Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12.[CH3:18][NH2:19]>>[CH3:18][NH:19][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[O:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[CH2:10][C:3]=12
Reactant: CN
Reactant: Clc1ccnc2c1CC1(CN3CCC1CC3)O2
Product: CNc1ccnc2c1CC1(CN3CCC1CC3)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 151 mg (0.60 mmol) of 4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] in 25 mL of 40% aqueous methylamine was heated to 175° C. in a steel bomb for 18 hours, then cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in 10 mL of ethanol containing 0.4 mL of concentrated hydrochloric acid and the solution was allowed to stand overnight. After filtering, the solution was concentrated in vacuo and the residue crystallized from isopropanol, giving 147 mg of the title compound as a white solid: electrospray MS (m/z, relative intensity) 246 ([MH]+).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[C:22]([O:24]C)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].O1CCCC1.CO.[OH-].[Na+]>O>[Br:1][C:2]1[C:3](=[O:31])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[C:22]([OH:24])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1ccc(OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Reaction time: 0.5 h

Procedure:
A 100 mL round bottomed flask was charged with the product of Step 4 (0.77 g, 1.55 mmol), tetrahydrofuran (10 mL), methanol (5 mL), and water (5 mL). To this slurry was added 2.5 N NaOH (1.2 mL, 3.1 mmol). The reaction mixture became clear after 30 minutes and the reaction was complete in 1 h by LC-MS. The organics were removed on the rotary evaporator and the remaining solution was acidified to pH 2-3 with 6N HCl. The desired compound was precipitated by the addition of water and diethyl ether and subsequent filtration. The title compound was isolated as a white powder (0.60 g, 81w). 1H NMR (400 MHz, CD3OD) δ 8.17 (dd, J=2.2 and 8.8 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.64 (q, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.34 (t, J=8.8 Hz, 2H), 6.60 (s, 1H), 5.34 (s, 2H), 3.87 (s, 3H), 2.01 (s, 3H) ppm. ES-HRMS m/z 480.0259 (M+H calcd for C21H17BrF2NO5 requires 480.0253).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8](B(O)O)[CH:9]=1)[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O.Cl[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>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.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:13])=[C:8]([C:28]2[C:29]([C:30]#[N:31])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: N#Cc1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(F)c(-c2ccccc2C#N)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
Under argon, 5-ethoxy-2-fluorophenylboronic acid (300 mg, 1.63 mmol), potassium phosphate (433 mg, 2.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol) were dissolved in abs. N,N-dimethylformamide (8 ml), and the mixture was stirred at room temperature for 5 minutes. 2-Chlorobenzonitrile (112 mg, 0.82 mmol) was then added, and the reaction mixture was stirred at 160° C. for 4 h. After cooling to room temperature, water (>100 ml) was added and the aqueous phase was repeatedly extracted thoroughly with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtered off and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 5′-ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 76% of theory) in the form of a colourless solid. 5′-Ethoxy-2′-fluorobiphenyl-2-carbonitrile (150 mg, 0.62 mmol) was then dissolved in methanol (5 ml), finely powdered potassium hydroxide (174 mg, 3.10 mmol) was added and the mixture was stirred under reflux conditions for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, water was added and the resulting precipitated solid was filtered off and dried. This gave 2-ethoxyphenanthridin-6(5H)-one (72 mg, 46% of theory) as a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.58 (br. s, 1H, NH), 8.56 (d, 1H), 8.32 (d, 1H), 7.86 (d, 1H), 7.82 (dd, 1H), 7.64 (dd, 1H), 7.29 (d, 1H), 7.13 (dd, 1H), 4.17 (q, 2H), 1.39 (t, 3H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1F
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1-n1cccn1
Temperature: 120 °C
Yield: 57.9 %

Procedure:
A mixture of 4-fluoro-3-methoxybenzaldehyde (2.00 g, 12.98 mmol), pyrazole (1.32 g, 19.39 mmol), and powdered K2CO3 (2.68 g, 19.39 mmol) in DMF (20 mL) was heated to 120° C. for 20 h. The cooled reaction mixture was diluted with ethyl acetate (200 mL), washed with water (3×200 mL), dried (Na2SO4), and concentrated. Purification by chromatography (SiO2, 4:1 hexane/ethyl acetate) yielded 1.52 g (58%) of the title compound as a yellow oil. MS 203 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[Br:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[C:20]([Cl:25])[CH:19]=1>CS(C)=O.CCOC(C)=O>[Br:17][C:18]1[CH:23]=[C:22]([O:8][C:7]2[C:6]([F:9])=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=2[Cl:1])[CH:21]=[C:20]([Cl:25])[CH:19]=1
Reactant: Cc1ccc(Cl)c(O)c1F
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (7.67 g, 47.7 mmol) in DMSO (100 ml) was added potassium t-butoxide (1.0 M solution in THF) (50.1 ml, 50.1 mmol) and the mixture was stirred at room temperature for 30 minutes. Next, 1-bromo-3-chloro-5-fluorobenzene (10.0 g, 47.7 mmol) was added and the mixture was heated at 135° C. for 3 days. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with water. The solvent was removed to give 2-[(3-bromo-5-chlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (9.54 g, 27.3 mmol, 57% yield) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.44 (s, 1H), 7.33-7.40 (m, 1H), 7.27 (t, 1H), 7.07 (s, 1H), 6.95-7.02 (m, 1H), 2.23 (d, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[N:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[O:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F-].[Cs+]>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.CO>[CH3:12][O:11][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:2]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][NH:4][C:5]=12
Reactant: OB(O)c1ccccc1Oc1ccccc1
Reactant: COc1nccc2c(I)c[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: COc1nccc2c(-c3ccccc3Oc3ccccc3)c[nH]c12
Temperature: 120 °C
Yield: 38.6 %

Procedure:
A mixture of 3-iodo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (0.274 g, 1.0 mmol), 2-phenoxyphenylboronic acid (0.278 g, 1.3 mmol, 1.3 equivalents), Pd(PPh3)4 (0.058 g, 0.05 mmol), and cesium fluoride (0.456 g, 3 mmol) in dimethxoyethane (3 mL) and methanol (1.5 mL) was heated under microwave conditions (120° C., 30 minutes). The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate/hexanes) to give the title compound (0.122 g, 38.6% yield).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Na+:12].[Na+].[CH2:14]([OH:16])[CH3:15]>>[C:4]([O:16][CH2:14][CH3:15])(=[O:5])/[CH:3]=[CH:2]\[C:1]([O-:6])=[O:7].[Na+:12]
Reactant: CCO
Reactant: O=C1C=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)/C=C\C(=O)[O-]

Procedure:
Fifty-seven grams (0.57 moles) maleic anhydride is dissolved in 500 mls ethanol. With the aid of a pH meter the pH is adjusted to 8.5-8.6 with sodium carbonate. The solution is evaporated on the roto evaporator and dried in a vacuum oven. Ninety-four grams (0.57 moles) of product having a purity of 99.4% (NMR analysis) is obtained.
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[Li+].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.[I-].C[CH:23]=[N+:24]=[CH:25]C>C1COCC1>[CH3:23][N:24]([CH2:25][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:2])[O:3]1)[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1OCc2ccccc21
Reactant: CC=[N+]=CC
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CC1OC(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of phthalide (0.50 g, 3.73 mmol) in THF (13.0 ml) at −78° C. was added 1.0M LiHMDS in THF (3.9 ml). The reaction was stirred for 10 minutes, and then N,N-dimethylmethyleneammonium iodide (0.76 g, 4.10 mmol) was added in one portion. The resulting mixture was continuously stirred at −78° C. for another 15 minutes. The mixture was then allowed to warm to 0° C. and then quenched into very dilute HCl aqueous solution. The aqueous layer was adjusted to acidic pH with 4% HCl aqueous solution and washed with EtOAc. The aqueous layer was basified with saturated NaHCO3 aqueous solution and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and rotary evaporated to a light yellow oil. The oil was taken up in CHCl3, filtered to remove an insoluble impurity, and then chromatographed through silica gel column (CHCl3 to 2.5% MeOH/CHCl3 gradient) to afford 3-dimethylaminomethyl-3H-isobenzofuran-1-one as a clear oil (0.24 g, 33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:25][C:26](Br)=[O:27].[CH:29]1([NH2:39])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH2:11][CH2:10][N:9]2[CH2:25][C:26]([NH:39][CH:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31][CH2:30]2)=[O:27])=[CH:22][CH:23]=1
Reactant: O=C(Br)CBr
Reactant: NC1CCCc2ccccc21
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCCc3ccccc32)cc1

Procedure:
prepared by reaction of 1-(4-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Li+].Cl>CO.O1CCCC1>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cnc2c(OCc3c(F)cccc3F)cccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cnc2c(OCc3c(F)cccc3F)cccn12
Temperature: 40 °C
Reaction time: 4 h

Procedure:
1 g of ethyl 8-[(2,6-difluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate (Example 30A, 3 mmol, 1 equivalent) was initially charged in 60 ml of methanol/tetrahydrofuran (5:1), 15 ml of a 1 N aqueous lithium hydroxide solution (15 mmol, 5 equivalents) were added and the mixture was warmed to 40° C. and stirred at this temperature for 4 h. The mixture was then cooled and, with ice cooling, adjusted to pH=4 using 6 N hydrochloric acid. The organic solvents were removed on a rotary evaporator, water was added to the precipitated product and the product was filtered off. The filter cake was washed with water and dried under high vacuum. This gave 797 mg (87% of theory) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](Cl)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:14][C:15]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:16]=1[C:17]([OH:19])=[O:18].N1C=CC=CC=1>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]([NH:14][C:15]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:16]=3[C:17]([OH:19])=[O:18])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)Cc1ccc2c(c1)OCO2
Reactant: Nc1cc(F)cc(F)c1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1ccc2c(c1)OCO2)Nc1cc(F)cc(F)c1C(=O)O
Temperature: 120 °C
Yield: 79.7 %

Procedure:
To a solution of commercially available benzo[1,3]dioxol-5-yl-acetyl chloride (3.70 g, 18.70 mmol) in anhydrous dichloromethane (20 mL) was added 2-amino-4,6-difluoro-benzoic acid (2.20 g, 12.5 mmol). After the addition of pyridine (5 mL), the mixture was heated under microwave condition at 120° C. for 5 minutes. The solvent was evaporated and the residue was diluted with 2 N HCl solution to induce the precipitation of a brown solid which was filtered, washed with water and dried under vacuum at 50° C., to afford the title compound (3.34 g, 80% yield).
Reaction SMILES: [C:1]([O-:5])(=O)[CH:2]=[O:3].N.O1CCOCC1.C(OP(O[N:22]1[C:27](=O)[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[N:24]=N1)(OCC)=O)C.C([N:36](C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[O:3]=[C:2]([C:29]1[C:26]2[CH:27]=[N:22][CH:31]=[CH:32][C:25]=2[NH:24][CH:30]=1)[C:1]([NH2:36])=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=CC(=O)[O-]
Reactant: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NC(=O)C(=O)c1c[nH]c2ccncc12

Procedure:
A mixture of methyl oxo-(1H-pyrrolo[3,2-c]-pyridin-3-yl)acetate (1 eq.) and K2CO3 (2 eq.) in methanol is stirred at room temperature for 8 h and filtered. The filtercake is air-dried to give potassium 5-azaindole 3-glyoxylate. A mixture of this glyoxylate salt, ammonia (solution in dioxane (5 eq.), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) (1 eq.) and diisopropylethylamine (DIEA) in DMF is stirred for 8 h, diluted with EtOAc and aqueous sodium carbonate. The organic phase is separated, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified over silica gel with EtOAc/MeOH as eluent to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH2:15][O:16][CH3:17])=[O:12])[NH:7][C:6]=2[CH:18]=1.Cl[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(N(CC)CC)C>CC(C)=O>[CH3:17][O:16][CH2:15][CH2:14][NH:13][C:11](=[O:12])[NH:10][C:8]1[NH:9][C:5]2[CH:4]=[CH:3][C:2]([O:1][S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:28]=3)(=[O:22])=[O:21])=[CH:18][C:6]=2[N:7]=1
Reactant: COCCNC(=O)Nc1nc2ccc(O)cc2[nH]1
Reactant: O=C(Oc1ccc(S(=O)(=O)Cl)cc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COCCNC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(OC(=O)c4ccccc4)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.4 %

Procedure:
A stirred solution of 1-(6-hydroxy-1H-benzoimidazol-2-yl)-3-(2-methoxy-ethyl)-urea (31 mg, example 82) and benzoic acid 4-chlorosulfonyl-phenyl ester (37 mg) in acetone (0.6 ml) was treated with triethylamine (33 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LCMS triggered purification to give benzoic acid 4-{2-[3-(2-methoxy-ethyl)-ureido]-1H-benzoimidazol-5-yloxysulfonyl}-phenyl ester (7.2 mg) as a off-white solid Mass spectrum: 511 [M+H]+; retention time=9.90 minutes.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:15][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(F)cc1
Yield: 91.5 %

Procedure:
A solution of 4-fluorobenzaldehyde (8.6 mL, 0.081 mol) and carboethoxymethylene triphenylphosphorane (34 g, 0.097 mol) in toluene (400 mL) was heated at reflux for 3 h. After this time the solvent was removed in vacuo and the residue triturated in petrol:Et2O (1:1). The mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica gel, eluting with petrol:Et2O (3:1), to afford the ester (14.4 g, 92%) as a low-melting colourless solid. 1H NMR (major isomer) (250 MHz, CDCl3) δ1.34 (3H, t, J=7.0 Hz), 4.26 (2H, q, J=7.0 Hz), 6.36 (1H, d, J=16 Hz), 7.07 (2H, dd, JHA-HB =8.6 Hz and JHA-F =8.6 Hz), 7.51 (2H, dd, JHB-HA =8.6 Hz and JHB-F =5.3 Hz), 7.65 (1H, d, J=16 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[O:5][C:6]=1[CH:7]=O.Cl.NO.[N:16]1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(#N)C.Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[O:5][C:6]=1[C:7]#[N:16]
Reactant: c1ccncc1
Reactant: COC(=O)c1cc(Br)c(C=O)o1
Agent: Cl
Agent: NO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc(Br)c(C#N)o1
Reaction time: 2.5 h

Procedure:
To a solution of 46.55 g (0.20 mol) of methyl 4-bromo-5-formyl-2-furoate in 465 mL of acetonitrile was added 15.28 g (0.22 mol) of hydroxylamine hydrochloride. To this suspension 96.6 mL (1.2 mol) of pyridine was added dropwise over a period of 35 min, at 20-25° C. After 90 min stirring neat trifluoroacetic anhydride (67.72 mL, 0.48 mol) was dropped in over 45 min at room temperature. After 2.5 hours stirring the reaction mass was poured in a mixture of HCl 1 M (0.75 L) and ethyl acetate (0.75 L); the aqueous layer was extracted again with 0.45 L of ethyl acetate. The organic extracts were washed with 0.45 L of 2 M HCl and the aqueous layer was back extracted with 0.3 L of ethyl acetate. The combined organic extracts were concentrated under reduced pressure to dryness. This crude material was dissolved in 100 mL of ethanol 95° and treated dropwise with 150 mL of water under efficient stirring at 40°-45° C. The resulting suspension was cooled to 0/+4° C. for 1 hour then filtered to afford, after drying, 44.2 g of product as light cream solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][C:8]([N+:15]#[C-:16])([CH3:14])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:17][C:18]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:19]=1[CH:20]=O>Cl(O)(=O)(=O)=O>[CH3:17][C:18]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:19]=1[C:20]1[N:1]=[C:2]2[N:6]=[CH:5][NH:4][N:3]2[C:16]=1[NH:15][C:8]([CH3:14])([CH3:7])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1nc[nH]n1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Reactant: Cc1ccc(C=O)c(C)c1
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccc(-c2nc3nc[nH]n3c2NC(C)(C)CC(C)(C)C)c(C)c1

Procedure:
Compound 53 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 3-amino-1,2,4-triazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) 1,1,3,3-tetramethylbutylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2,4-dimethylbenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%).
Reaction SMILES: [OH-].[NH4+:2].[CH2:3]([C:7]1[N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:12]([O-])=[CH:11][C:10]=2[N:20]=1)[CH2:4][CH2:5][CH3:6].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[NH2:2][C:11]1[C:10]2[N:20]=[C:7]([CH2:3][CH2:4][CH2:5][CH3:6])[N:8]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[C:9]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCCNC(=O)Nc1ccccc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)Nc1ccccc1

Procedure:
Concentrated ammonium hydroxide (35 mL) was added with stirring to a solution of N-[3-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea (2.25 g, 5.39 mmol) in dichloromethane (100 mL). Tosyl chloride (1.13 g, 5.93 mmol) was added in small portions over a period of 30 minutes. After 1 hour the layers were separated. The aqueous layer was extracted with dichloromethane (2×25 mL). The organics were combined and extracted with water (3×50 mL). The aqueous layers were combined and filtered to provide 1.64 g of an off white solid. This material was recrystallized sequentially from 1,2-dichloroethane, isopropyl alcohol and methanol to provide 960 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea as light tan needles, m.p. 191-192° C. Analysis: Calculated for C24H28N6O: % C, 69.21; % H, 6.78; % N, 20.18. Found: % C, 68.94; % H, 6.77; % N, 19.90.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:15]1[CH:19]=[CH:18]N=C1)(N1C=CN=C1)=[S:9].NC1C=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[C:23]([Cl:30])[CH:22]=1.Cl>O.C(Cl)Cl>[N:15]([C:19]1[CH:18]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[C:23]([Cl:30])[CH:22]=1)=[C:8]=[S:9]
Reactant: Nc1ccc(C(=O)O)c(Cl)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(N=C=S)cc1Cl
Reaction time: 1 h
Yield: 91 %

Procedure:
A methylene chloride solution (235 mL) of triethylamine (30.6 mL, 219.5 mmol) and thiocarbonyldiimidazole (23.01 g, 129.14 mmol) was dropped to a methylene chloride solution (130 mL) of 4-amino-2-chlorobenzoic acid (18.84 g, 109.82 mmol) under cooling with ice, followed by stirring for one hour while an internal temperature of at most 10° C. was maintained. 4M hydrochloric acid (120 mL, 480 mmol) was dropped so that the internal temperature became at most 10° C., followed by stirring under cooling with ice for one hour. Water (10 mL) was added, and the formed pink solid was collected by filtration, washed with water (100 mL) five times and dried under reduced pressure to obtain 4-isothiocyanato-2-chlorobenzoic acid as a colorless solid (21.36 g, yield: 91%, HPLC purity: 98.2%).