Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:19]([CH3:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:22][CH2:23][C:24]([CH2:33]O)([CH2:29][N:30]=[N+:31]=[N-:32])[CH2:25][N:26]=[N+:27]=[N-:28].N(CC1(CN=[N+]=[N-])COC(CCCCCCCCCC)(C)OC1)=[N+]=[N-]>>[N:30]([CH2:29][C:24]1([CH2:25][N:26]=[N+:27]=[N-:28])[CH2:23][O:22][C:19]([CH3:21])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:20][CH2:33]1)=[N+:31]=[N-:32]
Reactant: CCCCCCCCCCCCCCCCCCC(C)=O
Reactant: [N-]=[N+]=NCC(CO)(CO)CN=[N+]=[N-]
Agent: CCCCCCCCCCC1(C)OCC(CN=[N+]=[N-])(CN=[N+]=[N-])CO1
Product: CCCCCCCCCCCCCCCCCCC1(C)OCC(CN=[N+]=[N-])(CN=[N+]=[N-])CO1

Procedure:
The following compound was prepared analogously as described in Example 9, starting from methyl octadecyl ketone and compound 1. 5,5-Bis-(azidomethyl)-2-decyl-2-methyl-1,3-dioxane (compound 17).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[C:15](OCC)(OCC)(OCC)[CH2:16][CH3:17]>>[Cl:1][C:2]1[C:11]2[N:10]([C:15]([CH2:16][CH3:17])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2
Reactant: NNc1nc2cc(Cl)ccc2nc1Cl
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nnc2c(Cl)nc3ccc(Cl)cc3n12
Temperature: 25 °C
Yield: 62 %

Procedure:
2,6-Dichloro-3-hydrazinoquinoxaline (1.0 g., 0.0044 mole), the product of Preparation L(a), was refluxed with 15 ml. of triethyl orthopropionate for 4 hours and cooled to room temperature. The precipitate was recovered by filtration, washed with cyclohexane and air dried to afford 730 mg. (62% yield) of 4,8-dichloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >250° C. Mass spectrum: m/e, 266 (P); m/e, 268 (P+2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])/[CH:5]=[CH:6]/[C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([C:16]3[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:24][CH3:25])[CH:14]=2)[N:9]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([C:16]3[C:21]([CH2:22][CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:24][CH3:25])[CH:14]=2)[N:9]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cn(-c2ccc(C(C)C)cc2)c2cnc(-c3c(CC)cccc3CC)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (E)-3-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-acrylic acid ethyl ester (140 mg, 0.3 mmol) and 10% Pd/C (20 mg) in EtOH (4 mL) is stirred under hydrogen (1 atm) for 18 hour at room temperature. The mixture is filtered over celite and concentrated under reduced pressure to afford 3-[5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-propionic acid ethyl ester as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[OH-].[K+:34].CC(C)=O.O>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([O-:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[K+:34]
Reactant: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c([O-])c(=O)n2C)o1

Procedure:
Hydrated crystalline form 2 is prepared by sonicating a mixture of raltegravir, KOH, acetone and trace amount of water whereas anhydrous crystalline form 3 is obtained by crystallization of amorphous raltegravir potassium from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][C:13](=[O:15])[O:12][C:10](=[O:11])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([OH:24])[CH:18]=1>ClCCl>[OH:24][C:19]1[CH:18]=[C:17]([Cl:16])[CH:23]=[CH:22][C:20]=1[NH:21][C:13](=[O:15])[CH2:14][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: Nc1ccc(Cl)cc1O
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Solvent: ClCCl
Product: O=C(O)CC(CC(=O)Nc1ccc(Cl)cc1O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
Prepared by refluxing an equimolar mixture of 3-(4-chlorophenyl)glutaric anhydride and commercial 4-chloro-2-hydroxyaniline in dichloromethane for 0.5 h. After cooling to rt the precipitated product is isolated by suction filtration, washed, and dried to provide 90% of N-(2-hydroxy-4-chlorophenyl)-3-(4-chlorophenyl)glutaramic acid as light red crystals.
Reaction SMILES: ClC1C(Cl)=CN=C([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH:32]=[N:31][N:30]=[N:29]5)=[CH:24][CH:23]=4)[N:19]=3)[CH2:11][CH2:10]2)N=1.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>>[CH2:37]([O:36][C:34]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[N:31][N:30]=[N:29]4)=[CH:24][CH:23]=3)[N:19]=2)[CH2:11][CH2:10]1)=[O:35])[CH:38]=[CH2:39]
Reactant: C=CCOC(=O)Cl
Reactant: Clc1cnc(N2CCC(c3nc(COc4ccc(-n5cnnn5)cc4)cs3)CC2)nc1Cl
Product: C=CCOC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1

Procedure:
Example 209 was prepared from 4-[4-(4-Tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidine (Intermediate 4) and allyl chloroformate in a manner similar to that described in Example 22. 1H NMR (CDCl3): δ 8.96 (1H, s), 7.63 (2H, m), 7.20 (1H, s), 7.18 (2H, m), 5.96 (1H, m), 5.31 (1H, m), 5.22 (3H, m), 4.61 (2H, m), 4.29 (2H, m), 3.21 (1H, m), 2.97 (2H, m), 2.15 (2H, m), 1.78 (2H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=3)[N:9]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[C:30]([Cu])#[N:31].[CH3:33][NH:34]C.O>CN(C)C=O>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([N:9]2[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]#[N:34])=[CH:3][CH:4]=3)[CH2:12][CH2:11][CH:10]2[C:13]2[CH:18]=[CH:17][C:16]([C:30]#[N:31])=[CH:15][CH:14]=2)=[CH:21][CH:22]=1)([CH3:28])([CH3:29])[CH3:27]
Reactant: N#C[Cu]
Reactant: CC(C)(C)c1ccc(N2C(c3ccc(Br)cc3)CCC2c2ccc(Br)cc2)cc1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(N2C(c3ccc(C#N)cc3)CCC2c2ccc(C#N)cc2)cc1
Yield: 50 %

Procedure:
A mixture of Example 42C (1.0 g, 1.948 mmol) and CuCN (523 mg, 5.84 mmol) in Dimethylformamide (9.5 mL) was heated to 160° C. for 4.5 hours in a microwave. Mixture was poured into a dimethylamine/H2O mixture (1/10) and extracted with EtOAc (3×150 mL). The combined organics were washed with H2O and Brine. The organic was then dried (MgSO4), filtered and concentrated. Purification by chromatography (silica gel, 20% EtOAc in Hexanes) afforded 395 mg (50%) of the title compound. MS (ESI) m/z 406 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:44][N:43]=[C:42]([CH:45]=[CH2:46])[CH:41]=1)CCC.O>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:44][N:43]=[C:42]([CH:45]=[CH2:46])[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cc([Sn](CCCC)(CCCC)CCCC)sn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (80 mg, 0.160 mmol), 5-(tributylstannyl)-3-vinylisothiazole (96 mg, 0.240 mmol), and tetrakis(triphenylphosphine)palladium(0) (93 mg, 0.080 mmol) in toluene (4.0 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was subsequently poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and were concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid, which was used without further purification (81.3 mg, 88%). ESI-MS m/z [M+H]+ calc'd for C28H36FN5O5S, 574. found, 574.
Reaction SMILES: C(OC([NH:8][N:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>>[C:18]([N:9]([C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH2:8])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)N(N)C(=O)c1ccccc1
Yield: 86.7 %

Procedure:
The N-t-butoxycarbonyl-N'-t-butyl-N'-benzoylhydrazine (52 g, 0.18 mol) was stirred at room temperature in a methanolic hydrochloric acid solution for 4 days. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate. The white precipitate was filtered, washed with water and dried in vacuo to give 30 g of N'-t-butyl-N'-benzoylhydrazine. m.p. 124-125° C.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[CH2:15][OH:16].[Br:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20](F)[CH:19]=1>O1CCCC1>[Br:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([O:16][CH2:15][C:9]2[C:8]([F:7])=[CH:13][CH:12]=[CH:11][C:10]=2[F:14])[CH:19]=1
Reactant: OCc1c(F)cccc1F
Reactant: Fc1cc(Br)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1cccc(F)c1COc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
15.5 ml (15.5 mmol) of a 1 M solution of potassium tert-butoxide in tetrahydrofuran was added dropwise at 0° C. to a solution of 1.72 ml (15.5 mmol) of (2,6-difluorophenyl)methanol and 1.6 ml (15.5 mmol) of 4-bromo-2-fluoropyridine in 50 ml of anhydrous tetrahydrofuran. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was removed and washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel (40 g silica gel cartridge, mobile phase: cyclohexane/ethyl acetate, gradient 0% to 100%). This gave 4.12 g of the target compound (88% of theory).
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:20])[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C([O-])(=O)C.[Na+].O>[CH2:1]([NH:11][C:12]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:21](=[O:23])[CH3:22])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCNC(=O)CCCOCCO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCNC(=O)CCCOCCOC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
In a glass reaction vessel 17.7 grams (0.0616 mole) of N-decyl-4-(2-hydroxyethoxy)butyramide was admixed with 25.3 grams (0.25 mole) of acetic anhydride in the presence of 4 grams sodium acetate catalyst. This mixture was heated to 100° C. on a steam bath until a reaction was completed within a period of 3 hours. The mixture was then drowned in water, salted out and phase separated. The upper liquid phase was dried to 17.8 grams of liquid product having a refractive index η d25 =1.4586 and an IR of 6.09 mu.
Reaction SMILES: BrC(C)C([C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)C(OC)=O.CC[O:27]CC.[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:31][C:32]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:23])([C:15]([F:16])([F:18])[F:17])[C:19]([F:21])([F:22])[F:20])=[CH:12][CH:13]=1)=[CH:33][C:34]([OH:30])=[O:27]
Reactant: C1CCOC1
Reactant: COC(=O)C(c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)C(C)Br
Reactant: CCOCC
Product: CC(=CC(=O)O)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
To a solution of methyl 3-bromo-3-methyl-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}propanoate in tetrahydrofuran can be added an equivalent amount of 1,5-diazabicyclo[3.4.0]nonene-5. The resulting reaction mixture can be stirred at elevated temperature until thin layer chromatographic analysis of a reaction sample indicates the reaction to be complete. The solvent can be removed and the residual oil dissolved in ether to obtain an ether solution which can be extracted with 1N hydrochloride acid and then by 2N sodium hydroxide solution. The resulting sodium hydroxide solution can be heated on the steam bath, cooled and made acidic with concentrated hydrochloric acid to obtain a product which can be isolated from the aqueous phase with ether. The resulting ether solution can be dried with anhydrous magnesium sulfate, filtered, and evaporated to give 3-methyl-3-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-2-propenoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][O:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:45][CH2:46][CH2:47][CH2:48][CH2:49][N:50]1[C:62]2[C:61]3[CH:60]=[CH:59][C:58]([C:63]4[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=4)=[CH:57][C:56]=3[N:55]=[C:54]([NH2:69])[C:53]=2[N:52]=[C:51]1[CH2:70][O:71][CH2:72][CH3:73]>C(Cl)(Cl)Cl.CC(N(C)C)=O>[NH2:69][C:54]1[C:53]2[N:52]=[C:51]([CH2:70][O:71][CH2:72][CH3:73])[N:50]([CH2:49][CH2:48][CH2:47][CH2:46][NH:45][C:11](=[O:12])[C:10]3[CH:9]=[CH:8][C:7]([CH:6]([O:5][CH2:4][CH2:3][N:2]([CH3:22])[CH3:1])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:15][CH:14]=3)[C:62]=2[C:61]2[CH:60]=[CH:59][C:58]([C:63]3[CH:64]=[N:65][CH:66]=[CH:67][CH:68]=3)=[CH:57][C:56]=2[N:55]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCN
Reactant: CN(C)CCOC(c1ccccc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCNC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A mixture of 4-[(2-dimethylaminoethoxy)phenylmethyl]benzoic acid (0.433 g) and 1-hydroxybenzotriazole (0.196 g) in chloroform (7 mL) was cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.277 g) was added in small portions over a 2 minute period. The mixture was stirred for 1 hour and then added dropwise to a chilled (0° C.) solution of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1 H-imidazo[4,5-c]quinolin-4-amine (0.400 g) in anhydrous dimethylacetamide (7 mL). The cooling bath was removed and the reaction was stirred for an additional 16 hours. Water was added and the mixture was made acidic by the addition of 4N hydrochloric acid. The aqueous fraction was extracted with diethyl ether (3×) to remove the dimethylacetamide. Sodium hydroxide (10% in water) was added to make the aqueous fraction basic and the aqueous fraction was subsequently extracted with multiple portions of dichloromethane. The organic fractions were combined, washed sequentially with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using a gradient of CMA/chloroform as the eluent. A final recrystallization from acetonitrile provided 0.426 g of N-[4-(4-amino-2-ethoxymethyl-7-(pyridin-3-yl)imidazo[4,5-c]quinolin-1-yl)butyl]-4-[(2-dimethylaminoethoxy)phenylmethyl]benzamide as a white crystalline solid, mp 157.0–161.0° C.
Reaction SMILES: N(OC(C)(C)C)=O.[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([Cl:19])[C:10]=1[N:20]1[C:24]([Cl:25])=[C:23]([C:26]#[N:27])[C:22]([S:28][C:29]([F:32])([F:31])[F:30])=[C:21]1N.[ClH:34].[C:35](#[N:38])[CH:36]=[CH2:37]>C(#N)C>[Cl:19][C:11]1[CH:12]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:14]=[C:9]([Cl:8])[C:10]=1[N:20]1[C:24]([Cl:25])=[C:23]([C:26]#[N:27])[C:22]([S:28][C:29]([F:30])([F:31])[F:32])=[C:21]1[CH2:37][CH:36]([Cl:34])[C:35]#[N:38]
Reactant: N#Cc1c(SC(F)(F)F)c(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Reactant: Cl
Reactant: C=CC#N
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#Cc1c(SC(F)(F)F)c(CC(Cl)C#N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
To a suspension of 2.90 g (21.6 mmoles) of cupric chloride in a mixture of 20 mL of acetonitrile and 40 mL of acrylonitrile was added 2.73 mL (2.37 g, 23.0 mmoles) of t-butyl nitrite. The resulting black solution was cooled to 0° C., and a solution of 6.66 g (14.7 mmoles) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-amino-3-trifluoromethylthio-4-cyano-5-chloropyrrole prepared according to EXAMPLE 8 in 25 mL of acetonitrile was added dropwise and with stirring over a period of 20 minutes. The mixture was allowed to stir for 4 hours at room temperature and was then poured into 400 mL of 1N aqueous HCl and partitioned successively with dichloromethane and water. The organic extracts were dried over anydrous MgSO4 and concentrated. The residual brown oil was chromatographed on silica gel eluting initially with 2:1 and then 1:1 v/v dichloromethane-hexane to give 5.30 g (69%) of 1 -(2,6-dichloro-4-trifluoromethylphenyl)-2-(2-chloro-2-cyanoethyl)-3-trifluoromethylthio-4-cyano-5-chloropyrrole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[I-].[Na+]>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCCCN1CCOCC1
Yield: 98.1 %

Procedure:
A mixture of 1 g (2.38 mmol) of 4-(4-Chloro-2-fluoro-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile, 3.1 g (35.7 mmol) of morpholine, and 0.07 g of sodium iodide in 20 ml ethylene glycol dimethyl ether refluxed for 7 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and ether-hexane was added. One standing, the crystals were deposited giving 1.1 g of the title compound as a off-white solid: mass spectrum (electrospray, m/e) M+H 470.9.
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]1[O:20][CH2:19]1>O1CCCC1>[C:6]1([S:12]([C:15]([CH3:17])([CH3:16])[CH2:19][CH2:18][OH:20])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CCO)S(=O)(=O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of n-butyllithium in cyclohexanes (1.8M, 35.1 ml; 63.18 mmol) was added dropwise to a stirred solution of isopropyl phenyl sulphone (9.95 g, 54 mmol) in tetrahydrofuran (100 ml) keeping the temperature of the mixture below −60° C. The mixture was stirred for 30 min. and ethylene oxide was passed through the reaction mixture for 10 min. The mixture was warmed up to −40° C. for 30 min., then quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified on silica gel (i-hexane:ethyl acetate) to give the title compound (12.3 g, 99%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][C:36]([OH:38])=O)[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.[CH:41]([NH2:44])([CH3:43])[CH3:42].C(OCC)(=O)C>CN(C)C=O>[F:13][C:14]1[CH:40]=[CH:39][C:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][C:36](=[O:38])[NH:44][CH:41]([CH3:43])[CH3:42])[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1
Reactant: CC(C)N
Reactant: O=C(O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
Under ice cooling, 1,1′-carbonyldimidazole (15 g) was added to a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-carboxymethylindoline (30 g) in dimethylformamide (240 ml) and the resultant mixture was stirred for 2 hr. After adding isopropylamine (5.6 g), the mixture was warmed to room temperature and then stirred for additional 2 hr. Next, ice water (240 ml) and ethyl acetate (300 ml) were added to the reaction solution and the layers were separated. The organic layer was washed successively with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in hot ethyl acetate (80 ml). After allowing to cool to room temperature, the resulting crystals were collected by filtration to give the title compound (17.2 g) as a white powder (yield: 52%).