Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][CH:6]([CH3:8])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([NH:3][C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:9]([OH:11])=[O:10])=[O:20]
Reactant: COC(=O)Cl
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
An aqueous NaOH (1M, 2.6 mL) solution is added, while stirring, to L-Leucine (4 g, 30.5 mmol) in a round bottom flask (250 mL). To this solution was added sodium carbonate (1.62 g, 15.2 mmol). The flask is cooled to 0° C. in an ice-water bath. Methyl chloroformate (2.6 mL, 33.5 mmol) is added drop wise and the reaction mixture is allowed to stir for 15 hours and reach room temperature. The reaction mixture is separated with ether (3×50 mL), and the aqueous layer is contained in a round bottom flask and cooled over an ice-water bath. Concentrated HCl (aq) is added drop wise until pH 2. The reaction mixture is brought to room temperature and extracted with 2-Me-THF (3×50 mL). The organic layers are pooled, dried (MgSO4), the solids removed by filtration, and the solvents of the filtrate removed under reduced pressure. The compound was purified by silicagel chromatography with gradient elution from CH2Cl2 to CH2Cl2/MeOH/acetic acid 17/2/1. Fractions containing product were combined and the solvent were removed in vacuum, resulting in N-methoxycarbonyl-L-leucine (1.9 g, 32%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C:5]([CH3:8])([CH3:7])[C@@H:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[O:3]1>CCOC(C)=O.CC(O)C.[Pd]>[CH3:1][C:2]1([CH3:18])[O:3][C@H:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[C:5]([CH3:8])([CH3:7])[O:6]1
Reactant: CC1(C)O[C@H](c2ccc([N+](=O)[O-])cc2)C(C)(C)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC1(C)O[C@H](c2ccc(N)cc2)C(C)(C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.1 %

Procedure:
A mixture of (R)-2,2,4,4-tetramethyl-5-(4-nitrophenyl)-1,3-dioxolane (200 mg, 0.797 mmol) and Pd/C (10%, 60 mg) in EtOAc/IPA (10 mL/10 mL) was stirred under 1 atm H2 atmosphere (balloon) at RT for 16 h. The mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the desired product (180 mg, 100%), which was directly used into the next step without further purification.
Reaction SMILES: [Li].[C:2]([O:6][C:7](=[O:23])[NH:8][C@H:9]1[CH2:13][C@@H:12]([CH3:14])[N:11](CC2C=CC=CC=2)[C:10]1=[O:22])([CH3:5])([CH3:4])[CH3:3]>N.C1COCC1>[C:2]([O:6][C:7](=[O:23])[NH:8][C@H:9]1[CH2:13][C@@H:12]([CH3:14])[NH:11][C:10]1=[O:22])([CH3:4])([CH3:3])[CH3:5]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C(=O)N1Cc1ccccc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
To a blue solution of lithium metal (0.237 g, 34.2 mmol) in NH3 (1) (200 mL) at -78° C. was added a solution of 13-6 (2.60 g,8.54 mmol) in THF (15 mL). The mixture was stirred for 15 minutes, then quenched by the addition of ammonium chloride until the blue color dispersed. An additional 30 mL of THF was added, and the mixture warmed to 35° C. to evaporate the ammonia. MgSO4 was added,the mixture was filtered through a celite pad. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:20:10 chloroform/ethyl acetate/MeOH) to give 13-7 as a colorless oil
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18](=O)[CH3:19])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:18]([NH2:27])[CH3:19])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc2c(Cl)cccc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 84.7 %

Procedure:
A mixture of 1-[4-chloro-1-(3-fluorophenyl)-1H-indol-2-yl]ethanone (0.13 g, 0.45 mmol) and ammonium acetate (0.348 g, 4.52 mmol) in methanol (2.0 mL) and acetonitrile (2.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, to the resultant mixture was added sodium cyanoborohydride (57 mg, 0.91 mmol). The reaction was heated at 65° C. for another 4 hours. After cooling to room temperature, the reaction was quenched with aqueous saturated NaHCO3 solution and then extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (0.11 g), which was used directly in the next step. LCMS calculated for C16H12ClFN(M-NH2)+: m/z=272.1. Found: 272.0.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:8]1
Reactant: O=C(OCc1ccccc1)N1CCOC(CNC(=O)C(F)(F)F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: NCC1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 22 °C
Reaction time: 36 h
Yield: 71.4 %

Procedure:
To a stirred solution of Intermediate 4 (4.4 g) in 1:1 methanol/water (300 ml) was added potassium carbonate (17.5 g). The mixture was stirred at 22° C. for 36 h before the volatiles were evaporated in vacuo. The residue was dissolved in water and the solution extracted with dichloromethane (×3). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered before evaporation of the solvent in vacuo. The residue was dissolved in methanol and purified by solid phase extraction (Isolute SCX sulphonic acid column), initially washing the cartridge with methanol before eluting with 10% 0.880 ammonia solution in methanol to give the title compound as a colourless oil (2.27 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cccnc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2cccnc2c1
Temperature: 100 °C
Yield: 57.9 %

Procedure:
To a solution of 7-methylquinoline (0.10 g, 0.70 mmol) in 5 ml of CCl4 was added NBS (0.14 g, 0.77 mmol) and AIBN (0.025 g, 0.15 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400M) using 1% ethyl acetate/hexane eluent to give the desired product (0.090 g, 58%).
Reaction SMILES: [CH3:1][C:2]([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH3:18][C:2]([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH3:1])[CH2:3][N:4]1[C:16]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)(Cn1cnc2c(N)nc3ccccc3c21)OCCS(C)(=O)=O
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(Cn1cnc2c(N)nc3c(c21)CCCC3)OCCS(C)(=O)=O
Yield: 108.8 %

Procedure:
A mixture of 1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 29, 1.00 g, 2.76 mmol) and platinum(IV) oxide (0.5 g) in trifluoroacetic acid (14 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 20 hours. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (50 mL) and adjusted to pH 13 with 50% aqueous sodium hydroxide. A white solid formed that was isolated by filtration, washed with water, and dried under vacuum at 65° C. to afford 1.10 g of 1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 219-223° C.
Reaction SMILES: [CH3:1]NN.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]3[N:23](C)[N:24]=[CH:25][CH:26]=3)[CH:16]=2)=[O:13])=[CH:7][CH:6]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]3[CH:26]=[CH:25][N:24]([CH3:1])[N:23]=3)[CH:16]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Reactant: CNN
Solvent: c1ccncc1
Product: Cn1ccc(-c2cc(NC(=O)Nc3ccc(Cl)cc3)ccc2O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.1 %

Procedure:
To a cooled and stirred solution of methyl hydrazine (1.46 g, 31.6 mmol) in pyridine was added slurry of Compound 119 (2.5 g, 7.9 mmol) in pyridine over a period of 10 mins. The reaction mixture was left at this temperature for another 2 hrs and then warmed to room temperature slowly. After 6 hrs the reaction mixture turned clear. The reaction was stirred at this temperature for 18 hrs. Then pyridine was evaporated. The dark colored residue was dissolved in DMSO and purified using Varian Preparative HPLC system at a flow rate of 60 mL/Min. and λ=240. The regio isomers were separated. The fractions containing Compound 154 were dried in vacuo to produce an off-white solid 1-(4-Chloro-phenyl)-3-[4-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-phenyl]-urea (0.3 g, 12%). LCMS m/z (%)=343 (M+H, 35Cl 100), 345 (M+H, 37Cl, 32.5). 1H NMR (400 MHz, DMSO-d6) δ: 10.26 (bs, 1H), 8.73 (bs, 1H), 8.46 (bs, 1H), 7.82 (d, J=2.32 Hz, 1H), 7.77 (d, J=3.62 Hz, 1H), 7.44-7.49 (m, 2H), 7.16-7.19 (dd, J=8.74, 2.62 Hz, 1H), 6.83-6.85 (d, J=8.72 Hz, 1H), 6.71-6.72 (d, J=2.36 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]2[O:9][C:4]3[CH:3]=[C:2]([Br:1])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:25][CH:26]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Product: Brc1ccc2nc(-c3ccc(OCc4ccccc4)cc3)oc2c1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 4-benzyloxybenzoic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)(=[O:19])=[O:18].C1COCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.[Pd+2]>[F:15][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:17]([CH3:16])(=[O:19])=[O:18])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2F)cn1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2ccc(N)nc2)c(F)c1
Temperature: 60 °C
Yield: 29.3 %

Procedure:
5-(4-Chloro-2-fluorophenyl)pyridin-2-amine (100 mg, 0.449 mmol), 2-(methylsulfonyl)phenylboronic acid (112 mg, 0.561 mmol), and chloro(2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (33 mg, 0.045 mmol) were placed in a sealable reaction tube under nitrogen. THF (2 mL, sparged with nitrogen) and K3PO4 (2 mL, 0.5 M sparged with nitrogen) were added, and the reaction vessel was sealed and heated at 60° Celsius for 16 hours with vigorous stirring. The mixture was cooled to rt, diluted with EtOAc, and washed with 2 M K2CO3, then dried and concentrated to dryness. The residue was subjected to FCC to provide the title compound (45 mg, 29%). MS (CI): mass calcd. for C18H15FN2O2S, 342.08; m/z found, 343.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.38-8.31 (s, 1H), 8.29-8.22 (m, 1H), 7.77-7.71 (m, 1H), 7.71-7.65 (m, 1H), 7.64-7.57 (m, 1H), 7.52-7.45 (m, 1H), 7.42-7.37 (m, 1H), 7.36-7.27 (m, 2H), 6.64-6.59 (m, 1H), 4.66-4.51 (s, 2H), 2.81-2.69 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])=[CH:7][C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])=[CH:5][C:4]=2[N:3]=1.[CH:28]1([CH2:31][OH:32])[CH2:30][CH2:29]1.[H-].[Na+]>>[CH:16]1([NH:15][S:12]([C:8]2[C:9]3[CH:10]=[CH:11][C:2]([O:32][CH2:31][CH:28]4[CH2:30][CH2:29]4)=[N:3][C:4]=3[CH:5]=[C:6]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:7]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(Cl)nc2c1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2ccc(OCC3CC3)nc2c1
Temperature: 60 °C

Procedure:
A mixture of 2-chloro-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide (18 mg, 0.044 mmol) and cyclopropylmethanol (1 mL) was treated with excess sodium hydride and heated to 60° C. overnight. The mixture was concentrated and purified by preparative HPLC to give the desired product, N-cyclopentyl-2-(cyclopropylmethoxy)-7-(3,5-dimethylisoxazol-4-yl)quinoline-5-sulfonamide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10].N1C=CC=CC=1.Cl[C:18]([O:20][CH:21]=[CH2:22])=[O:19]>C(Cl)(Cl)Cl>[CH:21]([O:20][C:18]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[O:19])=[CH2:22]
Reactant: C=COC(=O)Cl
Reactant: O=C1CCC(=O)N1CCO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=COC(=O)OCCN1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
To a 500 mL 3-neck round bottom flask fitted with a mechanical stirrer, condenser, nitrogen blanket, dropping funnel, ice-saltwater bath, and thermometer were added 5.0 (35.0 mmol) of N-(2-hydroxyethyl) succinimide, 2.8 g (35.0 mmol) of pyridine, and 100 mL chloroform. To the reaction mixture was added 3.7 g (35.0 mmol) of vinyl chloroformate so that the temperature remained below 10° C. After stirring at room temperature for 18 hours the reaction mixture was washed with 100 mL 2N HCl and 100 mL 2N NaOH. The organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting red liquid chromatographed (silica gel, chloroform). The recovered oil totaled 3.0 g (14.1 mmol, 40.2% yield). FTIR (neat, capillary) 1755.10, 1694.90, 1648.77, 1427.00, 1396.38, 1366.15, 1329.97, 1298.34, 1239.58, 1185.85, 1152.26, 1111.20, 1085.92, 1024.25, 1005.00, 946.53, 894.87, 882.46, 848.52, 818.51, 778.99, 700.00, 661.32. NMR (CDCl3) 6.50-6.83 (1H,q), 4.13- 4.66 (2H,m), 3.93-4.13 (2H,m), 3.33-3.66 (2H,m), 2.41 (4H,S). ##STR17##
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:20](OCC)=[O:21])[CH:5]=[CH:4][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH2:20][OH:21])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)C(C)(C)CCC3(C)C)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C3=C(CO)CCCC3)ccc21

Procedure:
Ethyl 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexene-1-carboxylate, described in Example 1, is stirred with excess lithium aluminum hydride in diethyl ether at reflux temperature for 3 hours. The mixture is cooled and water is added dropwise. The organic layer is dried over sodium sulfate and evaporated to give 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexenylmethanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[NH:8][C:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:15]=2)[CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N:1]2[CH2:6][CH2:5][O:4][CH:3]([C:7]3[NH:8][C:9]4[CH:14]=[CH:13][N:12]=[CH:11][C:10]=4[N:15]=3)[CH2:2]2)[N:20]=[C:19]([NH2:24])[N:18]=1
Reactant: c1cc2[nH]c(C3CNCCO3)nc2cn1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCOC(c3nc4cnccc4[nH]3)C2)n1
Yield: 55.6 %

Procedure:
a solution of 2-(2-morpholinyl)-1H-imidazo[4,5-c]pyridine (0.996 g, 4.88 mmol), 4,6-dichloro-2-pyrimidinamine (0.8 g, 4.88 mmol) and Hunig's base (2.12 mL, 12.2 mmol) in ethanol (24.39 mL) was heated at 85° C. overnight. The mixture was concentrated and chromatographed (PE-EtOAc, 1:5) to afford the title compound (0.9 g). LC-MS (ES) m/z=332 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.CN(C)C=O.N1C=CN=C1.[CH3:19][C:20]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])[CH3:21]>O>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][Si:23]([C:20]([CH3:22])([CH3:21])[CH3:19])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:1][CH:2]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc(Br)cc1)(c1ccccc1)c1ccccc1
Yield: 95.1 %

Procedure:
80.89 g of p-bromophenol, 400 ml of dimethylformamide, 31.18 g of imidazole and 125.89 g of 1,1-dimethyl-ethyl-diphenylchlorosilane were stirred for 2 hours at ambient temperature and the reaction medium was poured into 2 liters of water. Extraction was carried out with ethyl acetate, followed by decanting, drying and evaporating under reduced pressure. After crystallization from pentane, separation was carried out, followed by drying to obtain 179.24 g of the expected product with a Rf=0.53 (thin layer chromatography, support: silica, eluant: cyclohexane/AcOEt 95/5) and a melting point of 56° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH2:34])[CH:6]=1)[CH3:2].[H-].[Na+].I[CH3:39].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:35])[C:5]1[CH:10]=[C:9]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:8]=[C:7]([NH:34][CH3:39])[CH:6]=1)[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1cc(N)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(NC)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1
Reaction time: 48 h

Procedure:
5-{2-[5-trifluoromethyl-2-benzyloxyphenyl]cyclopent-1-enyl}-3-aminobenzoic acid ethyl ester (210 mg, 0.43 mmol), sodium hydride (17 mg, 0.43 mmol), iodomethane (0.027 mL, 0.43 mmol), in 3 mL of DMF were stirred at room temperature for 24 hrs, then another 0.027 mL of iodomethane were added and the reaction mixture was stirred for another 48 hrs. The mixture was then poured into water and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), and concentrated. Purification was carried out on SPE using iso-hexane containing a gradient of ethylacetate (20–30%) to give the required product as a yellow oil. (85 mg, 39%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][C:17]([C:19]([NH:21][CH2:22][C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[O:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH:7]=[CH:8][CH:9]=1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30].CCN(CC)CC>C1COCC1>[CH3:36][C:35]1[CH:37]=[CH:38][C:32]([S:29]([NH:3][C:4]2[CH:5]=[C:6]([N:10]3[C:14]4[CH:15]=[CH:16][C:17]([C:19]([NH:21][CH2:22][C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)=[O:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH:7]=[CH:8][CH:9]=2)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(-n3cnc4cc(C(=O)NCc5cccnc5)ccc43)c2)cc1
Reaction time: 72 h

Procedure:
A mixture of 1-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide dihydrochloride (47 mg, 0.14 mmol) and TsCl (27 mg, 0.14 mmol) was dissolved in anhydrous THF (3 mL) at 0° C. and treated with Et3N (95 μL, 0.68 mmol). The reaction mixture was stirred for 72 h and then filtered. The solid residue was washed with THF and the combined washings and filtrate were concentrated in vacuo. The resultant residue was purified by silica gel chromatography (0-7% MeOH in CH2Cl2). Further purification was achieved by trituration with MeOH to afford 1-(3-{[(4-methylphenyl)sulfonyl]amino}phenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as a white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 2.35 (s, 3H), 4.54 (d, J=5.6 Hz, 2H), 7.20 (d, J=8.0 Hz, 1H), 7.32-7.44 (m, 4H), 7.50 (t, J=7.6 Hz, 1H), 7.68-7.81 (m, 3H), 7.89 (d, J=8.8 Hz, 1H), 8.36 (s, 1H), 8.47 (brs, 1H), 8.61 (s, 1H), 9.19 (brs, 1H). MS (ES+): m/z 498 [MH+].
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:18]>O>[Br:18][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Br
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 88 %

Procedure:
To a solution of 3-amino-5-nitro-benzoic acid (17.6 g, 96.6 mmol, 1 equiv) in 48% aqueous HBr solution (180 ml) at 0° C. was added portionwise NaNO2 (8.67 g, 126 mmol, 1.3 equiv) over 20 min. The temperature was kept below 8° C. during this addition. The resulting mixture was then added to a suspension of CuBr (9.7 g, 67.6 mmol, 0.7 equiv) in 48% aqueous HBr solution (50 ml) at 65° C. over 40 min. The temperature was kept above 60° C. during the addition. The resulting mixture was stirred at 70° C. for 45 min, cooled to room temperature and diluted with 1 L of water. The aqueous phase was extracted three times with Et2O. The combined organic layers were washed twice with H2O, dried over MgSO4 and concentrated in vacuo to give 3-bromo-5-nitro-benzoic acid (D5) (21 g, 88%) as a brown solid. [M−H]−=245.7, RT=2.82 min