Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[CH2:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[O:18][C:10]=12.Cl>>[C:1]([C:21]1[CH:20]=[CH:19][C:17]2[O:18][C:10]3=[N:9][CH:14]=[CH:13][CH:12]=[C:11]3[CH2:15][C:16]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)Cc1cccnc1O2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1ccc2c(c1)Cc1cccnc1O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
30.5 g of acetyl chloride is placed in a four-necked flask fitted with a stirrer. A mixture of 49 g of crushed aluminum chloride and 20 g of crushed 5H-[1]benzopyrano[2,3-b]pyridine is added in small portions over a period of 30 minutes, keeping the temperature at 10°-20°C by cooling with ice water. After the addition the temperature is raised to 50°-60°C over 1 hour. Violent release of hydrogen chloride takes place. The contents gradually become viscous, and stirring becomes difficult. The contents are allowed to stand at 80°-85°C for 2 hours without stirring. The contents are broken to pieces and thrown into 1 liter of ice water. The crystalline precipitate is filtered off, washed with water, dried, and then recrystallized from ethyl acetate to give 18.5 g of 7-acetyl-5H-[1]benzopyrano[2,3-b]pyridine melting at 142°-144°C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:12][C:13]([OH:15])=[O:14]>O>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)CCl
Solvent: O
Product: O=C(O)CNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
To a suspension of 4-nitroaniline (13.8 g, 100 mmol) in water (300 mL) was added chloroacetic acid (18.9 g, 200 mmol). The reaction mixture was refluxed overnight and cooled to rt. The title compound was collected by filtration, washed with water and a mixture of hexane and ether (1:1) and dried in vacuo to yield 14.6 g (74%). 1H NMR (400 MHz, DMSO-d6) δ: 12.83 (s, 1H), 8.00 (d, 2H), 7.45 (t, 1H), 6.65 (d, 2H), 4.00 (d, 2H).
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[N:16]=[C:15](Cl)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[CH3:18][O:19][C:20]([C:22]1[C:23]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]>O1CCCC1>[CH3:18][O:19][C:20]([C:22]1[C:23]([C:28]2[CH:29]=[CH:30][C:31]([CH2:34][NH:35][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=[C:7]([Cl:6])[N:16]=3)=[CH:32][CH:33]=2)=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(CNc2nc(Cl)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium acetate (0.65 g), 2,4-dichloroquinazoline (0.52 g) and 4'-aminomethyl[1,1'-biphenyl]-2-carboxylic acid methyl ester (0.73 g) were suspended in 25 mL of tetrahydrofuran. The reaction was stirred at room temperature for approximately 18 hours at which time the solvents were evaporated. The residue was loaded onto a silica gel column and the desired product was eluted with ethyl acetate/hexane (1:1). The yield was 0.75 g (71%) (m.p.=75°-90° C.): 1H NMR (DMSO-d6, 300 MHz) δ9.30 (t, J=6 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.81 (m, 1H), 7.71 (m, 1H), 7.60 (m, 3H), 7.45 (m, 4H), 7.25 (d, J=8.1 Hz, 2H), 4.80 (d, J=5.8 Hz, 2H), 3.58 (s, 3H); positive FAB MS m/e 404(MH). Anal. calcd for C23H18ClN3O2 : C, 68.40; H, 4.49; N, 10.40. Found: C, 68.09; H, 4.57; N, 10.10.
Reaction SMILES: [CH:1]1([O:6][CH2:7][C:8]([O:10]CC)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[OH-].[K+]>O>[CH:1]1([O:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)COC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)COC1CCCC1
Temperature: 25 °C

Procedure:
The product from Example 133A (2.56 g) was combined with MeOH (10 mL) and 40% aqueous KOH (8 mL) and water (8 mL) were added. The mixture was heated at reflux for 6 hours, and then cooled to room temperature. The mixture was concentrated under vacuum, and the residue was diluted with water (15 mL) and washed with hexanes (20 mL). The aqueous layer was cooled with ice and brought to pH<3 by addition of 10% HCl (30 mL). The resulting mixture was extracted with CH2Cl2 (3×20 mL). The combined extract was concentrated under vacuum to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.52-1.83 (m, 8H) 4.05 (s, 2H) 4.06-4.12 (m, 1H).
Reaction SMILES: O.[OH-].[Li+].[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH2:18][C@@H:17]([N:19]([C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:16][C@H:15]3[C:36]([O:38]C)=[O:37])=[CH:12][C:7]=2[O:6][CH2:5]1.CO>O>[O:4]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH2:18][C@@H:17]([N:19]([C:29](=[O:35])[CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH2:16][C@H:15]3[C:36]([OH:38])=[O:37])=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: COC(=O)[C@@H]1C[C@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(CN(C(=O)CC(C)(C)C)[C@H]2C[C@@H](C(=O)O)N(Cc3ccc4c(c3)OCO4)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Lithium hydroxide monohydrate (17 mg, 0.405 mmol) was added to a solution of methyl(2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]tetrahydro-1H-2-pyrrolecarboxylate (20) (100 mg, 0.20 mmol) in 66% v/v methanol in water (1.0 mL). The mixture was stirred overnight at room temperature, then the solvent was removed under reduced pressure and the residue partitioned between dichloromethane (1.0 mL) and water (1.0 ml). The aqueous phase was acidified with 1.0 M aqueous citric acid solution and the two layers were vigorously stirred for 10 min at room temperature. The layers were separated and the aqueous layer was back-extracted with dichloromethane. The combined dichloromethane extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using dichloromethane/ethyl acetate (1:1, v/v) and then dichloromethane/methanol (9:1, v/v) as eluents to give the title acid (21) (88 mg, 91%) as an off-white solid:
Reaction SMILES: [C:1]([O:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([OH:28])[C:22]([CH3:30])([CH3:29])[CH2:21]1)(=[O:18])[CH2:2][CH2:3][C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([OH:15])[C:9]([CH3:17])([CH3:16])[CH2:8]1)=[O:5].[CH3:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[C:1]([O:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([O:28][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[C:22]([CH3:30])([CH3:29])[CH2:21]1)(=[O:18])[CH2:2][CH2:3][C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([O:15][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[C:9]([CH3:17])([CH3:16])[CH2:8]1)=[O:5]
Reactant: CC1(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CCCCCCCCCCCCCCCCCC
Product: CCCCCCCCCCCCCCCCCCON1C(C)(C)CC(OC(=O)CCC(=O)OC2CC(C)(C)N(OCCCCCCCCCCCCCCCCCC)C(C)(C)C2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of bis(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) succinate and octadecane following a procedure similar to that of Example 4.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[O:16])[CH3:13].CN(CCN(C)C)C.[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH2:12]([NH:14][C:15]([C:17]1[CH:21]=[CH:20][S:19][C:18]=1[Cl:30])=[O:16])[CH3:13]
Reactant: CCNC(=O)c1ccsc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCNC(=O)c1ccsc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (44 mL, 57.2 mmol) was added dropwise to a -78° C. cooled solution of N-ethyl-3-thiophenecarboxamide (4.04 g, 26 mmol) and TMEDA (6.65 g, 57.2 mmol) in THF (100 mL). After stirring for 30 min at -78° C., a solution of hexachloroethane (13.54 g, 57.2 mmol) in THF (20 mL) was added dropwise. The resulting reaction mixture was warmed to RT over 1 h, quenched with dilute aq citric acid, and extracted with EtOAc (3×). The combined organic extracts were dried (MgSO4), concentrated, and purified by HPLC with 3:7 EtOAc/hexanes to give 2.8 g of N-ethyl-2-chloro-3-thiophenecarboxamide as a yellow oil, a 57% yield.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]1[O:8][C:6](=[O:7])[C@H:5]([OH:9])[C@@H:4]([OH:10])[C@@H:3]1[OH:11].[NH2:13][CH2:14][CH2:15][CH2:16][Si:17]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH2:22]([O:21][Si:17]([O:24][CH2:25][CH3:26])([O:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH2:14][NH:13][C:6]([C@@H:5]([C@H:4]([C@@H:3]([C@@H:2]([CH2:1][OH:12])[OH:8])[OH:11])[OH:10])[OH:9])=[O:7])[CH3:23]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCO[Si](CCCNC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)(OCC)OCC

Procedure:
In this work, sol-gel precursors that are based on covalent linkage of D-gluconolactone or D-maltonolactone to aminopropyltriethoxysilane to form N-(3-triethoxysilylpropyl)gluconamide (GLTES-1) or N-(3-triethoxysilylpropyl)maltonamide. (MLTES-2) were prepared. Diglycerylsilane (DGS), GLTES, MLTES and allylgluconamide (allyGL) were prepared by methods described above. For DGS based sol-gel preparations, sols were prepared by sonicating DGS (400 mg, 1.34 mM) and water (1000 L) at 0iC for 45 min to hydrolyze the monomer. The resulting sol was mixed with equal portions of Tricine buffer (25 mM, pH 7.8) containing 5 mM MgSO4, 0.1 mg.mL−1 BSA, 0.5 mM DTT and 0.5 mM EDTA. The buffer also contained either 0.2 M allylGL or a range of concentrations of GLTES or MLTES, respectively, to obtain a sugar/DGS molar ratio of 0.05, 0.1, 0.15, 0.2 or 0.25. Immediately after vortexing the sol, a solution of Firefly luciferase from Photinus pyralis was added at a volume ratio of 30:1 sol:enzyme solution. The sol was very briefly and carefully mixed to obtain a homogeneous solution and was then loaded in portions of 62 L into a 96-well white microplate. The total quantity of protein per well was 200 ng (3 pM). TEOS-derived materials were prepared using a similar procedure, except that DGS was replaced by a TEOS-derived sol that was prepared by sonicating with a diluted hydrochloric acid, as described elsewhere.22 The concentration of the enzyme in all gels was the same. TEOS was also prepared by a procedure in which the hydrolyzed sol containing TEOS was combined with an equal volume of deionized water and rotoevaporated until the volume was reduced to half,70 with the aim of removing the ethanol liberated during the hydrolysis. The obtained sol was then mixed with the buffer solution and the enzyme as described above. Sodium silicate-based gels were prepared from 0.9 mL sodium silicate solution and 4 mL of water. This solution was agitated for 1 min with 2.0 g Dowex 50WX8-100 resin and vacuum filtered consecutively through a filter paper in a Buchner funnel and a 0.45 M membrane filter with the aid of a syringe.71 The resulting sol was then combined with the buffer and the enzymes in the same proportions as for previous sols. In all cases, the plates were covered with Parafilm™ and over each well a small orifice was opened with a syringe in order to allow slow drying of the gel. The gel was aged at 4iC for 5 days forming a glass disk that adhered to the bottom of the wells.
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:14]([O:16][C:17](=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21](Br)[CH:20]=1)[CH3:15]>C1COCC1.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>[CH2:14]([O:16][C:17](=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:20]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(OC)c(Br)c1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OC)c(S[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C

Procedure:
Triisopropylsilanethiol (6.7 mL, 31.2 mmol) was dissolved in THF (75 mL) at 0° C. and sodium hydride (1.25 g, 60% dispersion in mineral oil, 31.3 mmol) was added, then the solution was allowed to warm to room temperature. Meanwhile, (3-bromo-4-methoxy-phenyl)-acetic acid ethyl ester (6.38 g, 23.4 mmol) was dissolved in THF (75 mL) and sparged with N2 (g). The first solution was added to the second and tetrakis(triphenylphosphine)palladium(0) (1.3 g, 1.1 mmol) was also added. The reaction was heated to reflux overnight then treated to standard aqueous workup. The residue was purified by silica gel chromatography (0-10% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH2:5][C:6](=[O:8])[CH3:7])[CH:3]1[CH2:9][CH:10]=O.C[Si]([N:17]([CH3:19])[CH3:18])(C)C>>[CH3:18][N:17]([CH3:19])[CH:10]=[CH:9][CH:3]1[CH:4]([CH2:5][C:6](=[O:8])[CH3:7])[C:2]1([CH3:12])[CH3:1]
Reactant: CN(C)[Si](C)(C)C
Reactant: CC(=O)CC1C(CC=O)C1(C)C
Product: CC(=O)CC1C(C=CN(C)C)C1(C)C
Yield: 86.1 %

Procedure:
To 6.7 g of 2,2-dimethyl-3-(2-oxopropyl)cyclopropylacetaldehyde at 0° C. was added 5.2 g of trimethylsilyldimethylamine over a 5 min period. The resulting product was distilled through a spiral bantamware column to yield 6.7 g of the desired product having a boiling point of 85°-90° at 1 mm Hg.
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:12]#[N:13])=[N:9][C:10]=1[CH3:11]>C(O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([C:12](=[NH:13])[NH:2][NH2:3])=[N:9][C:10]=1[CH3:11]
Reactant: Cc1nc(C#N)ccc1Br
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(C(=N)NN)ccc1Br
Temperature: 50 °C

Procedure:
Hydrazine monohydrate (2 equiv) was added to a stirring 1.2 M suspension of 5-bromo-6-methylpicolinonitrile (1 equiv) in ethanol. The reaction mixture was heated to 50° C. for 24 h. The reaction was cooled to room temperature and filtered. The collected solid was washed with ethanol and t-butyl methyl ether. The solid was dried under vacuum to provide the title compound, as a solid. MS (ESI) m/z 228.9 [M]+, 230.9 [M+2]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([O:13][CH3:14])[C:6]=1[F:15])[CH3:2].[C:17]([O:21][C:22](=[O:29])[NH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:26]2[CH2:27][CH2:28][CH:24]([NH:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:29])[CH2:25]2)=[C:7]([O:13][CH3:14])[C:6]=1[F:15])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(F)c(OC)c1F
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cc(F)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(OC)c1F
Yield: 77.6 %

Procedure:
A solution of 2,4,5-trifluoro-3-methoxybenzoic acid ethyl ester (Example 1f, 2.821 g, 12.05 mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (3.310 g, 17.77 mmol), and triethylamine (9.13 g, 12.6 mL, 90.23 mmol) in acetonitrile (50 mL) is heated at 40° C. under nitrogen for 2 days. The yellow solution is concentrated to near dryness and poured into saturated NaHCO3 solution and extracted with dichloromethane. The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue is purified by flash column chromatography (1:7 ethyl acetate/hexanes) to afford the title compound as a yellow solid (3.743 g). MS EI: m/z 401 (MH+).
Reaction SMILES: [N:1]1([CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1COCC1.[CH3:26][NH2:27]>O>[N:1]1([CH2:14][CH2:15][C:16]([NH:27][CH3:26])=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CCn1cnc2cnc3ccccc3c21
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)CCn1cnc2cnc3ccccc3c21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)propanoate (4.70 g, 17.5 mmol), THF (5 mL), and methylamine (available as a 40% solution in water, 10 mL) was sealed in a high-pressure vessel, stirred at 100° C. overnight, and concentrated under reduced pressure to provide 4.4 g of 3-(1H-imidazo[4,5-c]quinolin-1-yl)-N-methylpropanamide.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[CH:14]1([CH:17]([N:25]([CH2:29][CH2:30][CH3:31])[C:26]([NH2:28])=[S:27])[C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:28]=[C:26]([N:25]([CH:17]([CH:14]2[CH2:16][CH2:15]2)[C:18]2[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=2)[CH2:29][CH2:30][CH3:31])[S:27][C:2]=1[CH3:13]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCCN(C(N)=S)C(c1ccc(Br)cc1)C1CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(Br)cc1)C1CC1
Temperature: 65 °C

Procedure:
14 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone (Compound 1), 17.1 g of N-(α-cyclopropyl-4-bromobenzyl)-N-propylthiourea (Compound 64) and 7.6 ml of triethylamine are dissolved in 200 ml of ethanol and the solution is heated to 65° C. The reaction is monitored by TLC. At the end of the reaction, the ethanol is removed and the residue is hydrolysed with water and extracted with methylene chloride. The organic phases are washed and dried. The product is purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (20:1 v/v) as eluent.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O:21][CH2:22][CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:20])[NH:18][NH2:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:17]([NH:18][NH:19][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)NNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A 250 ml round bottom flask was charged with 4.190 g (0.0181 mol) of N-BOC-6-aminocaproic acid, 4.60 g of 9-fluorenylmethyl carbazate (FMOC), (prepared by the method of Carpino et. al., 1972, J. Org. Chem., 37: 3404) and 35 ml of N,N-dimethylformamide. The reaction solution was cooled to 0° C. and then 3.75 g (0.0182 mol) of 1,3-dicyclohexylcarbodiimide (Aldrich) was added. The reaction mixture was allowed to stir for 2 h at 0° C. The white precipitate which formed during this time was filtered off and the solvents evaporated under reduced pressure. The distillation residue was applied to a 225 cc pad of silica gel (Merck), which was then washed with 1L of chloroform. The product was then eluted from the column using 1 L of 50% methanol in chloroform. The solvents were evaporated from the desired eluent fractions to give 4.98 g (0.011 mol, 59% yield) of N-BOC-6-aminocaproic acid (N'-FMOC-hydrazide) as a yellow oil. 1H NMR (DMSO-d6) showed the peaks observed in the starting material and new protons in the aromatic region between 7-8 ppm (FMOC group).
Reaction SMILES: [F:1][C:2]([F:28])([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([F:27])=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13](O)=[O:14])[C:8]([Cl:11])=[CH:9][CH:10]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:56][CH2:57][C:58]1[CH:59]=[CH:60][C:61]([NH:65][C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])=[N:62][C:63]=1[CH3:64].CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:2]([F:1])([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([F:27])=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:56][CH2:57][C:58]2[C:63]([CH3:64])=[N:62][C:61]([NH:65][C:66]([O:68][C:69]([CH3:71])([CH3:70])[CH3:72])=[O:67])=[CH:60][CH:59]=2)=[O:14])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)OC(C)(C)C)ccc1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccc(F)c3ccccc23)c1F
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of 2-(3-{[2,2-difluoro-2-(4-fluoronaphthyl)ethyl]amino}-6-chloro-2-fluorophenyl)acetic acid (15 mg, 37 μmol), as prepared according to the procedure of step 10 of Example 4, in DMF (0.3 mL) was added BOP (26 mg, 58 μmol), N-[5-(aminomethyl)-6-methyl(2-pyridyl)](tert-butoxy)carboxamide (12 mg, 51 μmol), and a solution of DIEA (19 mg, 146 μmol) in DMF (0.1 mL) (Sanderson, P. E., et al., WO 97/01338 (1997)). The mixture was stirred overnight, the solvents evaporated, and the resulting mixture was partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with 10% KHSO4, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0.3, 0.6, and 1%) to give the title compound (11 mg, 49% yield) as a white solid. 1H-NMR (400 MHz, CD3OD) δ 8.33 (d, J=8.4 Hz, 1H), 8.17-8.14 (m, 1H), 7.72-7.61 (m, 4H), 7.55 (d, J=8.5 Hz, 1H), 7.19 (dd, J=10.0, 8.3 Hz, 1H), 6.81 (dd, J=8.8, 1.7 Hz, 1H), 6.47 (t, J=9.1 Hz, 1H), 4.32 (s, 2H), 4.12-4.03 (m, 2H), 3.67 (d, J=2.0 Hz, 2H), 2.40 (s, 3H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calc'd for C32H32ClF4N4O3 (M+H): 631.2. Found: 631.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:11](C1C2C=CC=C(Br)C=2SC=1)(=[O:13])[CH3:12]>>[C:11]([C:7]1[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[S:9][CH:8]=1)(=[O:13])[CH3:12]
Reactant: Brc1ccc2sccc2c1
Reactant: CC(=O)c1csc2c(Br)cccc12
Product: CC(=O)c1csc2ccc(Br)cc12
Yield: 70 %

Procedure:
Prepared in 70% yield from 5-bromo-benzothiophene (See Ple, P. A.; Marnett, L. J. J. Heterocycl. Chem., vol. 25, pp. 1271-1272 (1988), incorporated herein by references), analogous to the procedure for the preparation of 3-acetyl-7-bromo-benzo[b]thiophene. 1H NMR (300 MHz, CDCl3) δ8.04 (d, H. J=1.8Hz), 7.86 (s, 1H), 7.74 (d, 1H, J=8.4Hz), 7.56 (dd, 1H, J=8.4, 1.8Hz), 2.67 (s, 3H). Anal. (C10H7BrOS) C, H, Br, S. Calculated C=47.07, H=2.77, Br=31.32, S=12.57; found C=47.18, H=2.76, Br=31.42, S=12.55.