)nc1
Reactant: CCOc1ccc([C@H](C)N)cn1
Agent: Cl
Product: CCOc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1

Procedure:
Prepared analogously to Compound 2 using IM46 and commercially available (S)-1-(6-ethoxy-pyridin-3-yl)-ethylamine hydrochloride (Supplier Sial Gmbh, Catalog No 528261-HCl, Lot no LNA098). Yield=0.30 g (39%). 1H NMR (500 MHz, DMSO) δ 8.54 (d, 1H), 8.08 (s, 1H), 7.82 (d, 1H), 7.27 (m, 2H), 7.16 (m, 1H), 7.12 (d, 2H), 8.73 (d, 1H), 4.92 (m, 1H), 4.25 (q, 2H), 2.20 (m, 1H), 1.91 (m, 1H), 1.35 (m, 4H), 1.30 (t, 3H), 1.19 (m, 1H). LC-MS (m/z) 311.4 (MH+), tR=1.45 min (method A).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].CS[C:31]1[NH:36][C:35](=[O:37])[CH:34]=[CH:33][N:32]=1>C(O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:31]2[NH:36][C:35](=[O:37])[CH:34]=[CH:33][N:32]=2)=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CSc1nccc(=O)[nH]1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCO
Product: CCOC(=O)C1=C(COCCNc2nccc(=O)[nH]2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
2-[2-Aminoethoxymethyl]-3-ethoxycarbonyl-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.75 g) and 2-methylthio-3H-pyrimid-4-one (0.5 g) were dissolved in ethanol (5 ml) and heated under reflux for 20 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with 2N hydrochloric acid to remove any unreacted amine, and then with dilute sodium hydroxide solution. It was then washed with water, dried, filtered and evaporated to give a yellow gum. Chromatography on silica "Kieselgel 60H" (Trade Mark) eluting with ethyl acetate gave the title compound, which was recrystallised from ethyl acetate, yield 171 mg, m.p. 148°-150°.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][N:23](C)[C:24](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:38]>C(O)C>[ClH:38].[F:1][C:2]1[C:3]([CH2:22][NH:23][CH3:24])=[CH:4][N:5]([S:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)N2CCCC2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)N2CCCC2)c(-c2cccnc2F)c1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyrrolidin-1-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (260 mg) was dissolved in ethanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 40° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 148 mg, 66%).
Reaction SMILES: [OH-].[Na+].CC1(C)C(C)(C)OB([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)O1.Br[C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]>[Pd].C1COCC1>[NH:15]1[C:16]2[C:12](=[C:11]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([CH:30]=3)[C:27]([OH:29])=[O:28])[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cncc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
Palladium catalyst Pd(PPh3)4 (693 mg, 0.6 mmol) and freshly prepared aqueous sodium hydroxide (3.2 g in 29 mL of water) were added to a mixture of 4-(4,4,5,5-tetramethyl[1,3,2]-dioxaborolan-2-yl)-1H-indole (4.9 g, 20.2 mmol) and 5-bromonicotinic acid (4.04 g, 20 mmol) in THF (70 mL). The system was degassed and then purged three times with nitrogen. The mixture was refluxed under nitrogen for 6 hours. It was then cooled to room temperature and ethyl acetate (400 mL) added. The organic layer was separated and washed twice with 2N NaOH solution. The aqueous layer and hydroxide washes were combined, washed with dichloromethane and then acidified with 6N HCl. The resulting precipitate was collected by vacuum filtration, washed with water and dried to give 2.3 g (48%) 5-(1H-indol-4-yl)-nicotinic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)([O-])=O.Cl>CO>[N:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccncc1
Agent: Cl
Solvent: CO
Product: Nc1ccccc1-c1ccncc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 500 mL round-bottomed flask was added a solution of 4-(2-nitrophenyl)-pyridine (Step a) (7.1 g, 36 mmol) in MeOH (300 mL). The solution was treated dropwise with concd HCl (6.7 mL, 84 mmol) and purged with N2. Pd/C (10%, Aldrich) (2.5 g) was added, H2 was introduced and the suspension was magnetically stirred under atmospheric H2 pressure for 15 h at 25° C. The suspension was purged with N2, filtered through Celite® (Aldrich) (25 g) and the filter cake was washed with MeOH (400 mL). The filtrate was concentrated in vacuo to a yellow powder which was partitioned between EtOAc (200 mL) and 1 N NaOH (100 mL). The organic layer was washed with water (100 mL), satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a viscous yellow oil which solidified upon standing (6.0 g). MP 81-83° C. MS (ESI, pos. ion) m/z: 171 (M+1); (ESI, neg. ion) m/z: 169 (M−1). Calc'd for C11H10N2: 170.21.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][N:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:23])C(=O)C1>C(#N)C>[Br:23][C:2]1[S:1][C:5]2[CH2:6][N:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCCc2ccsc2C1
Solvent: CC#N
Product: CCOC(=O)N1CCCc2cc(Br)sc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of Compound 1044 (1.78 g, 7.90 mmol) in acetonitrile (80 mL) at 0° C. was slowly added NBS (1.69 g, 9.48 mmol). The reaction was stirred at room temperature for 30 minutes, at which point HPLC analysis indicated disappearance of starting material. The reaction was quenched by addition of saturated sodium bicarbonate (50 mL) and stirred for one hour. The reaction was then extracted with diethyl ether (3×100 mL), the organics concentrated, and the residue purified by silica chromatography (5-30% ethyl acetate in hexanes) to give ethyl 2-bromo-5,6-dihydro-4H-thieno[2,3-c]azepine-7(8H)-carboxylate as a pale yellow oil (Compound 1045, 2.07 g, 86% yield); 1H NMR (300 MHz, CDCl3): δ 6.67 (s, 1H), 4.38 (s, 2H), 4.15-3.99 (m, 4H), 3.64 (d, J=3.8 Hz, 2H), 2.73-2.67 (m, 2H) and 1.22-1.09 (m, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1.[Cl:12][C:13]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][NH:17]2.C([O-])([O-])=O.[K+].[K+]>>[Cl:12][C:13]1[N:21]=[C:20]([NH2:22])[N:19]=[C:18]2[C:14]=1[N:15]=[CH:16][N:17]2[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: Cc1cnc(CBr)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cnc(Cn2cnc3c(Cl)nc(N)nc32)c(C)c1C

Procedure:
The compound was obtained by reacting 2-bromomethyl-3,4,5-trimethyl-pyridine with 6-chloro-9H-purin-2-ylamine in the presence of K2CO3 at 5° C. for 0.5 h as described in the general procedure 1.1. HPLC Rt: 3.903 min. 1H-NMR (CDCl3): δ 8.18 (s, 1H), 7.84 (s, 1H), 5.38 (s, 2H), 5.08 (s, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([OH:37])([CH3:36])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:28][CH2:29][C:30]1([CH3:35])[O:34][CH2:33][CH2:32][O:31]1>C(Cl)(Cl)Cl>[CH3:36][C:13]([OH:37])([CH3:12])[CH2:14][N:15]1[C:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:20]([O-:9])=[CH:19][C:18]=2[N:17]=[C:16]1[CH2:28][CH2:29][C:30]1([CH3:35])[O:34][CH2:33][CH2:32][O:31]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(O)Cn1c(CCC2(C)OCCO2)nc2cnc3ccccc3c21
Solvent: ClC(Cl)Cl
Product: CC(C)(O)Cn1c(CCC2(C)OCCO2)nc2c[n+]([O-])c3ccccc3c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
mCPBA (2.2 g of 60% pure material, 7.7 mmol) was added in portions over a period of five minutes to a stirred solution of 2-methyl-1-{2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-1H-imidazo[4,5-c]quinolin-1-yl}propan-2-ol (2.5 g, 7.0 mmol) in chloroform (47 mL), and the reaction was stirred at room temperature for 20 minutes. The reaction mixture was partitioned between dichloromethane (200 mL) and saturated aqueous sodium carbonate (100 mL). The organic layer was separated and washed with saturated aqueous sodium carbonate (100 mL). The combined aqueous fractions were extracted with dichloromethane (50 mL). The combined organic fractions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 2-methyl-1-{2-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl}propan-2-ol as a tan solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[C:15]1([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])=[O:27])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCCCNC(=O)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: NCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
Batch size: 5.5 g (14.4 mmol) N-(4-diphenylacetylamino-butyl)-carbamic acid tert-butyl ester and 4.1 ml (49 mmol) concentrated hydrochloric acid in 60 ml ethanol.