Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([C:14](=O)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]([O:11]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:24]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[S:25]([C:28]1[CH:29]=[N:30][C:31]([NH:34][NH2:35])=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH3:23].C([O-])(=O)C>>[CH2:1]([C:8]1[C:9](=[O:11])[N:34]([C:31]2[CH:32]=[CH:33][C:28]([S:25](=[O:27])(=[O:26])[N:24]([CH2:22][CH3:23])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:29][N:30]=2)[NH:35][C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: CCN(c1ccccc1)S(=O)(=O)c1ccc(NN)nc1
Agent: CC(=O)[O-]
Product: CCOC(=O)Cc1[nH]n(-c2ccc(S(=O)(=O)N(CC)c3ccccc3)cn2)c(=O)c1Cc1ccccc1

Procedure:
According to the process described in Example 1.3, starting with 5 g (17.1 mmol) of diethyl 2-benzyl-3-oxopentanedioate and 5 g (17.1 mmol) of N-ethyl-6-hydrazino-N-phenylpyridine-3-sulfonamide, 3 g of ethyl 4-benzyl-1-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)acetate are obtained in the form of a white powder.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[CH:14]1([CH2:19][C:20](=O)[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1.[Cl-].[Na+].O>[CH:14]1([CH2:19]/[C:20](/[CH3:21])=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(=O)CC1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C(\C)CC1CCCC1
Temperature: 0 °C
Yield: 99 %

Procedure:
To a suspension of sodium hydride (956 mg, 60% in oil, 23.9 mmol) in THF (60 mL) cooled at 0° C. was added dropwise trimethyl phosphonoacetate (3.87 mL, 4.35 g, 23.9 mmol). The mixture was stirred for 20 mn at 0° C. and cyclopentylacetone (2.22 mL, 2.00 g, 15.9 mmol) was added dropwise. The solution was warmed to 25° C., then refluxed for 2 h, and poured in a solution of brine (100 mL). The reaction mixture was extracted with ethyl acetate (2×50 mL) and the combined organic phase was dried over sodium sulfate and concentrated to give the ester (2.87 g, 99%) as a mixture of E and Z isomers 3:1. MS (m/z) 182 (M).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]1[CH:41]=[C:42]([CH:45]=[CH:46][CH:47]=1)[CH2:43][NH2:44]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:44][CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[C:40]([CH3:39])[CH:41]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: Cc1cccc(CN)c1
Product: Cc1cccc(CNC(=O)c2ccc(Sc3ccc(NC(=O)OC(C)(C)C)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)c1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and m-methylbenzylamine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=O)(C)(C)C.S(Cl)(Cl)=O.[CH3:21]O>>[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]([O:16][CH3:21])=[O:15]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1COCCN1
Temperature: 25 °C

Procedure:
To a solution of (R)-morpholine-3,4-dicarboxylic acid-4-tert-butyl ester (5.00 g, 21.6 mmol) in MeOH (54 mL) was added thionyl chloride (3.16 mL, 43.2 mmol) dropwise, and the resulting mixture was heated at reflux for 16 h. The solution was cooled to ambient temperature and concentrated in vacuo. The residue was made basic with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)C=CC=CC=1.[H-].[Na+].[CH2:35]([N:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CS(C)=O>[CH2:35]([N:42]1[CH2:47][CH2:46][C:45](=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=2)[CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)Oc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: FC(F)(F)Oc1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Triphenyl-(4-trifluoromethoxybenzyl) phosphonium bromide (21.6 g, 41.75 mmol) was dissolved in DMSO (110 ml), to which sodium hydride (1.82 g, 45.52 mmol) was added, and the mixture was stirred for 30 minutes. 1-Benzyl-4-piperidone (7.18 g, 37.96 mmol) was added to the mixture, and the resulting mixture was stirred at 60° C. for 2 hours. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) to afford 1-benzyl-4-(4-trifluoromethoxybenzylidene)piperidine (9.75 g, yield 74%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].CS(O[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc([N+](=O)[O-])c2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A round-bottom flask was charged with 2-amino-3-nitrophenol (10.64 g, 60 mmol, commercially available from Aldrich), tert-butyl 4-(methylsulfonyloxy)-piperidine-1-carboxylate (18.05 g, 66 mmol, commercially available from AnandChem Ltd.,), DMA (100 mL) and cesium carbonate (21.6 g). The mixture was stirred at room temperature overnight. The mixture was filtered, and the recovered solid was washed with ethyl acetate. The filtrate was further diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and combined organic solvent was washed with saturated brine, dried and concentrated under reduced pressure. The residue was triturated with ether to give tert-butyl 4-(2-amino-3-nitrophenoxy)piperidine-1-carboxylate (8.0 g, 56% yield). MS (EI): 338 (MH+).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[CH2:14]([O:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:15]>C(OCC)C>[CH2:14]([O:16][C:17]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[C:18]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:15]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCCCC#COCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCC1=C(OCC)C(C)(C)C1=O
Reaction time: 96 h
Yield: 61 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et al, [J. Org. Chem, 38, 1451-1455, (1973)]; triethylamine (22 ml) was added dropwise at room temperature to a well-stirred solution of isobutyryl chloride (7.3 ml, 69 mmol) and 1-ethoxy-1-octyne [prepared according to the method of Kocienski, P. et al. Tetrahedron Lett. 1833, 30, (1989)] (6.5 g, 63 mmol) in diethylether (100 ml). The reaction was warmed to 35° and stirred for 96 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80:EtOAc 20) to give the title compound as a brown oil (8.6 g, 38 mmol, 61%). δH (CDCl3, 300K) 4.34 (2H, d, J 7.1 Hz), 2.05 (2H, dd, J 5.6 Hz, 7.3 Hz), 1.44 (3H, t, J 7.1 Hz), 1.27-1.12 (8H, m), 1.23 (6H, s), 0.89 (3H, t, J 2.7 Hz). m/z (ES+, 70V) 225.0 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:9]1[CH:13]([O:14][Si](C(C)(C)C)(C)C)[CH2:12][N:11]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:10]1)[C:5](=[O:8])[CH2:6]Cl.NCCN(C1C(O)CN(C(=O)C2C=CC(Cl)=CC=2)C1)C(=O)CCl.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([N:11]2[CH2:12][CH:13]([OH:14])[CH:9]([N:4]3[CH2:3][CH2:2][NH:1][CH2:6][C:5]3=[O:8])[CH2:10]2)=[O:30])=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2ccc(Cl)cc2)CC1N(CCN)C(=O)CCl
Agent: NCCN(C(=O)CCl)C1CN(C(=O)c2ccc(Cl)cc2)CC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCNCC2=O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of N-(2-amino-ethyl)-N-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-2-chloro-acetamide and N-(2-amino-ethyl)-2-chloro-N-[1-(4-chloro-benzoyl)-4-hydroxy-pyrrolidin-3-yl]-acetamide (200 mg) was dissolved in 2 mL of DMF. Then K2CO3 (117 mg, 0.84 mmol) and Cat. KI were added. The mixture was stirred at 90° C. for overnight. EtOAc (5 mL) was added. The organic phase was washed with Sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Methanol:Et3N:3:1:0.04) to give the desired product (50 mg, 37% yield) as a colorless oil. MS (ESI), M/Z, 324 (M+1). Retention time: 1.13 min (FA-polar).
Reaction SMILES: [N+:1]([C:4]1[C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][C:7](=[O:18])[N:6]2[CH2:19][CH2:20][S:21][C:5]=12)([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[C:27]([I:29])[CH:26]=[CH:25][C:24]=1[NH2:30].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:22][C:23]1[CH:28]=[C:27]([I:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[S:21][CH2:20][CH2:19][N:6]2[C:7](=[O:18])[CH:8]=1
Reactant: Nc1ccc(I)cc1F
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2n1CCS2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n1CCS2
Yield: 12.2 %

Procedure:
Trifluoro-methanesulfonic acid 8-nitro-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridin-7-yl ester (0.6 g, 1.7 mmol) was reacted with 2-fluoro-4-iodo-phenylamine (0.45 g, 1.9 mmol), Pd(OAc)2 (38 mg, 0.17 mmol), BINAP (0.1 g, 0.17 mmol) and cesium carbonate (0.84 g, 2.6 mmol) in toluene (20 mL) at reflux for 3 hours to afford the crude product. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 90 mg of the product (12% yield).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[F:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:8]=[C:7]([CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Nc1ccc(Cc2ccncc2)cc1Br
Product: Nc1ccc(Cc2ccncc2)cc1-c1ccc(F)c(Cl)c1

Procedure:
2-bromo-4-(4-pyridylmethyl)aniline and 3-chloro-4-fluorobenzene boronic acid were combined to form 2-(3-chloro-4-fluorophenyl)-4-(4-pyridylmethyl)aniline,
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[CH:13](NC(=O)CC3SC=CC=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])=[O:2].[C:24]1([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N+]=[N-])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH:30]([O:11][C:9]([C:8]1[N:7]2[C:12](=[O:23])[CH2:13][C@H:6]2[S:5][CH2:4][C:3]=1[CH:1]=[O:2])=[O:10])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C[C@H]2SC1
Reaction time: 0.5 h
Yield: 130 %

Procedure:
To a stirred solution of 3.5 g of 3-formyl-7-thienylacetamido-3-cephem-4-carboxylic acid in 100 ml of tetrahydrofuran is added 2.3 g of diphenyldiazomethane, and the stirring is continued for 30 min. The solvent is distilled off under reduced pressure, and the residue is washed with petroleum ether to give 4.9 g of the corresponding 3-formyl-3-cephem-4-carboxylic acid benzhydryl ester.
Reaction SMILES: [CH:1]([C:4]1[C:9]([OH:10])=[C:8]([N+:11]([O-])=O)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[NH2:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:9]=1[OH:10]
Reactant: CC(C)c1cccc([N+](=O)[O-])c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1cccc(N)c1O
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of 6-isopropyl-2-nitrophenol (3.000 g, 16.56 mmol) and sodium hydrosulfite (11.53 g, 66.23 mmol) in ethanol (180 mL) and water (90 mL) was stirred at 80° C. for 20 h and then cooled to room temperature. The resulting orange solution was concentrated and then partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was separated and washed with brine (25 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 2-amino-6-isopropylphenol as an orange solid (1.792 g, 72%). RP-HPLC Rt 8.171 min, 92% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); m/z 150 (M−H)−.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH2:11]([O:13][C:14](=[O:29])[CH:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:12]>CC(C)=O>[CH2:11]([O:13][C:14](=[O:29])[CH:15]([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCCCCCCCCC(Br)C(=O)OCC
Solvent: CC(C)=O
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Reaction time: 60 h

Procedure:
153 g (1.1 mol) of p-nitrophenol, 1.3 liters acetone and 336 g (1.0 mol) of ethyl-α-bromo-tetradecanoate were placed in a 5-liter 3-necked flask and heated on a steam bath with stirring, for 60 hours. The product was filtered to remove inorganic salt and then the acetone was distilled off under vacuo. The residual oil was taken up in hexane, filtered, and concentrated under vacuo. Yield of Intermediate I was 361 g. TLC Analysis (benzene) showed only one spot, indicating a single product.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:17]([S:21](Cl)(=[O:23])=[O:22])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl.CCOC(C)=O>[CH2:17]([S:21]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:23])=[O:22])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution at ambient temperature of phenethylamine (200 mg, 1.65 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.35 mL, 2.48 mmol) and butanesulfonyl chloride (0.24 mL, 1.82 mmol). After 4 hours of stirring at ambient temperature, the reaction was diluted with EtOAc and washed with water, 1.0M NaHCO3, and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH2:35][C:36]([F:39])([F:38])[F:37])(=O)=O>CC#N.CN(C=O)C>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:35][C:36]([F:39])([F:38])[F:37])[C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a solution of ethyl 5-[(phenylmethyl)oxy]-1H-indole-2-carboxylate (0.3 g, 1 mmol) in 3:2 MeCN/DMF (5 mL) was added Cs2CO3 (0.36 g, 1.1 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.26 g, 1.1 mmol). The mixture was stirred at rt, under N2, for 4 h. Additional Cs2CO3 (0.033 g, 0.1 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.023 g, 0.1 mmol) were added and stirring was continued at rt for 15 h. The mixture was partitioned between Et2O and 0.05N HCl. The organic phase was washed with 0.05N HCl and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc-hexanes gradient) to afford the title compound (0.23 g, 61% yield): 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=7.1 Hz, 2H), 7.38 (t, J=7.1 Hz, 2H), 7.34-7.29 (m, 3H), 7.16-7.13 (m, 2H), 5.28 (q, J=8.5 Hz, 2H), 5.10 (s, 2H), 4.37 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).
Reaction SMILES: C[O-].[Na+].C([S:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])(=O)C.[CH:21]1[C:26]([C:27]([CH2:29]Br)=[O:28])=[CH:25][CH:24]=[C:23]([F:31])[CH:22]=1>C(O)C>[F:31][C:23]1[CH:24]=[CH:25][C:26]([C:27]([CH2:29][S:7][CH2:8][CH2:9][N:10]2[C:11](=[O:20])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]2=[O:19])=[O:28])=[CH:21][CH:22]=1
Reactant: CC(=O)SCCN1C(=O)c2ccccc2C1=O
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CSCCN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
0.803 kg (14.8M) sodium methoxide in 16 1 of ethanol is added to a stirred solution of 3.7 kg (14.8M) 2-(acetylthioethyl)-1,3-isoindoledione in 29.2 1 ethanol at 0° . The temperature is maintained between 0°-5° and the reaction mixture is stirred for one hour. 3.23 kg (14.8M) a-bromo-4-fluoroacetophenone in 14.6 1 of ethanol is added at such a rate to maintain the temperature between 0° and 10° . The reaction mixture is stirred overnight at room temperature. The product is collected by filtration, washed with ethanol and ether and dried. M.P. 123.5°-125.5°.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.O[N:25]1[C:29]2C=CC=[CH:33][C:28]=2N=N1.Cl.CN(C)CCCC(N=C=N)C.C(N)C=C>C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[CH2:29]([NH-:25])[CH:28]=[CH2:33]
Reactant: On1nnc2ccccc21
Agent: CC(CCCN(C)C)N=C=N
Agent: Cl
Agent: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: C=CCN
Solvent: O
Solvent: ClCCl
Product: C=CC[NH-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, Cbz-Phe-OH (1.00 g, 3.35 mmol) was dissolved in 10 mL of anhydrous methylene chloride containing 1-hydroxybenzotriazole monohydrate (0.57 g, 3.69 mmol) and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (0.71 g, 3.69 mmol) and stirred at ice bath temperature for 1.5 hour. Allylamine (0.19 g, 3.35 mmol) was added and the solution was stirred at 0° C. for 5 hours and then allowed to warm to ambient temperature overnight. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with saturated aqueous KHSO4, water, saturated aqueous sodium bicarbonate, water, and brine, prior to drying and evaporation. Recrystallization from ethyl acetate/hexane afforded 0.56 g (50% yield) of the title compound as a white solid product; 1H NMR (CDCl3) δ3.03 (dd, J=15 and 7.5 Hz, 1H), 3.14 (dd, J=15 and 7.5 Hz, 1H), 3.76-3.82 (m, 2H), 4.33-4.42 (m, 1H), 4.96-5.08 (m, 2H), 5.10 (s, 2H), 5.33 (br s, 1H), 5.59-5.74 (m, 2H), 7.15-7.40 (m, 10H). MS (DCI) m/e 356 (M+NH4)+, 339 (M+H)+.
Reaction SMILES: C([O:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:22])[C:12]=2[N:11]=[C:10]1[CH2:23][CH2:24][CH3:25])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[NH2:22][C:13]1[C:12]2[N:11]=[C:10]([CH2:23][CH2:24][CH3:25])[N:9]([OH:8])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1nc2c(N)nc3ccccc3c2n1O
Reaction time: 1.33 h

Procedure:
A mixture of 1-(benzyloxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (3.2 g, 9.6 mmol) and 10% palladium on carbon (0.15 g) in ethanol (125 mL) was placed under hydrogen pressure (30 psi, 2.1×105 Pa) and shaken on a Parr apparatus for 80 minutes. After 40 minutes the hydrogen pressure had decreased to 20 psi, (14×105 Pa). The reaction mixture was filtered through a layer of CELITE filter agent, and the filtrate was concentrated under reduced pressure. The residue (2.4 g) was recrystallized three times from methanol/water and dried overnight in a vacuum oven at 70° C. to provide 4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-ol as white crystals, mp 232-235° C.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)([OH:3])=[O:2].S(Cl)(Cl)=O>ClCCl>[CH2:5]([O:2][C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)=[O:3])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Compound 9 (0.291 g) obtained in Example 9 was dissolved in dichloromethane (2.9 ml) and thionyl chloride (1.5 ml) was added thereto, followed by stirring at room temperature for one hour. The solvent was distilled off under reduced pressure, the residue was again dissolved in toluene, and the solvent was distilled off under reduced pressure. Benzyl alcohol (2 ml) was added to the residue followed by heating under reflux for 30 minutes. The reaction solution was concentrated and the residue was recrystallized from ethanol to give Compound 13 (0.3.04 g, 85.2%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])[CH3:2].[CH:13]([Si:16]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[SH:17])([CH3:15])[CH3:14]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:17][Si:16]([CH:18]([CH3:20])[CH3:19])([CH:21]([CH3:23])[CH3:22])[CH:13]([CH3:14])[CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc(Br)n1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(S[Si](C(C)C)(C(C)C)C(C)C)n1

Procedure:
Prepared according to the procedure described in Example 6, Step 1, using the following starting materials: 6-bromo-pyridine-2-carboxylic acid ethyl ester and triisopropylsilane-thiol.